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Mari Dezawa

Section

Graduate School of Medicine

Job title

Professor

Degree

博士（医学）（千葉大学）

researchmap

https://researchmap.jp/7000006862

J-GLOBAL ID

201401030566409415

e-Rad No.

50272323

Research History 6

2019/11 - Present

Dokkyo Medical University　School of Medicine　Specially Appointed Professor
2008/04 - Present

Tohoku University Graduate School of Medicine　Department of Stem Cell Biology and Histology　Professor and Chair
2003/01 - 2008/03

Kyoto University Graduate School of Medicine　Department of Anatomy and Neurobiology　Associate Professor
2000/04 - 2002/12

Yokohama City University School of Medicine　Department of Anatomy　Assistant Professor
1997/04 - 2000/03

School of Medicine Chiba University　Department of Ophthalmology　Research Associate
1995/04 - 1997/03

School of Medicine Chiba University　Department of Anatomy　Research Associate

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Education 1

Graduate School of Medicine, Chiba University　Ph.D

1991/04 - 1995/03

Committee Memberships 16

日本抗加齢医学会　評議員

2023 - Present
青森県教育委員会SSH(スーパーサイエンスハイスクール)　運営指導委員

2016 - Present
東洋紡バイオテクノロジー研究財団　理事

2016 - Present
先進医薬研究振興財団　選考委員

2015 - Present
日本学術振興会　科学研究費生物系審査委員

2015 - Present
American Association of Anatomists　Chair of the Postdoc Fellowship Selection Committee

2014 - Present
脳梗塞の細胞治療に関する開発ガイドライン作成WG委員

2013 - Present
産業構造審議会　再生医療等製品の特許権の存続期間検討WG委員

2013 - Present
Japanese Society of Microscopy　Councilor

2012 - Present
Japanese Association of Anatomists　Councilor

2004 - Present
日本再生医療学会　理事長補佐

2021 - 2024
The Japanese Society of Regenerative Medicine　Commissioner

2019 - 2020
The Japanese Society of Regenerative Medicine　Auditor

2015 - 2019
The Japanese Society of Regenerative Medicine　Chairman of the 16th Japanese Society for Regenerative Medicine

2017/03 - 2017/03
The Japanese Society of Regenerative Medicine　Commissioner

2010 - 2015
Japanese Society of Microscopy　Commissioner

2007 - 2011

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Professional Memberships 6

日本抗加齢医学会

2023/04 - Present
量子生命科学会

2022/10 - Present
Pan Pacific Symposium on Stem Cells and Cancer Research
THE JAPANESE SOCIETY FOR REGENERATIVE MEDICINE
THE JAPANESE SOCIETY OF MICROSCOPY
THE JAPANESE ASSOCIATION OF ANATOMISTS

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Research Interests 3

Muse Cell
Stem Cells
Regenerative biomedicine

Research Areas 1

Life sciences / Anatomy /

Awards 6

Fellow

2018　National Academy of Inventors（NAI）
Everfront Award

2015　the 8th Pan Pacific Symposium on Stem Cells and Cancer Research (PPSSC)
Prizes for Science and Technology

2011　the Minister of Education, Culture, Sports, Science and Technology
Incitement Award

2003　Japanese Society of Microscopy
Incitement Award

1999　Japanese Association of Anatomists
Research Aid of Inoue Foundation for Science

1997　Inoue Foundation for Science

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Papers 219

Comparison of MSCs and Muse cells: the possible use for healthspan optimization. International-journal Peer-reviewed

Mari Dezawa

Biogerontology　26　(4)　139-139　2025/07/02

DOI： 10.1007/s10522-025-10275-2 　

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The exploration for safe, effective intervention strategies to improve longevity and aging-related diseases is attracting attention to prolong the healthy lifespan. Since aging is based on cellular changes, including telomere attrition, DNA damage, and mitochondrial dysfunction, therapies related to stem cells are expected to be a rational strategy for solving aging problems at the cellular level. Mesenchymal stem cells (MSCs) are an easily accessible, safe candidate, as they supply paracrine factors and extracellular vesicles to deliver pleiotropic effects for aging tissues. Multilineage-differentiating stress enduring (Muse) cells represent endogenous, reparative macrophage-like/pluripotent-like stem cells distributed in various tissues, including extraembryonic tissues such as the umbilical cord, and are also found in MSCs as a small percentage of the total population. Muse cell characteristics are different from those of MSCs. Intravenously injected Muse cells sharply sense the universal damage signal sphingosine-1-P and selectively migrate to damaged tissue rather than being trapped in the lung, phagocytose damaged/apoptotic cells in the tissue and directly differentiate into the same cell type. Muse cells then repair the three dimensional structure of the tissue by replacing multiple tissue component with healthy cells through pluripotent-like differentiation. Clinical trials have shown that HLA-mismatched donor Muse cells escape immune rejection and survive in the recipient tissue for an extended period without immunosuppressant treatment. Therefore, the pleiotropic bystander effects of Muse cells are more potent than those of MSCs. Due to heterogeneity, the properties of MSCs are still not fully understood; they have limited differentiation ability into osteogenic, chondrogenic, and adipogenic cells, and the main biological action in vivo is bystander effects. Muse cells are key, not only to the medical benefits of MSCs, but also to their potential use in anti-aging therapy. Enriching and purifying Muse cells will significantly enhance the therapeutic effect of MSCs, leading to further expansion of the use of MSCs. This review discusses the fundamental differences between MSCs and Muse cells and their potential applications in anti-aging therapy.
Nose-to-brain delivery of human muse cells enhances structural and functional recovery in the murine ischemic stroke model. International-journal Peer-reviewed

Shusuke Yamamoto, Keitaro Shiraishi, Yoshihiro Kushida, Yo Oguma, Shohei Wakao, Mari Dezawa, Satoshi Kuroda

Scientific reports　15　(1)　16243-16243　2025/05/09

DOI： 10.1038/s41598-025-96451-3 　

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Muse cells are endogenous, non-tumorigenic, pluripotent-like stem cells already applied to clinical trials based on intravenous injection. They can selectively home to the post-infarct area, replenish apoptotic neural cells by phagocytosis-induced differentiation, and enhance functional recovery. The effect of nose-to-brain delivery of Muse cells on cerebral infarct was examined. Permanent middle cerebral artery occlusion model BALB/c mice received intranasal administration of either human Muse cells (6.0 × 104 cells), high-dose human-mesenchymal stem cells (MSCs) (1.6 × 106 cells), low-dose human-MSCs (6.0 × 104 cells), or vehicle at 7 days after onset. An accelerated rotarod test and a histological assessment were done. The vehicle- or low-dose MSC groups showed no significant improvement in the rotarod test. In the high-dose MSC group, motor function was transiently recovered, but the therapeutic effect disappeared thereafter. The Muse group continuously improved motor function, with statistical significance to the other groups. The engraftment of administered cells in the peri-infarct area was the highest in the Muse group, while few cells were detected in other groups. 63.6 ± 8.5% and 26.2 ± 3.0% of Muse cells were positive for NeuN and GSTpi, respectively. Intranasal administration of Muse cells might be a viable approach to improving functional recovery with less invasiveness after ischemic stroke.
Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice. International-journal Peer-reviewed

Ryo Ozuru, Shohei Wakao, Takahiro Tsuji, Naoya Ohara, Takashi Matsuba, Muhammad Y Amran, Junko Isobe, Morio Iino, Naoki Nishida, Sari Matsumoto, Kimiharu Iwadate, Noriko Konishi, Kaori Yasuda, Kosuke Tashiro, Misato Hida, Arisato Yadoiwa, Shinsuke Kato, Eijiro Yamashita, Sohkichi Matsumoto, Yoichi Kurozawa, Mari Dezawa, Jun Fujii

Molecular therapy : the journal of the American Society of Gene Therapy　33　(2)　823-823　2025/02/05

DOI： 10.1016/j.ymthe.2025.01.022 　
Macrophage- and pluripotent-like reparative Muse cells are unique endogenous stem cells distinct from other somatic stem cells. International-journal Peer-reviewed

Mari Dezawa

Frontiers in bioengineering and biotechnology　13　1553382-1553382　2025

DOI： 10.3389/fbioe.2025.1553382 　

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Muse cells are endogenous reparative stem cells with dual characteristics: pluripotent-like and macrophage-like. They can be identified by the pluripotent surface marker stage-specific embryonic antigen-3-positive (SSEA-3 (+)) cells in the bone marrow, peripheral blood, and various organs, including the umbilical cord and amnion. Muse cells can differentiate into ectodermal, endodermal, and mesodermal lineage cells, self-renew, and selectively migrate to damaged sites by sensing one of the universal tissue damage signals, sphingosine-1-phosphate (S1P). At these sites, they phagocytose damaged/apoptotic cells and differentiate into the same cell type as the phagocytosed cells. In this manner, Muse cells replace damaged/apoptotic cells with healthy, functioning cells, thereby repairing tissues. Due to their specific immunosuppressive and immunotolerant mechanism, clinical trials have been conducted for acute myocardial infarction (AMI), subacute ischemic stroke, epidermolysis bullosa, amyotrophic lateral sclerosis (ALS), cervical spinal cord injury, neonatal hypoxic-ischemic encephalopathy (HIE), and COVID-19 acute respiratory distress syndrome. These trials involved the intravenous injection of ∼1.5 × 107 donor Muse cells without human leukocyte antigen (HLA) matching or immunosuppressant treatment, and they demonstrated safety and therapeutic efficacy. Thus, donor Muse cell treatment does not require gene manipulation, differentiation induction, or surgical intervention. These unique characteristics distinguish Muse cells from other somatic stem cells, such as mesenchymal stem cells, VSEL stem cells, and marrow-isolated adult multi-lineage inducible (MIAMI) cells.
Safety and Effectiveness of Muse Cell Transplantation in a Large-Animal Model of Hepatic Fibrosis. International-journal Peer-reviewed

Taketo Nishina, Hiroaki Haga, Shohei Wakao, Keita Maki, Kei Mizuno, Tomohiro Katsumi, Kyoko Tomita Hoshikawa, Takafumi Saito, Masahiro Iseki, Michiaki Unno, Mari Dezawa, Yoshiyuki Ueno

Stem cells international　2025　6699571-6699571　2025

DOI： 10.1155/sci/6699571 　

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Background: In recent years, liver regeneration therapy using mesenchymal stem cells (MSC) has been investigated as an alternative therapy for end-stage liver diseases. Among these MSCs, multilineage-differentiating stress enduring (Muse) cells are reported to be effective in mouse models. The present study investigated the safety and effectiveness of Muse cell transplantation in large animal models of hepatic fibrosis. Methods: Muse cells and MSC were prepared from bone marrow cells of male mini pigs (Göttingen strain). Recipients mini pigs (female Göttingen strain) were repeatedly administered with carbon tetrachloride (CCl4) intraperitoneally for 12 weeks to induce liver fibrosis. Thereafter, either Muse cells or MSCs were transplanted intravenously. After the cell transplantation, laboratory tests, vital signs, and liver histology were evaluated (Muse cell group (n = 6), MSC group (n = 6), and vehicle group (n = 7)). Results: Liver fibrogenesis was successfully induced after 12 weeks of CCl4 administration. Engraftment of transplanted cells and differentiation into hepatocytes were confirmed in recipients' liver. In Muse cell group, significant increase of serum albumin (Alb) level was observed at 4 weeks compared to those of control groups (p < 0.05). Hepatic proliferating cell nuclear antigen (PCNA) positive cells were significantly increased in the Muse cell group (p < 0.05). Hepatic fibrogenesis at 12 weeks after transplantation were significantly improved in Muse cell group (p < 0.05). Alpha-smooth muscle actin (α-SMA) immunostaining revealed significant decrease in liver from Muse cell transplanted recipients. No serious adverse effects were observed. Conclusions: Muse cell transplantation was safe and effective in large animal models of hepatic fibrosis. The positive effects were observed in namely 4 weeks after transplantation. Since biochemical as well as histological improvements were demonstrated, future studies including establishing ideal administration protocol seem to be feasible as a preclinical study.
Accumulation of endogenous Muse cells in the myocardium and its pathophysiological role in patients with fulminant myocarditis. International-journal Peer-reviewed

Shigeru Toyoda, Masashi Sakuma, Kazuyuki Ishida, Yoshihiro Kushida, Ryoichi Soma, Hidehito Takayama, Kazumi Akimoto, Mari Dezawa, Teruo Inoue

Clinical and translational science　17　(11)　e70067　2024/11

DOI： 10.1111/cts.70067 　

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Multi-lineage differentiating stress-enduring (Muse) cells, identified as pluripotent surface marker SSEA-3(+) cells, are stress tolerant endogenous pluripotent-like stem cells, and are involved in tissue repair. However, the significance of Muse cells in acute myocarditis has not been evaluated. In the present study, we counted Muse cells/area in biopsied myocardial tissue samples from 17 patients with fulminant myocarditis, and 6 with non-inflammatory myocardial disease as controls. Compared with controls, patients with fulminant myocarditis had significantly more Muse cells (p = 0.00042). Patients with mechanical circulatory support (p = 0.006) and myocardial degeneration (p = 0.023) had significantly more Muse cells than those without them. The Muse cell number was correlated with acute phase CK-MB level (ρ = 0.547, p = 0.029), indicating the severity of myocardial injury, and was also correlated with acute/recovery phase ratio of CK-MB (ρ = 0.585, p = 0.023) and cardiac troponin I (ρ = 0.498, p = 0.047) levels, indicating resilience of myocardial injury. In fulminant myocarditis, the Muse cell number was associated with the severity of clinical features in the acute phase, and also with the recovery from myocardial damage in the chronic phase. Endogenous Muse cells might be mobilized and accumulate to the myocardial tissues in fulminant myocarditis, and might participate in the repair of injured myocardium.
Structural reconstruction of mouse acute aortic dissection by intravenously administered human Muse cells without immunosuppression. International-journal Peer-reviewed

Makoto Takahashi, Yoshihiro Kushida, Yasumasa Kuroda, Shohei Wakao, Yasuhiro Horibata, Hiroyuki Sugimoto, Mari Dezawa, Yoshikatsu Saiki

Communications medicine　4　(1)　174-174　2024/09/09

DOI： 10.1038/s43856-024-00597-6 　

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BACKGROUND: Stanford type B-acute aortic dissection (type B-AAD) is often life-threatening without invasive surgery. Multilineage-differentiating stress enduring cell (Muse cells), which comprise several percent of mesenchymal stem cells (MSCs), are endogenous pluripotent-like stem cells that selectively home to damaged tissue and replace damaged/apoptotic cells by in-vivo differentiation. METHODS: Mortality, aortic diameter expansion, cell localization, cell differentiation, and inflammation of the dissected aorta were evaluated in type B-AAD model mice intravenously injected with human-Muse cells, -elastin-knockdown (KD)-Muse cells, -human leukocyte antigen-G (HLA-G)-KD-Muse cells, or MSCs, all without immunosuppressant. RESULTS: Here, we show the Muse (50,000 cells) group has a lower incidence of aortic rupture and mortality of AAD compared with the MSC-50K (50,000 human-MSCs) and vehicle groups. Spectrum computed tomography in-vivo dynamics and 3-dimensional histologic analyses demonstrate that Muse cells more effectively home to the AAD tissue and survive for 8 weeks in the Muse group than in the MSC-750K (750,000 human-MSCs containing 50,000 Muse cells) group. Homing of Muse cells is impeded in the HLA-G-KD-Muse (50,000 cells) group. Differentiation of homed Muse cells into CD31(+) and alpha-smooth muscle actin (+) cells, production and reorganization of elastic fibers in the AAD tissue, and suppression of diameter expansion are greater in the Muse group than in the MSC-750K and elastin-KD-Muse (50,000 cells) groups. CONCLUSIONS: Intravenously administered Muse cells reconstruct the dissected aorta and improve mortality and diameter enlargement rates. Moreover, small doses of purified Muse cells are more effective than large doses of MSCs. HLA-G is suggested to contribute to the successful survival and homing of Muse cells.
Human post-implantation blastocyst-like characteristics of Muse cells isolated from human umbilical cord Peer-reviewed

Yoshihiro Kushida, Yo Oguma, Kana Abe, Taichi Deguchi, Federico Girolamo Barbera, Noriyuki Nishimura, Kazumichi Fujioka, Sota Iwatani, Mari Dezawa

Cellular and Molecular Life Sciences　81　(1)　2024/07/11
Publisher: Springer Science and Business Media LLC
DOI： 10.1007/s00018-024-05339-4 　

ISSN： 1420-682X

eISSN： 1420-9071

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Abstract Muse cells, identified as cells positive for the pluripotent surface marker SSEA-3, are pluripotent-like endogenous stem cells located in the bone marrow (BM), peripheral blood, and organ connective tissues. The detailed characteristics of SSEA-3(+) cells in extraembryonic tissue, however, are unknown. Here, we demonstrated that similar to human-adult tissue-Muse cells collected from the BM, adipose tissue, and dermis as SSEA-3(+), human-umbilical cord (UC)-SSEA-3(+) cells express pluripotency markers, differentiate into triploblastic-lineage cells at a single cell level, migrate to damaged tissue, and exhibit low telomerase activity and non-tumorigenicity. Notably, ~ 20% of human-UC-SSEA-3(+) cells were negative for X-inactive specific transcript (XIST), a naïve pluripotent stem cell characteristic, whereas all human adult tissue-Muse cells are XIST-positive. Single-cell RNA sequencing revealed that the gene expression profile of human-UC-SSEA-3(+) cells was more similar to that of human post-implantation blastocysts than human-adult tissue-Muse cells. The DNA methylation level showed the same trend, and notably, the methylation levels in genes particularly related to differentiation were lower in human-UC-SSEA-3(+) cells than in human-adult tissue-Muse cells. Furthermore, human-UC-SSEA-3(+) cells newly express markers specific to extraembryonic-, germline-, and hematopoietic-lineages after differentiation induction in vitro whereas human-adult tissue-Muse cells respond only partially to the induction. Among various stem/progenitor cells in living bodies, those that exhibit properties similar to post-implantation blastocysts in a naïve state have not yet been found in humans. Easily accessible human-UC-SSEA-3(+) cells may be a valuable tool for studying early-stage human development and human reproductive medicine.
New rat model of spinal cord infarction with long-lasting functional disabilities generated by intraspinal injection of endothelin-1 Peer-reviewed

Masayuki Otani, Yoshihiro Kushida, Yasumasa Kuroda, Shohei Wakao, Yo Oguma, Keisuke Sasaki, Shintaro Katahira, Ryohei Terai, Rie Ryoke, Hiroi Nonaka, Ryuta Kawashima, Yoshikatsu Saiki, Mari Dezawa

Stroke and Vascular Neurology　svn-2023　2024/06/21
Publisher: BMJ
DOI： 10.1136/svn-2023-002962 　

ISSN： 2059-8688

eISSN： 2059-8696

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Background The current method for generating an animal model of spinal cord (SC) infarction is highly invasive and permits only short-term observation, typically limited to 28 days. Objective We aimed to establish a rat model characterised by long-term survival and enduring SC dysfunction by inducing selective ischaemic SC damage. Methods In 8-week-old male Wistar rats, a convection-enhanced delivery technique was applied to selectively deliver endothelin-1 (ET-1) to the anterior horn of the SC at the Th13 level, leading to SC infarction. The Basso, Beattie and Bresnahan (BBB) locomotor score was assessed for 56 days. The SC was examined by a laser tissue blood flowmeter, MRI, immunohistochemistry, triphenyl tetrazolium chloride (TTC) staining, Western blots and TUNEL staining. Results The puncture method was used to bilaterally inject 0.7 µL ET-1 (2.5 mg/mL) from the lateral SC into the anterior horns (40° angle, 1.5 mm depth) near the posterior root origin. Animals survived until day 56 and the BBB score was stably maintained (5.5±1.0 at day 14 and 6.2±1.0 at day 56). Rats with BBB scores ≤1 on day 1 showed stable scores of 5–6 after day 14 until day 56 while rats with BBB scores >1 on day 1 exhibited only minor dysfunction with BBB scores >12 after day 14. TTC staining, immunostaining and TUNEL staining revealed selective ischaemia and neuronal cell death in the anterior horn. T2-weighted MR images showed increasing signal intensity at the SC infarction site over time. Western blots revealed apoptosis and subsequent inflammation in SC tissue after ET-1 administration. Conclusions Selective delivery of ET-1 into the SC allows for more precise localisation of the infarcted area at the targeted site and generates a rat SC infarction model with stable neurological dysfunction lasting 56 days.
Human Muse cells isolated from preterm- and term-umbilical cord delivered therapeutic effects in rat bleomycin-induced lung injury model without immunosuppressant. International-journal Peer-reviewed

Kaung Htet Nay Win, Yoshihiro Kushida, Keiji Yamana, Sota Iwatani, Makiko Yoshida, Nanako Nino, Cho Yee Mon, Hiroyuki Ohsaki, Shingo Kamoshida, Kazumichi Fujioka, Mari Dezawa, Noriyuki Nishimura

Stem cell research & therapy　15　(1)　147-147　2024/05/22

DOI： 10.1186/s13287-024-03763-8 　

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BACKGROUND: Bleomycin (BLM)-induced lung injury is characterized by mixed histopathologic changes with inflammation and fibrosis, such as observed in human patients with bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Although no curative therapies for these lung diseases exist, stem cell therapy has emerged as a potential therapeutic option. Multilineage-differentiating stress-enduring (Muse) cells are endogenous pluripotent- and macrophage-like stem cells distributed in various adult and fetal tissues as stage-specific embryonic antigen-3-positive cells. They selectively home to damaged tissue by sensing sphingosine-1-phosphate and replace the damaged/apoptotic cells by in vivo differentiation. Clinical trials for some human diseases suggest the safety and therapeutic efficacy of intravenously injected human leukocyte antigen-mismatched allogenic Muse cells from adult bone marrow (BM) without immunosuppressant. Here, we evaluated the therapeutic effects of human Muse cells from preterm and term umbilical cord (UC), and adult BM in a rat BLM-induced lung injury model. METHODS: Rats were endotracheally administered BLM to induce lung injury on day 0. On day 3, human preterm UC-Muse, term UC-Muse, or adult BM-Muse cells were administered intravenously without immunosuppressants, and rats were subjected to histopathologic analysis on day 21. Body weight, serum surfactant protein D (SP-D) levels, and oxygen saturation (SpO2) were monitored. Histopathologic lung injury scoring by the Ashcroft and modified American Thoracic Society document scales, quantitative characterization of engrafted Muse cells, RNA sequencing analysis, and in vitro migration assay of infused Muse cells were performed. RESULTS: Rats administered preterm- and term-UC-Muse cells exhibited a significantly better recovery based on weight loss, serum SP-D levels, SpO2, and histopathologic lung injury scores, and a significantly higher rate of both Muse cell homing to the lung and alveolar marker expression (podoplanin and prosurfactant protein-C) than rats administered BM-Muse cells. Rats receiving preterm-UC-Muse cells showed statistically superior results to those receiving term-UC-Muse cells in many of the measures. These findings are thought to be due to higher expression of genes related to cell migration, lung differentiation, and cell adhesion. CONCLUSION: Preterm UC-Muse cells deliver more efficient therapeutic effects than term UC- and BM-Muse cells for treating BLM-induced lung injury in a rat model.
Donor Muse Cell Treatment Without HLA-Matching Tests and Immunosuppressant Treatment. International-journal Peer-reviewed

Shinya Minatoguchi, Yasuyuki Fujita, Kuniyasu Niizuma, Teiji Tominaga, Toru Yamashita, Koji Abe, Mari Dezawa

Stem cells translational medicine　2024/04/01

DOI： 10.1093/stcltm/szae018 　

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The strength of stem cell therapy is the regeneration of tissues by synergistic pleiotropic effects. Among many stem cell types, mesenchymal stem cells (MSCs) that are comprised of heterogenous population are widely used for clinical applications with the expectation of pleiotropic bystander effects. Muse cells are pluripotent-like/macrophage-like stem cells distributed in the bone marrow, peripheral blood, and organ connective tissues as cells positive for the pluripotent surface marker stage-specific-embryonic antigen -3. Muse cells comprise ~1% to several percent of MSCs. While Muse cells and MSCs share several characteristics, such as mesenchymal surface marker expression and their bystander effects, Muse cells exhibit unique characteristics not observed in MSCs. These unique characteristics of Muse cells include selective homing to damaged tissue after intravenous injection rather than being trapped in the lung like MSCs, replacement of a wide range of damaged/apoptotic cells by differentiation through phagocytosis, and long-lasting immunotolerance for donor cell use. In this review, we focus on the basic properties of Muse cells clarified through preclinical studies and clinical trials conducted by intravenous injection of donor-Muse cells without HLA-matching tests or immunosuppressant treatment. MSCs are considered to differentiate into osteogenic, chondrogenic, and adipogenic cells, whereas the range of their differentiation has long been debated. Muse cells may provide clues to the wide-ranging differentiation potential of MSCs that are observed with low frequency. Furthermore, the utilization of Muse cells may provide a novel strategy for clinical treatment.
Intravenously engrafted human multilineage-differentiating stress-enduring (Muse) cells rescue erectile function after rat cavernous nerve injury. International-journal Peer-reviewed

Juntaro Koyama, Shinichi Yamashita, Yuya Kato, Kunihisa Nezu, Takuro Goto, Shinji Fujii, Yu Suzuki, Atsushi Nakayashiki, Yoshihide Kawasaki, Naoki Kawamorita, Hitomi Okita, Takako Ito, Yoshihiro Kushida, Masafumi Goto, Mari Dezawa, Teiji Tominaga, Kuniyasu Niizuma, Akihiro Ito

BJU international　2023/11/20

DOI： 10.1111/bju.16232 　

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OBJECTIVE: To evaluate the effect of intravenous administration of human multilineage-differentiating stress-enduring (Muse) cells on rat postoperative erectile dysfunction (ED) with cavernous nerve (CN) injury without an immunosuppressant. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomised into three groups after CN crush injury. Either human-Muse cells, non-Muse mesenchymal stem cells (MSCs) (both 1.0 × 105 cells), or vehicle was infused intravenously at 3 h after CN injury without immunosuppressant. Erectile function was assessed by measuring intracavernous pressure (ICP) and arterial pressure (AP) during pelvic nerve electrostimulation 28 days after surgery. At 48 h and 28 days after intravenous infusion of Muse cells, the homing of Muse cells and non-Muse MSCs was evaluated in the major pelvic ganglion (MPG) after CN injury. In addition, expressions of C-X-C motif chemokine ligand (Cxcl12) and glial cell line-derived neurotrophic factor (Gdnf) in the MPG were examined by real-time polymerase chain reaction. Statistical analyses and comparisons among groups were performed using one-way analysis of variance followed by the Tukey test for parametric data and Kruskal-Wallis test followed by the Dunn-Bonferroni test for non-parametric data. RESULTS: The mean (SEM) ICP/AP values at 28 days were 0.51 (0.02) in the Muse cell group, 0.37 (0.03) in the non-Muse MSC group, and 0.36 (0.04) in the vehicle group, showing a significant positive response in the Muse cell group compared with the non-Muse and vehicle groups (P = 0.013 and P = 0.010, respectively). In the MPG, Muse cells were observed to be engrafted at 48 h and expressed Schwann cell markers S100 (~46%) and glial fibrillary acidic protein (~24%) at 28 days, while non-Muse MSCs were basically not engrafted at 48 h. Higher gene expression of Cxcl12 (P = 0.048) and Gdnf (P = 0.040) was found in the MPG of the Muse group than in the vehicle group 48 h after infusion. CONCLUSION: Intravenously engrafted human Muse cells recovered rat erectile function after CN injury in a rat model possibly by upregulating Cxcl12 and Gdnf.
Meta-analysis of senescent cell secretomes to identify common and specific features of the different senescent phenotypes: a tool for developing new senotherapeutics Peer-reviewed

Yo Oguma, Nicola Alessio, Domenico Aprile, Mari Dezawa, Gianfranco Peluso, Giovanni Di Bernardo, Umberto Galderisi

Cell Communication and Signaling　21　(1)　2023/09/28
Publisher: Springer Science and Business Media LLC
DOI： 10.1186/s12964-023-01280-4 　

eISSN： 1478-811X

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Abstract DNA damage resulting from genotoxic injury can initiate cellular senescence, a state characterized by alterations in cellular metabolism, lysosomal activity, and the secretion of factors collectively known as the senescence-associated secretory phenotype (SASP). Senescence can have beneficial effects on our bodies, such as anti-cancer properties, wound healing, and tissue development, which are attributed to the SASP produced by senescent cells in their intermediate stages. However, senescence can also promote cancer and aging, primarily due to the pro-inflammatory activity of SASP. Studying senescence is complex due to various factors involved. Genotoxic stimuli cause random damage to cellular macromolecules, leading to variations in the senescent phenotype from cell to cell, despite a shared program. Furthermore, senescence is a dynamic process that cannot be analyzed as a static endpoint, adding further complexity. Investigating SASP is particularly intriguing as it reveals how a senescence process triggered in a few cells can spread to many others, resulting in either positive or negative consequences for health. In our study, we conducted a meta-analysis of the protein content of SASP obtained from different research groups, including our own. We categorized the collected omic data based on: i) cell type, ii) harmful agent, and iii) senescence stage (early and late senescence). By employing Gene Ontology and Network analysis on the omic data, we identified common and specific features of different senescent phenotypes. This research has the potential to pave the way for the development of new senotherapeutic drugs aimed at combating the negative consequences associated with the senescence process.
Systemic administration of clinical-grade multilineage-differentiating stress-enduring cells ameliorates hypoxic-ischemic brain injury in neonatal rats. International-journal Peer-reviewed

Kazuto Ueda, Yoshiaki Sato, Shinobu Shimizu, Toshihiko Suzuki, Atsuto Onoda, Ryosuke Miura, Shoji Go, Haruka Mimatsu, Yuma Kitase, Yuta Yamashita, Keiichi Irie, Masahiro Tsuji, Kenichi Mishima, Masaaki Mizuno, Yoshiyuki Takahashi, Mari Dezawa, Masahiro Hayakawa

Scientific reports　13　(1)　14958-14958　2023/09/11

DOI： 10.1038/s41598-023-41026-3 　

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Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative pluripotent stem cells present in the bone marrow, peripheral blood, and organ connective tissues. We assessed the homing and therapeutic effects of systemically administered nafimestrocel, a clinical-grade human Muse cell-based product, without immunosuppressants in a neonatal hypoxic-ischemic (HI) rat model. HI injury was induced on postnatal day 7 (P7) and was confirmed by T2-weighted magnetic resonance imaging on P10. HI rats received a single dose nafimestrocel (1 × 106 cells/body) or Hank's balanced salt solution (vehicle group) intravenously at either three days (on P10; M3 group) or seven days (on P14; M7 group) after HI insult. Radioisotope experiment demonstrated the homing of chromium-51-labeled nafimestrocel to the both cerebral hemispheres. The cylinder test (M3 and M7 groups) and open-field test (M7 group) showed significant amelioration of paralysis and hyperactivity at five weeks of age compared with those in the vehicle group. Nafimestrocel did not cause adverse events such as death or pathological changes in the lung at ten weeks in the both groups. Nafimestrocel attenuated the production of tumor necrosis factor-α and inducible nitric oxide synthase from activated cultured microglia in vitro. These results demonstrate the potential therapeutic benefits and safety of nafimestrocel.
Tumor suppressor let-7 acts as a key regulator for maintaining pluripotency gene expression in Muse cells Peer-reviewed

Gen Li, Shohei Wakao, Masaaki Kitada, Mari Dezawa

2023/08/25
Publisher: Cold Spring Harbor Laboratory
DOI： 10.1101/2023.08.24.554727 　

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Abstract In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), the expression of an RNA-binding pluripotency-relevant protein, LIN28, and the absence of its antagonist, the tumor-suppressor microRNA (miRNA) let-7, play a key role in maintaining pluripotency. Muse cells are non-tumorigenic pluripotent-like stem cells residing in the bone marrow, peripheral blood, and organ connective tissues as pluripotent surface marker SSEA-3(+). They express pluripotency genes, differentiate into triploblastic-lineage cells, and self-renew at the single cell level. Muse cells do not express LIN28 but do express let-7 at higher levels than in iPSCs. In Muse cells, we demonstrated that let-7 inhibited the PI3K-AKT pathway, leading to sustainable expression of the key pluripotency regulator KLF4 as well as its downstream genes,POU5F1,SOX2, andNANOG. Let-7 also suppressed proliferation and glycolysis by inhibiting the PI3K-AKT pathway, suggesting its involvement in non-tumorigenicity. Furthermore, the MEK/ERK pathway is not controlled by let-7 and may have a pivotal role in maintaining self-renewal and suppression of senescence. The system found in Muse cells, in which the tumor suppressor let-7, but not LIN28, tunes the expression of pluripotency genes, might be a rational cell system conferring both pluripotency-like properties and a low risk for tumorigenicity.
Comparison of the Anti-Inflammatory Effects of Mouse Adipose- and Bone-Marrow-Derived Multilineage-Differentiating Stress-Enduring Cells in Acute-Phase Spinal Cord Injury. International-journal Peer-reviewed

Toshihide Nagaoki, Gentaro Kumagai, Yohshiro Nitobe, Ayako Sasaki, Taku Fujita, Tatsuhiro Fukutoku, Kenya Saruta, Manami Tsukuda, Toru Asari, Kanichiro Wada, Mari Dezawa, Yasuyuki Ishibashi

Journal of neurotrauma　2023/05/16

DOI： 10.1089/neu.2022.0470 　

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Abstract Spinal cord injury (SCI) is a serious neurological disorder, with the consequent disabilities conferred by this disorder typically persisting for life. Multilineage-differentiating stress-enduring (Muse) cells are endogenous stem cells that can be collected from various tissues as well as from mesenchymal stem cells (MSCs); additionally, these Muse cells are currently being used in clinical trials. The anti-inflammatory effect of stem cell transplantation prevents secondary injuries of SCI; however, its effect on Muse cells remains unclear. In this study, we aimed to compare the anti-inflammatory effects of adipose (AD)- and bone marrow (BM)-Muse cells that were isolated from mice (6-week-old C57BL/6J) following intralesional administration during the acute phase of SCI. Flow cytometry was used to isolate Muse cells from AD and BM MSCs. The percentage of Muse cells was 3.9 and 2.7% for AD and BM MSCs, respectively. To examine cell viability, Muse cells were incubated under H2O2-induced oxidative stress conditions. Overall, AD-Muse cells exhibited higher viability than BM-Muse cells (p = 0.032). In enzyme-linked immunosorbent assay analysis, AD-Muse cells displayed greater secretion of brain-derived neurotrophic factor (BDNF; p = 0.008), vascular endothelial growth factor (p = 0.032), and hepatocyte growth factor (p = 0.016). DNA microarray analysis revealed higher expression of Bdnf, neurotrophin-3 (Ntf3), nerve growth factor (Ngf), pleiotrophin (Ptn), and midkine (Mdk) in AD-Muse cells than in BM-Muse cells. To assess their anti-inflammatory effects in vitro, Muse cells and macrophages were co-cultured, and the levels of cytokines (tumor necrosis factor [TNF] α and interleukin [IL] 10) were measured in the medium. Consequently, we found that TNFα levels were lower in AD-Muse cells than in BM-Muse cells (p = 0.009), and IL10 levels were higher in AD-Muse cells than in BM-Muse cells (p = 0.008). Further, we induced moderate injuries via contusion of the spinal cord at the T10 level; Muse cells were transplanted intralesionally 7 days post-SCI. The number of surviving cells, alongside the number of CD86+ (M1 inflammatory effect), and CD206+ (M2 anti-inflammatory effect) macrophages in the spinal cord were measured 7 days post-transplantation. The number of surviving AD-Muse cells was higher than the number of surviving BM-Muse cells (ratio of AD-Muse/BM-Muse = 2.5, p > 0.05). The M1/M2 ratio in the AD-Muse cell-group (0.37) was lower than that in the control (phosphate-buffered saline) group (3.60, p = 0.008). The lesion area in the AD-Muse cell group was smaller than that in the BM-non-Muse (p = 0.049) and control groups (p = 0.012). As AD-Muse cells conferred a higher cell survival and neurotrophic factor secretion ability in vitro, AD-Muse cells demonstrated reduced inflammation after SCI. Overall, intralesional AD-Muse cell therapy is a potential therapeutic candidate that is expected to exhibit anti-inflammatory effects following acute SCI.
Single-cell RNA sequencing reveals different signatures of mesenchymal stromal cell pluripotent-like and multipotent populations. International-journal Peer-reviewed

Yo Oguma, Yasumasa Kuroda, Shohei Wakao, Yoshihiro Kushida, Mari Dezawa

iScience　25　(11)　105395-105395　2022/11/18

DOI： 10.1016/j.isci.2022.105395 　

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Somatic stem cells are advantageous research targets for understanding the properties required to maintain stemness. Human bone marrow-mesenchymal stromal cells (BM-MSCs) were separated into pluripotent-like SSEA-3(+) Muse cells (Muse-MSCs) and multipotent SSEA-3(-) MSCs (MSCs) and were subjected to single-cell RNA sequencing analysis. Compared with MSCs, Muse-MSCs exhibited higher expression levels of the p53 repressor MDM2; signal acceptance-related genes EGF, VEGF, PDGF, WNT, TGFB, INHB, and CSF; ribosomal protein; and glycolysis and oxidative phosphorylation. Conversely, MSCs had higher expression levels of FGF and ANGPT; Rho family and caveola-related genes; amino acid and cofactor metabolism; MHC class I/II, and lysosomal enzyme genes than Muse-MSCs. Unsupervised clustering further divided Muse-MSCs into two clusters stratified by the expression of cell cycle-related genes, and MSCs into three clusters stratified by the expression of cell cycle-, cytoskeleton-, and extracellular matrix-related genes. This study evaluating the differentiation ability of BM-MSC subpopulations provides intriguing insights for understanding stemness.
Naïve pluripotent-like characteristics of non-tumorigenic Muse cells isolated from human amniotic membrane. International-journal Peer-reviewed

Eiji Ogawa, Yo Oguma, Yoshihiro Kushida, Shohei Wakao, Kana Okawa, Mari Dezawa

Scientific reports　12　(1)　17222-17222　2022/10/14

DOI： 10.1038/s41598-022-22282-1 　

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Multilineage-differentiating stress-enduring (Muse) cells are non-tumorigenic pluripotent-like stem cells that exhibit triploblastic differentiation and self-renewability at the single-cell level, and are collectable as pluripotent surface marker SSEA-3(+) from the bone marrow (BM), peripheral blood, and organ connective tissues. SSEA-3(+) cells from human amniotic membrane mesenchymal stem cells (hAMSCs) were compared with hBM-Muse cells. Similar to hBM-Muse cells, hAMSC-SSEA-3(+) cells expressed pluripotency genes (OCT3/4, NANOG, and SOX2), differentiated into triploblastic cells from a single cell, self-renewed, and exhibited non-tumorigenicity. Notably, however, they exhibited unique characteristics not seen in hBM-Muse cells, including higher expression of genes related to germline- and extraembryonic cell-lineages compared with those in hBM-Muse cells in single-cell RNA-sequencing; and enhanced expression of markers relevant to germline- (PRDM14, TFAP2C, and NANOS3) and extraembryonic cell- (CDX2, GCM1, and ID2) lineages when induced by cytokine subsets, suggesting a broader differentiation potential similar to naïve pluripotent stem cells. t-SNE dimensionality reduction and Gene ontology analysis visualized hAMSC-SSEA-3(+) cells comprised a large undifferentiated subpopulation between epithelial- and mesenchymal-cell states and a small mesenchymal subpopulation expressing genes relevant to the placental formation. The AM is easily accessible by noninvasive approaches. These unique cells are a potentially interesting target naïve pluripotent stem cell-like resource without tumorigenicity.
Phagocytosing differentiated cell-fragments is a novel mechanism for controlling somatic stem cell differentiation within a short time frame. International-journal Peer-reviewed

Shohei Wakao, Yo Oguma, Yoshihiro Kushida, Yasumasa Kuroda, Kazuki Tatsumi, Mari Dezawa

Cellular and molecular life sciences : CMLS　79　(11)　542-542　2022/10/06

DOI： 10.1007/s00018-022-04555-0 　

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Stem cells undergo cytokine-driven differentiation, but this process often takes longer than several weeks to complete. A novel mechanism for somatic stem cell differentiation via phagocytosing 'model cells' (apoptotic differentiated cells) was found to require only a short time frame. Pluripotent-like Muse cells, multipotent mesenchymal stem cells (MSCs), and neural stem cells (NSCs) phagocytosed apoptotic differentiated cells via different phagocytic receptor subsets than macrophages. The phagocytosed-differentiated cell-derived contents (e.g., transcription factors) were quickly released into the cytoplasm, translocated into the nucleus, and bound to promoter regions of the stem cell genomes. Within 24 ~ 36 h, the cells expressed lineage-specific markers corresponding to the phagocytosed-differentiated cells, both in vitro and in vivo. At 1 week, the gene expression profiles were similar to those of the authentic differentiated cells and expressed functional markers. Differentiation was limited to the inherent potential of each cell line: triploblastic-, adipogenic-/chondrogenic-, and neural-lineages in Muse cells, MSCs, and NSCs, respectively. Disruption of phagocytosis, either by phagocytic receptor inhibition via small interfering RNA or annexin V treatment, impeded differentiation in vitro and in vivo. Together, our findings uncovered a simple mechanism by which differentiation-directing factors are directly transferred to somatic stem cells by phagocytosing apoptotic differentiated cells to trigger their rapid differentiation into the target cell lineage.
Inhibition of Gap Junctional Intercellular Communication Upregulates Pluripotency Gene Expression in Endogenous Pluripotent Muse Cells. International-journal Peer-reviewed

Khaled Hatabi, Yukari Hirohara, Yoshihiro Kushida, Yasumasa Kuroda, Shohei Wakao, James Trosko, Mari Dezawa

Cells　11　(17)　2022/08/30

DOI： 10.3390/cells11172701 　

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Gap junctions (GJ) are suggested to support stem cell differentiation. The Muse cells that are applied in clinical trials are non-tumorigenic pluripotent-like endogenous stem cells, can be collected as stage-specific embryonic antigen 3 (SSEA-3+) positive cells from multiple tissues, and show triploblastic differentiation and self-renewability at a single cell level. They were reported to up-regulate pluripotency gene expression in suspension. We examined how GJ inhibition affected pluripotency gene expression in adherent cultured-Muse cells. Muse cells, mainly expressing gap junction alpha-1 protein (GJA1), reduced GJ intercellular communication from ~85% to 5-8% after 24 h incubation with 120 μM 18α-glycyrrhetinic acid, 400 nM 12-O-tetradecanoylphorbol-13-acetate, and 90 μM dichlorodiphenyltrichloroethane, as confirmed by a dye-transfer assay. Following inhibition, NANOG, OCT3/4, and SOX2 were up-regulated 2-4.5 times more; other pluripotency-related genes, such as KLF4, CBX7, and SPRY2 were elevated; lineage-specific differentiation-related genes were down-regulated in quantitative-PCR and RNA-sequencing. Connexin43-siRNA introduction also confirmed the up-regulation of NANOG, OCT3/4, and SOX2. YAP, a co-transcriptional factor in the Hippo signaling pathway that regulates pluripotency gene expression, co-localized with GJA1 (also known as Cx43) in the cell membrane and was translocated to the nucleus after GJ inhibition. Adherent culture is usually more suitable for the stable expansion of cells than is a suspension culture. GJ inhibition is suggested to be a simple method to up-regulate pluripotency in an adherent culture that involves a Cx43-YAP axis in pluripotent stem cells, such as Muse cells.
Stem cell therapy for acute myocardial infarction - focusing on the comparison between Muse cells and mesenchymal stem cells. International-journal Peer-reviewed

Yoshihisa Yamada, Shingo Minatoguchi, Hiromitsu Kanamori, Atsushi Mikami, Hiroyuki Okura, Mari Dezawa, Shinya Minatoguchi

Journal of cardiology　80　(1)　80-87　2022/07

DOI： 10.1016/j.jjcc.2021.10.030 　

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Rapid percutaneous coronary intervention for acute myocardial infarction (AMI) reduces acute mortality, but there is an urgent need for treatment of left ventricular dysfunction and remodeling after AMI to improve the prognosis. The myocardium itself does not have a high regenerative capacity, and it is important to minimize the loss of cardiomyocytes and maintain the cardiac function after AMI. To overcome these problems, attention has been focused on myocardial regeneration therapy using cells derived from bone marrow. The clinical use of bone marrow stem cells is considered to have low safety concerns based on the experience of using bone marrow transplantation for blood diseases in clinical practice. It has been reported that bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells (BM-MSC) differentiate into cardiomyocytes both in vitro and in vivo, and they have been considered a promising source for stem cell therapy. To prevent heart failure after human AMI, studies have been conducted to regenerate myocardial tissue by transplanting bone marrow stem cells, such as BM-MSCs and BM-MNCs. Therapies using those cells have been administered to animal models of AMI, and were effective to some extent, but the effect in clinical trials was limited. Recently, it was reported that multilineage-differentiating stress enduring cells (Muse cells), which are endogenous pluripotent stem cells obtainable from various tissues including the bone marrow, more markedly reduced the myocardial infarct size and improved the cardiac function via regeneration of cardiomyocytes and vessels and paracrine effects compared with BM-MSCs. Here, we describe stem cell therapies using conventional BM-MNCs and BM-MSCs, and Muse cells which have potential for clinical use for the treatment of AMI.
Effects of human Muse cells on bladder inflammation, overactivity, and nociception in a chemically induced Hunner-type interstitial cystitis-like rat model. International-journal Peer-reviewed

Akira Furuta, Yasumasa Kuroda, Tokunori Yamamoto, Shin Egawa, Mari Dezawa, Naoki Yoshimura

International urogynecology journal　33　(5)　1293-1301　2022/05

DOI： 10.1007/s00192-022-05166-w 　

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INTRODUCTION AND HYPOTHESIS: We investigated the effects of locally administered human multilineage-differentiating stress enduring (Muse) cells, nontumorigenic pluripotent-like endogenous stem cells, on bladder tissues, function, and nociceptive behavior in a chemically induced Hunner-type interstitial cystitis (HIC)-like rat model without immunosuppressant. METHODS: Chemical cystitis was induced by intravesical instillation of 0.2 N hydrochloride (HCl) for 15 min in female F344 rats. SSEA-3+ Muse cells, SSEA-3- non-Muse cells or Hanks' balanced salt solution (HBSS; vehicle) were injected into the anterior and posterior bladder wall at each 1×104 cells/10 μl 6 h after HCl application. The sham group received HBSS without HCl instillation. Urinary frequency was assessed using metabolic cages, cystometrograms, nociceptive behavior, and histological analysis of the bladder and L6 spinal cord. RESULTS: Increases in urinary frequency and decreases in bladder capacity compared with the sham group were observed in the vehicle and non-Muse groups, but not in the Muse group, at 1 week. Significant increases in nociceptive behavior compared with the sham group and the expression of TNFα in the bladder and c-Fos in the bilateral dorsal horns of L6 spinal cord were also observed in the vehicle and non-Muse groups, whereas these changes were not seen in the Muse group at 1 week. Histological analysis exhibited a higher proportion of injected Muse cells remaining in the urothelial basal layer and lamina propria of the bladder than non-Muse cells until 4 weeks. CONCLUSIONS: Muse cell therapy could be a promising modality for treating HIC.
Intravenous injection of human multilineage-differentiating stress-enduring cells alleviates mouse severe acute pancreatitis without immunosuppressants. Peer-reviewed

Masahiko Fukase, Naoaki Sakata, Yoshihiro Kushida, Shohei Wakao, Michiaki Unno, Mari Dezawa

Surgery today　52　(4)　603-615　2022/04

DOI： 10.1007/s00595-021-02382-7 　

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INTRODUCTION: We examined the effect of intravenously injected human multilineage-differentiating stress-enduring (Muse) cells, non-tumorigenic endogenous reparative stem cells already used in clinical trials, on a severe acute pancreatitis (SAP) mouse model without immunosuppressants. METHODS: Human Muse cells (1.0 × 105 cells) collected from mesenchymal stem cells (MSCs) as SSEA-3(+) were injected into a C57BL/6 mouse model via the jugular vein 6 h after SAP-induction with taurocholate. The control group received saline or the same number of SSEA-3(-)-non-Muse MSCs. RESULTS: Edematous parameters, F4/80(+) macrophage infiltration and terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity was the lowest and the number of proliferating endogenous pancreatic progenitors (CK18(+)/Ki67(+) cells) the highest in the Muse group among the three groups, with statistical significance, at 72 h. An enzyme-linked immunosorbent assay and quantitative polymerase chain reaction demonstrated that in vitro production of VEGF, HGF, IGF-1, and MMP-2, which are relevant to tissue protection, anti-inflammation, and anti-fibrosis, were higher in Muse cells than in non-Muse MSCs, particularly when cells were cultured in SAP mouse serum. Consistently, the pancreas of animals in the Muse group contained higher amounts of those factors according to Western blotting at 18 h than that in the non-Muse MSCs and control groups. CONCLUSIONS: Intravenous injection of human Muse cells was suggested to be effective for attenuating edema, inflammation and apoptosis in the acute phase of SAP.
Endogenous reparative pluripotent Muse cells with a unique immune privilege system: Hint at a new strategy for controlling acute and chronic inflammation. International-journal Peer-reviewed

Yasumasa Kuroda, Yo Oguma, Kerrigan Hall, Mari Dezawa

Frontiers in pharmacology　13　1027961-1027961　2022

DOI： 10.3389/fphar.2022.1027961 　

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Multilineage-differentiating stress enduring (Muse) cells, non-tumorigenic endogenous pluripotent stem cells, reside in the bone marrow (BM), peripheral blood, and connective tissue as pluripotent surface marker SSEA-3(+) cells. They express other pluripotent markers, including Nanog, Oct3/4, and Sox2 at moderate levels, differentiate into triploblastic lineages, self-renew at a single cell level, and exhibit anti-inflammatory effects. Cultured mesenchymal stromal cells (MSCs) and fibroblasts contain several percent of SSEA-3(+)-Muse cells. Circulating Muse cells, either endogenous or administered exogenously, selectively accumulate at the damaged site by sensing sphingosine-1-phosphate (S1P), a key mediator of inflammation, produced by damaged cells and replace apoptotic and damaged cells by spontaneously differentiating into multiple cells types that comprise the tissue and repair the tissue. Thus, intravenous injection is the main route for Muse cell treatment, and surgical operation is not necessary. Furthermore, gene introduction or cytokine induction are not required for generating pluripotent or differentiated states prior to treatment. Notably, allogenic and xenogenic Muse cells escape host immune rejection after intravenous injection and survive in the tissue as functioning cells over 6 and ∼2 months, respectively, without immunosuppressant treatment. Since Muse cells survive in the host tissue for extended periods of time, therefore their anti-inflammatory, anti-fibrotic, and trophic effects are long-lasting. These unique characteristics have led to the administration of Muse cells via intravenous drip in clinical trials for stroke, acute myocardial infarction, epidermolysis bullosa, spinal cord injury, neonatal hypoxic ischemic encephalopathy, amyotrophic lateral sclerosis, and COVID-19 acute respiratory distress syndrome without HLA-matching or immunosuppressive treatment.
Intravenous administration of human Muse cells recovers blood flow in a mouse model of hindlimb ischemia. International-journal Peer-reviewed

Yusuke Hori, Tomoya Kitani, Kenji Yanishi, Takaomi Suga, Masaya Kogure, Tetsuro Kusaba, Yoshihiro Kushida, Mari Dezawa, Satoaki Matoba

Frontiers in cardiovascular medicine　9　981088-981088　2022

DOI： 10.3389/fcvm.2022.981088 　

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Cell-based therapies hold great promise for the treatment of peripheral arterial disease (PAD), especially in patients presenting with severe limb ischemia, although the optimal strategy remains to be explored. In this study, we evaluated the therapeutic effect of intravenous administration of human Muse cells, a unique subpopulation of mesenchymal stem cells (MSC), using a mouse model of hindlimb ischemia (HLI) without an immunosuppressant. Compared with the phosphate buffered saline (PBS) or non-Muse MSC groups, the Muse group showed significantly higher laser doppler blood flow in the ischemic limb at days 7 and 14 after HLI. Increased microvascular density [percent area of CD31(+) cells] and reduced interstitial fibrosis in the ischemic limb muscle were also observed in the Muse group. mCherry-expressing Muse cells were found in the ischemic border zone and expressed CD31 but did not in the non-ischemic limb. Muse cells produced higher amounts of vascular endothelial growth factor (VEGF) than non-Muse cells under normoxic and hypoxic conditions in vitro. In the ischemic muscle, tissue VEGF concentration and angiogenesis-related genes such as Vegfa, Angpt1, Pdgfb, and Igf1 were significantly higher in the Muse group than in the other two groups. In addition, the proportion of M2 macrophages to total macrophages and the ratio of anti-inflammatory-related genes such as IL-10, Arg1, and CD206 per iNOS were significantly higher in the Muse group than in the other two groups. In summary, Muse cells exert pleiotropic effects in a mouse model of HLI, and therefore may provide a novel therapeutic approach for the treatment of PAD patients with severe limb ischemia.
Human Muse cells reduce myocardial infarct size and improve cardiac function without causing arrythmias in a swine model of acute myocardial infarction. International-journal Peer-reviewed

Yoshihisa Yamada, Shingo Minatoguchi, Shinya Baba, Sanae Shibata, Satoshi Takashima, Shohei Wakao, Hiroyuki Okura, Mari Dezawa, Shinya Minatoguchi

PloS one　17　(3)　e0265347　2022

DOI： 10.1371/journal.pone.0265347 　

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BACKGROUND: We recently reported that multilineage-differentiating stress enduring (Muse) cells intravenously administered after acute myocardial infarction (AMI), selectively engrafted to the infarct area, spontaneously differentiated into cardiomyocytes and vessels, reduced the infarct size, improved the left ventricular (LV) function and remodeling in rabbits. We aimed to clarify the efficiency of Muse cells in a larger animal AMI model of mini-pigs using a semi-clinical grade human Muse cell product. METHOD AND RESULT: Mini-pigs underwent 30 min of coronary artery occlusion followed by 2 weeks of reperfusion. Semi-clinical grade human Muse cell product (1x107, Muse group, n = 5) or saline (Vehicle group, n = 7) were intravenously administered at 24 h after reperfusion. The infarct size, LV function and remodeling were evaluated by echocardiography. Arrhythmias were evaluated by an implantable loop recorder. The infarct size was significantly smaller in the Muse group (10.5±3.3%) than in the Vehicle group (21.0±2.0%). Both the LV ejection fraction and fractional shortening were significantly greater in the Muse group than in the Vehicle group. The LV end-systolic and end-diastolic dimensions were significantly smaller in the Muse group than in the Vehicle group. Human Muse cells homed into the infarct border area and expressed cardiac troponin I and vascular endothelial CD31. No arrhythmias and no blood test abnormality were observed. CONCLUSION: Muse cell product might be promising for AMI therapy based on the efficiency and safety in a mini-pig AMI.
Intravenous injection of human multilineage-differentiating stress-enduring cells alleviates mouse severe acute pancreatitis without immunosuppressants Peer-reviewed

Masahiko Fukase, Naoaki Sakata, Yoshihiro Kushida, Shohei Wakao, Michiaki Unno, Mari Dezawa

Surgery Today　2021/10/23
Publisher: Springer Science and Business Media LLC
DOI： 10.1007/s00595-021-02382-7 　

ISSN： 0941-1291

eISSN： 1436-2813
Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy International-journal Peer-reviewed

Toshihiko Suzuki, Yoshiaki Sato, Yoshihiro Kushida, Masahiro Tsuji, Shohei Wakao, Kazuto Ueda, Kenji Imai, Yukako Iitani, Shinobu Shimizu, Hideki Hida, Takashi Temma, Shigeyoshi Saito, Hidehiro Iida, Masaaki Mizuno, Yoshiyuki Takahashi, Mari Dezawa, Cesar V Borlongan, Masahiro Hayakawa

Journal of Cerebral Blood Flow & Metabolism　41　(7)　1707-1720　2021/07
Publisher: SAGE Publications
DOI： 10.1177/0271678x20972656 　

ISSN： 0271-678X

eISSN： 1559-7016

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Perinatal hypoxic ischemic encephalopathy (HIE) results in serious neurological dysfunction and mortality. Clinical trials of multilineage-differentiating stress enduring cells (Muse cells) have commenced in stroke using intravenous delivery of donor-derived Muse cells. Here, we investigated the therapeutic effects of human Muse cells in an HIE model. Seven-day-old rats underwent ligation of the left carotid artery then were exposed to 8% oxygen for 60 min, and 72 hours later intravenously transplanted with 1 × 10⁴ of human-Muse and -non-Muse cells, collected from bone marrow-mesenchymal stem cells as stage-specific embryonic antigen-3 (SSEA-3)+ and −, respectively, or saline (vehicle) without immunosuppression. Human-specific probe revealed Muse cells distributed mainly to the injured brain at 2 and 4 weeks, and expressed neuronal and glial markers until 6 months. In contrast, non-Muse cells lodged in the lung at 2 weeks, but undetectable by 4 weeks. Magnetic resonance spectroscopy and positron emission tomography demonstrated that Muse cells dampened excitotoxic brain glutamatergic metabolites and suppressed microglial activation. Muse cell-treated group exhibited significant improvements in motor and cognitive functions at 4 weeks and 5 months. Intravenously transplanted Muse cells afforded functional benefits in experimental HIE possibly via regulation of glutamate metabolism and reduction of microglial activation.
Author Correction: Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis. International-journal Peer-reviewed

Toru Yamashita, Yoshihiro Kushida, Shohei Wakao, Koh Tadokoro, Emi Nomura, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Mari Dezawa, Koji Abe

Scientific reports　11　(1)　12828-12828　2021/06/14

DOI： 10.1038/s41598-021-91963-0 　
Protection of liver sinusoids by intravenous administration of human Muse cells in a rat extra-small partial liver transplantation model. International-journal Peer-reviewed

Yoshihiro Shono, Yoshihiro Kushida, Shohei Wakao, Yasumasa Kuroda, Michiaki Unno, Takashi Kamei, Shigehito Miyagi, Mari Dezawa

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons　21　(6)　2025-2039　2021/06

DOI： 10.1111/ajt.16461 　

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Small-for-size syndrome (SFSS) has a poor prognosis due to excessive shear stress and sinusoidal microcirculatory disturbances in the acute phase after living-donor liver transplantation (LDLT). Multilineage-differentiating stress enduring (Muse) cells are reparative stem cells found in various tissues and currently under clinical trials. These cells selectively home to damaged sites via the sphingosine-1-phosphate (S1P)-S1P receptor 2 system and repair damaged tissue by pleiotropic effects, including tissue protection and damaged/apoptotic cell replacement by differentiating into tissue-constituent cells. The effects of intravenously administered human bone marrow-Muse cells and -mesenchymal stem cells (MSCs) (4 × 105 ) on liver sinusoidal endothelial cells (LSECs) were examined in a rat SFSS model without immunosuppression. Compared with MSCs, Muse cells intensively homed to the grafted liver, distributed to the sinusoids and vessels, and delivered improved blood chemistry and Ki-67(+) proliferative hepatocytes and -LSECs within 3 days. Tissue clearing and three-dimensional imaging by multiphoton laser confocal microscopy revealed maintenance of the sinusoid continuity, organization, and surface area, as well as decreased sinusoid interruption in the Muse group. Small-interfering RNA-induced knockdown of hepatocyte growth factor and vascular endothelial growth factor-A impaired the protective effect of Muse cells on LSECs. Intravenous injection of Muse cells might be a feasible approach for LDLT with less recipient burden.
Isolation and characterization of bone marrow-derived mesenchymal stem cells in Xenopus laevis. International-journal Peer-reviewed

Rina Otsuka-Yamaguchi, Masaaki Kitada, Yasumasa Kuroda, Yoshihiro Kushida, Shohei Wakao, Mari Dezawa

Stem cell research　53　102341-102341　2021/05

DOI： 10.1016/j.scr.2021.102341 　

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Mesenchymal stem cells (MSCs) are multipotent cells that exist in mesenchymal tissues such as bone marrow and are able to differentiate into osteocytes, chondrocytes, and adipocytes. MSCs are generally collected as adherent cells on a plastic dish, and are positive for markers such as CD44, CD73, CD90, CD105 and CD166, and negative for CD11b, CD14, CD19, CD31, CD34, CD45, CD79a and HLA-DR. MSCs have been established from many kinds of mammals, but MSCs from amphibians have not yet been reported. We cultured adherent cells from the bone marrow of Xenopus laevis by modifying the protocol for culturing mammalian MSCs. The morphology of these cells was similar to that of mammalian MSCs. The amphibian MSCs were positive for cd44, cd73, cd90 and cd166, and negative for cd11b, cd14, cd19, cd31, cd34, cd45, cd79a and hla-dra. Moreover, they could be induced to differentiate into osteocyte-, chondrocyte-, and adipocyte-lineage cells by cytokine induction systems that were similar to those used for mammalian MSC differentiation. Thus, they are considered to be similar to mammalian MSCs. Unlike mammals, amphibians have high regenerative capacity. The findings from the present study will allow for future research to reveal how Xenopus MSCs are involved in the amphibian regenerative capacity and to elucidate the differences in the regenerative capacity between mammals and amphibians.
Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases. International-journal Peer-reviewed

Toru Yamashita, Yoshihiro Kushida, Koji Abe, Mari Dezawa

Cells　10　(4)　2021/04/20

DOI： 10.3390/cells10040961 　

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Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.
The evaluation of the safety and efficacy of intravenously administered allogeneic multilineage-differentiating stress-enduring cells in a swine hepatectomy model. Peer-reviewed

Masahiro Iseki, Masamichi Mizuma, Shohei Wakao, Yoshihiro Kushida, Katsuyoshi Kudo, Masahiko Fukase, Masaharu Ishida, Tomoyuki Ono, Mitsuhiro Shimura, Ichiro Ise, Yukie Suzuki, Teruko Sueta, Ryuta Asada, Shinobu Shimizu, Yoshiyuki Ueno, Mari Dezawa, Michiaki Unno

Surgery today　51　(4)　634-650　2021/04

DOI： 10.1007/s00595-020-02117-0 　

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INTRODUCTION: Multilineage-differentiating stress-enduring (Muse) cells are non-tumorigenic endogenous pluripotent-like cells residing in the bone marrow that exert a tissue reparative effect by replacing damaged/apoptotic cells through spontaneous differentiation into tissue-constituent cells. Post-hepatectomy liver failure (PHLF) is a potentially fatal complication. The main purpose of this study was to evaluate the safety and efficiency of allogeneic Muse cell administration via the portal vein in a swine model of PHLF. METHODS: Swine Muse cells, collected from swine bone marrow-mesenchymal stem cells (MSCs) as SSEA-3(+) cells, were examined for their characteristics. Then, 1 × 107 allogeneic-Muse cells and allogeneic-MSCs and vehicle were injected via the portal vein in a 70% hepatectomy swine model. RESULTS: Swine Muse cells exhibited characteristics comparable to previously reported human Muse cells. Compared to the MSC and vehicle groups, the Muse group showed specific homing of the administered cells into the liver, resulting in improvements in the control of hyperbilirubinemia (P = 0.04), prothrombin international normalized ratio (P = 0.05), and suppression of focal necrosis (P = 0.04). Integrated Muse cells differentiated spontaneously into hepatocyte marker-positive cells. CONCLUSIONS: Allogeneic Muse cell administration may provide a reparative effect and functional recovery in a 70% hepatectomy swine model and thus may contribute to the treatment of PHLF.
四半世紀に及んだ腸管出血性大腸菌感染症の戦いと未来感染症ミューズ細胞治療の挑戦(Quarter century battle against EHEC infectious disease; Muse cell therapy challenge on infectious diseases)

藤井潤, 出澤真理, 尾鶴亮, 若尾昌平, 辻高寛, 松葉隆司, 黒沢洋一, 大原直也, 松本壮吉, 安田香央里, 飯野守男

日本細菌学雑誌　76　(1)　126-126　2021/02
Publisher: 日本細菌学会
ISSN： 0021-4930

eISSN： 1882-4110
Comparison of separation methods for tissue-derived extracellular vesicles in the liver, heart, and skeletal muscle. International-journal Peer-reviewed

Adam Matejovič, Shohei Wakao, Masaaki Kitada, Yoshihiro Kushida, Mari Dezawa

FEBS open bio　11　(2)　482-493　2021/02

DOI： 10.1002/2211-5463.13075 　

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Extracellular vesicles (EVs), which are nanosized vesicles released by cells as intracellular messengers, have high potential as biomarkers. EVs are usually collected from in vitro sources, such as cell culture media or biofluids, and not from tissues. Techniques enabling direct collection of EVs from tissues will extend the applications of EVs. We compared methods for separating EVs from solid liver, heart, and skeletal muscle. Compared with a precipitation method, an ultracentrifugation-based method for collection of EVs from solid tissues yielded a higher proportion of EVs positive for EV-related markers, with minimum levels of intracellular organelle-related markers. Some tissue-specific modifications, such as a sucrose cushion step, may improve the yield and purity of the collected EVs.
Cell-based treatment for perinatal hypoxic-ischemic encephalopathy Peer-reviewed

CesarioV Borlongan, YouJeong Park, Mari Dezawa

Brain Circulation　7　(1)　13-13　2021
Publisher: Medknow
DOI： 10.4103/bc.bc_7_21 　

ISSN： 2394-8108
Intravenous Injection of Muse Cells as a Potential Therapeutic Approach for Epidermolysis Bullosa. International-journal Peer-reviewed

Yasuyuki Fujita, Miho Komatsu, San Eun Lee, Yoshihiro Kushida, Chihiro Nakayama-Nishimura, Wakana Matsumura, Shota Takashima, Satoru Shinkuma, Toshifumi Nomura, Naoya Masutomi, Makoto Kawamura, Mari Dezawa, Hiroshi Shimizu

The Journal of investigative dermatology　141　(1)　198-202　2021/01

DOI： 10.1016/j.jid.2020.05.092 　
マウスラクナ梗塞モデルに対するMuse細胞製品CL2020の治療効果の検討

阿部考貢, 油川大輝, 新妻邦泰, 串田良祐, 若尾昌平, 出澤真理, 冨永悌二

脳循環代謝　32　(1)　99-99　2020/11
Publisher: (一社)日本脳循環代謝学会
ISSN： 0915-9401

eISSN： 2188-7519
Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis. International-journal Peer-reviewed

Toru Yamashita, Yoshihiro Kushida, Shohei Wakao, Koh Tadokoro, Emi Nomura, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Mari Dezawa, Koji Abe

Scientific reports　10　(1)　17102-17102　2020/10/13

DOI： 10.1038/s41598-020-74216-4 　

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Muse cells are endogenous reparative pluripotent-like stem cells distributed in various tissues. They can selectively home to damaged sites after intravenous injection by sensing sphingosine-1-phosphate produced by damaged cells, then exert pleiotropic effects, including tissue protection and spontaneous differentiation into tissue-constituent cells. In G93A-transgenic ALS mice, intravenous injection of 5.0 × 104 cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. In contrast, such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Relative to the vehicle groups, the Muse group significantly improved scores in the rotarod, hanging-wire and muscle strength of lower limbs, recovered the number of motor neurons, and alleviated denervation and myofiber atrophy in lower limb muscles. These results suggest that Muse cells homed in a lesion site-dependent manner and protected the spinal cord against motor neuron death. Muse cells might also be a promising cell source for the treatment of ALS patients.
Cell-Based Therapy for Stroke: Musing With Muse Cells. International-journal Peer-reviewed

You Jeong Park, Kuniyasu Niizuma, Maxim Mokin, Mari Dezawa, Cesar V Borlongan

Stroke　51　(9)　2854-2862　2020/09

DOI： 10.1161/STROKEAHA.120.030618 　

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Stem cell-based regenerative therapies may rescue the central nervous system following ischemic stroke. Mesenchymal stem cells exhibit promising regenerative capacity in in vitro studies but display little to no incorporation in host tissue after transplantation in in vivo models of stroke. Despite these limitations, clinical trials using mesenchymal stem cells have produced some functional benefits ascribed to their ability to modulate the host's inflammatory response coupled with their robust safety profile. Regeneration of ischemic brain tissue using stem cells, however, remains elusive in humans. Multilineage-differentiating stress-enduring (Muse) cells are a distinct subset of mesenchymal stem cells found sporadically in connective tissue of nearly every organ. Since their discovery in 2010, these endogenous reparative stem cells have been investigated for their therapeutic potential against a variety of diseases, including acute myocardial infarction, stroke, chronic kidney disease, and liver disease. Preclinical studies have exemplified Muse cells' unique ability mobilize, differentiate, and engraft into damaged host tissue. Intravenously transplanted Muse cells in mouse lacunar stroke models afforded functional recovery and long-term engraftment into the host neural network. This mini-review article highlights these biological properties that make Muse cells an exceptional candidate donor source for cell therapy in ischemic stroke. Elucidating the mechanism behind the therapeutic potential of Muse cells will undoubtedly help optimize stem cell therapy for stroke and advance the field of regenerative medicine.
Intravenously Transplanted Human Multilineage-Differentiating Stress-Enduring Cells Afford Brain Repair in a Mouse Lacunar Stroke Model. International-journal Peer-reviewed

Takatsugu Abe, Daiki Aburakawa, Kuniyasu Niizuma, Naoya Iwabuchi, Takumi Kajitani, Shohei Wakao, Yoshihiro Kushida, Mari Dezawa, Cesar V Borlongan, Teiji Tominaga

Stroke　51　(2)　601-611　2020/02

DOI： 10.1161/STROKEAHA.119.026589 　

ISSN： 0039-2499

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Background and Purpose- Multilineage-differentiating stress-enduring cells are endogenous nontumorigenic reparative pluripotent-like stem cells found in bone marrow, peripheral blood, and connective tissues. Topically administered human multilineage-differentiating stress-enduring cells into rat/mouse stroke models differentiated into neural cells and promoted clinically relevant functional recovery. However, critical questions on the appropriate timing and dose, and safety of the less invasive intravenous administration of clinical-grade multilineage-differentiating stress-enduring cell-based product CL2020 remain unanswered. Methods- Using an immunodeficient mouse lacunar model, CL2020 was administered via the cervical vein in different doses (high dose=5×104 cells/body; medium dose=1×104 cells/body; low dose=5×103 cells/body) at subacute phase (≈9 days after onset) and chronic phase (≈30 days). Cylinder test, depletion of human cells by diphtheria toxin administration, immunohistochemistry, and human specific-genome detection were performed. Results- Tumorigenesis and adverse effects were not detected for up to 22 weeks. The high-dose group displayed significant functional recovery compared with the vehicle group in cylinder test in subacute-phase-treated and chronic-phase-treated animals after 6 weeks and 8 weeks post-injection, respectively. In the high-dose group of subacute-phase-treated animals, robust and stable recovery in cylinder test persisted up to 22 weeks compared with the vehicle group. In both groups, intraperitoneal injection of diphtheria toxin abrogated the functional recovery. Anti-human mitochondria revealed CL2020 distributed mainly in the peri-infarct area at 1, 10, and 22 weeks and expressed NeuN (neuronal nuclei)- and MAP-2 (microtubule-associated protein-2)-immunoreactivity. Conclusions- Intravenously administered CL2020 was safe, migrated to the peri-infarct area, and afforded functional recovery in experimental stroke.
Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice. International-journal Peer-reviewed

Ryo Ozuru, Shohei Wakao, Takahiro Tsuji, Naoya Ohara, Takashi Matsuba, Muhammad Y Amuran, Junko Isobe, Morio Iino, Naoki Nishida, Sari Matsumoto, Kimiharu Iwadate, Noriko Konishi, Kaori Yasuda, Kosuke Tashiro, Misato Hida, Arisato Yadoiwa, Shinsuke Kato, Eijiro Yamashita, Sohkichi Matsumoto, Yoichi Kurozawa, Mari Dezawa, Jun Fujii

Molecular therapy : the journal of the American Society of Gene Therapy　28　(1)　100-118　2020/01/08

DOI： 10.1016/j.ymthe.2019.09.023 　

ISSN： 1525-0016

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Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, hemolytic uremic syndrome, and acute encephalopathies that may lead to sudden death or severe neurologic sequelae. Current treatments, including immunoglobulin G (IgG) immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative non-tumorigenic stem cells that naturally reside in the body and are currently under clinical trials for regenerative medicine. When administered intravenously, Musecells accumulate to the damaged tissue, where they exert anti-inflammatory, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, and replace damaged cells by differentiating into tissue-constituent cells. Here, severely immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice orally inoculated with 9 × 109 colony-forming units of STEC O111 and treated 48 h later with intravenous injection of 5 × 104 Muse cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNAi abolished the beneficial effects of Muse cells, leading to a 40% death and significant body weight loss, suggesting the involvement of G-CSF in the beneficial effects of Muse cells in STEC-infected mice. Thus, intravenous administration of Muse cells could be a candidate therapeutic approach for preventing fatal encephalopathy after STEC infection.
A Novel Type of Stem Cells Double-Positive for SSEA-3 and CD45 in Human Peripheral Blood Peer-reviewed

Tetsuya Sato, Shohei Wakao, Yoshihiro Kushida, Kazuki Tatsumi, Masaaki Kitada, Takatsugu Abe, Kuniyasu Niizuma, Teiji Tominaga, Shigeki Kushimoto, Mari Dezawa

Cell Transplantation　29　096368972092357-096368972092357　2020/01/01
Publisher: SAGE Publications
DOI： 10.1177/0963689720923574 　

ISSN： 0963-6897

eISSN： 1555-3892

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Peripheral blood (PB) contains several types of stem/progenitor cells, including hematopoietic stem and endothelial progenitor cells. We identified a population positive for both the pluripotent surface marker SSEA-3 and leukocyte common antigen CD45 that comprises 0.04% ± 0.003% of the mononuclear cells in human PB. The average size of the SSEA-3(+)/CD45(+) cells was 10.1 ± 0.3 µm and ∼22% were positive for CD105, a mesenchymal marker; ∼85% were positive for CD19, a B cell marker; and ∼94% were positive for HLA-DR, a major histocompatibility complex class II molecule relevant to antigen presentation. These SSEA-3(+)/CD45(+) cells expressed the pluripotency markers Nanog, Oct3/4, and Sox2, as well as sphingosine-1-phosphate (S1P) receptor 2, and migrated toward S1P, although their adherence and proliferative activities in vitro were low. They expressed NeuN at 7 d, Pax7 and desmin at 7 d, and alpha-fetoprotein and cytokeratin-19 at 3 d when supplied to mouse damaged tissues of the brain, skeletal muscle and liver, respectively, suggesting the ability to spontaneously differentiate into triploblastic lineages compatible to the tissue microenvironment. Multilineage-differentiating stress enduring (Muse) cells, identified as SSEA-3(+) in tissues such as the bone marrow and organ connective tissues, express pluripotency markers, migrate to sites of damage via the S1P-S1P receptor 2 system, and differentiate spontaneously into tissue-compatible cells after homing to the damaged tissue where they participate in tissue repair. After the onset of acute myocardial infarction and stroke, patients are reported to have an increase in the number of SSEA-3(+) cells in the PB. The SSEA-3(+)/CD45(+) cells in the PB showed similarity to tissue-Muse cells, although with difference in surface marker expression and cellular properties. Thus, these findings suggest that human PB contains a subset of cells that are distinct from known stem/progenitor cells, and that CD45(+)-mononuclear cells in the PB comprise a novel subpopulation of cells that express pluripotency markers.
Intravenously Transplanted Human Muse Cells Afford Brain Repair in a Mouse Lacunar Stroke Model Peer-reviewed

Takatsugu Abe, Daiki Aburakawa, Kuniyasu Niizuma, Naoya Iwabuchi, Takumi Kajitani, Shohei Wakao, Yoshihiro Kushida, Mari Dezawa, Cesar Borlongan, Teiji Tominaga

Stroke (STROKE/2019/026589R1, http://stroke-submit.aha-journals.org) inpress　2019/12
Actualization of Neural Regenerative Medicine by Intravenous Drip of Donor-derived Muse Cells

DEZAWA M, NIIZUMA K, TOMINAGA T

Brain Nerve　71　(8)　895-900　2019/08

DOI： 10.11477/mf.1416201372 　

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Muse cells are non-tumorigenic reparative endogenous stem cells identified by SSEA-3+. They are pluripotent and are stably mobilized from the bone marrow to the peripheral blood and distribute to organ connective tissue, where they contribute to daily minute repair of damaged/lost cells by spontaneous differentiation into tissue-constituent cells. Muse cells specifically home to damaged site to repair the tissue by simultaneous differentiation into multiple tissue-constituent cells. When the number of endogenous Muse cells is not sufficient, administration of exogenous Muse cells delivers robust functional recovery. Muse cells do not need to be "induced" or genetically manipulated. Intravenous drip is the main method of administration, making surgical operation unnecessary. Because Muse cells have an immunomodulatory system similar to the placenta, donor-derived Muse cells can be directly administered to patients without HLA-matching or immunosuppression therapy. Allogeneic Muse cells remain in the host tissue as differentiated cells for more than half a year. Clinical trials for the treatment of myocardial infarction, stroke and epidermolysis bullosa with intravenous injection of donor-derived Muse cells are currently conducted by the Life Science Institute Inc. Muse cells may safely provide clinically relevant effects compatible with the 'body's natural repair systems' by a simple cost-effective strategy.
18-Oxocortisol Synthesis in Aldosterone-Producing Adrenocortical Adenoma and Significance of KCNJ5 Mutation Status. International-journal Peer-reviewed

Yuta Tezuka, Yuto Yamazaki, Masaaki Kitada, Ryo Morimoto, Masataka Kudo, Kazumasa Seiji, Kei Takase, Yoshihide Kawasaki, Koji Mitsuzuka, Akihiro Ito, Jun Nishikawa, Noriko Asai, Yasuhiro Nakamura, Celso E Gomez-Sanchez, Sadayoshi Ito, Mari Dezawa, Hironobu Sasano, Fumitoshi Satoh

Hypertension (Dallas, Tex. : 1979)　73　(6)　1283-1290　2019/06

DOI： 10.1161/HYPERTENSIONAHA.118.12064 　

ISSN： 0194-911X

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Peripheral 18-oxocortisol (18oxoF) level could contribute to the detection of aldosterone-producing adenoma (APA) in patients with primary aldosteronism. However, peripheral 18oxoF varies among such patients, which is a big drawback concerning its clinical application. We studied 48 cases of APA, 35 harboring KCNJ5 mutation, to clarify the significance of clinical and pathological parameters about peripheral 18oxoF. Peripheral 18oxoF concentration ranged widely from 0.50 to 183.13 ng/dL and correlated positively with intratumoral areas stained positively for steroidogenic enzymes ( P<0.0001). The peripheral 18oxoF level also correlated significantly with that of circulating aldosterone ( P<0.0001) but not with that of cortisol, a precursor of 18oxoF. However, a significant correlation was detected between peripheral 18oxoF and intratumoral glucocorticoids ( P<0.05). In addition, peripheral 18oxoF correlated positively with the number of hybrid cells double positive for 11β-hydroxylase and aldosterone synthase ( P<0.0001). Comparing between the cases with and those without KCNJ5 mutation, the KCNJ5-mutated group demonstrated a significantly higher concentration of peripheral 18oxoF (28.4±5.6 versus 3.0±0.9 ng/dL, P<0.0001) and a larger intratumoral environment including the hybrid cells ( P<0.001), possibly representing a deviation from normal aldosterone biosynthesis. After multivariate analysis, KCNJ5 mutation status turned out to be the most associated factor involved in 18oxoF synthesis in APA ( P<0.0001). Results of our present study first revealed that enhanced 18oxoF synthesis in APA could come from a functional deviation of aldosterone biosynthesis from the normal zona glomerulosa and the utility of peripheral 18oxoF measurement could be influenced by the prevalence of KCNJ5 mutation in an APA.
Direct conversion of adult human skin fibroblasts into functional Schwann cells that achieve robust recovery of the severed peripheral nerve in rats. International-journal Peer-reviewed

Kitada M, Murakami T, Wakao S, Li G, Dezawa M

Glia　67　(5)　950-966　2019/05

DOI： 10.1002/glia.23582 　

ISSN： 0894-1491

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Direct conversion is considered a promising approach to obtain tissue-specific cells for cell therapies; however, this strategy depends on exogenous gene expression that may cause undesired adverse effects such as tumorigenesis. By optimizing the Schwann cell induction system, which was originally developed for trans-differentiation of bone marrow mesenchymal stem cells into Schwann cells, we established a system to directly convert adult human skin fibroblasts into cells comparable to authentic human Schwann cells without gene introduction. Serial treatments with beta-mercaptoethanol, retinoic acid, and finally a cocktail of basic fibroblast growth factor, forskolin, platelet-derived growth factor-AA, and heregulin-β1 (EGF domain) converted fibroblasts into cells expressing authentic Schwann cell markers at an efficiency of approximately 75%. Genome-wide gene expression analysis suggested the conversion of fibroblasts into the Schwann cell-lineage. Transplantation of induced Schwann cells into severed peripheral nerve of rats facilitated axonal regeneration and robust functional recovery in sciatic function index comparable to those of authentic human Schwann cells. The contributions of induced Schwann cells to myelination of regenerated axons and re-formation of neuromuscular junctions were also demonstrated. Our data clearly demonstrated that cells comparable to functional Schwann cells feasible for the treatment of neural disease can be induced from adult human skin fibroblasts without gene introduction. This direct conversion system will be beneficial for clinical applications to peripheral and central nervous system injuries and demyelinating diseases.
Quantitative Analysis of SSEA3+ Cells from Human Umbilical Cord after Magnetic Sorting. Peer-reviewed

Leng Z, Sun D, Huang Z, Tadmori I, Chiang N, Kethidi N, Sabra A, Kushida Y, Fu YS, Dezawa M, He X, Young W

Cell transplantation　28　(7)　963689719844260-923　2019/04
Publisher: SAGE Publications
DOI： 10.1177/0963689719844260 　

ISSN： 0963-6897

eISSN： 1555-3892

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Multilineage-differentiating stress-enduring (Muse) cells are a population of pluripotent stage-specific embryonic antigen 3 (SSEA3)+ mesenchymal stem cells first described by Mari Dezawa in 2010. Although some investigators have reported SSEA3+ mesenchymal cells in umbilical cord tissues, none have quantitatively compared SSEA3+ cells isolated from Wharton’s jelly (WJ) and the cord lining (CL) of human umbilical cords (HUCs). We separated WJ and the CL from HUCs, cultured mesenchymal stromal cells (MSCs) isolated from these two tissues with collagenase, and quantified the percentage of SSEA3+ cells over three passages. The first passage had 5.0% ± 4.3% and 5.3% ± 5.1% SSEA3+ cells from WJ and the CL, respectively, but the percentage of SSEA3+ cells decreased significantly ( P < 0.05) between P0 and P2 in the CL group and between P0 and P1 in the WJ group. Magnetic-activated cell sorting (MACS) markedly enriched SSEA3+ cells to 91.4% ± 3.2%. Upon culture of the sorted population, we found that the SSEA3+ percentage ranged from 62.5% to 76.0% in P2–P5 and then declined to 42.0%–54.7% between P6 and P9. At P10, the cultures contained 37.4% SSEA3+ cells. After P10, we resorted the cells and achieved 89.4% SSEA3+ cells in culture. The procedure for MACS-based enrichment of SSEA3+ cells, followed by expansion in culture and a re-enrichment step, allows the isolation of many millions of SSEA3+ cells in relatively pure culture. When cultured, the sorted SSEA3+ cells differentiated into embryoid spheres and survived 4 weeks after transplant into a contused Sprague-Dawley rat spinal cord. The transplanted SSEA3+ cells migrated into the injury area from four injection points around the contusion site and did not produce any tumors. The umbilical cord is an excellent source of fetal Muse cells, and our method allows the practical and efficient isolation and expansion of relatively pure populations of SSEA3+ Muse cells that can be matched by human leukocyte antigen for transplantation in human trials.
The Muse Cell Discovery, Thanks to Wine and Science. Peer-reviewed

Dezawa M

Advances in experimental medicine and biology　1103　1-11　2018/12

DOI： 10.1007/978-4-431-56847-6_1 　

ISSN： 0065-2598
Basic Characteristics of Muse Cells. Peer-reviewed

Wakao S, Kushida Y, Dezawa M

Advances in experimental medicine and biology　1103　13-41　2018/12
Publisher: Springer Japan
DOI： 10.1007/978-4-431-56847-6_2 　

ISSN： 0065-2598

eISSN： 2214-8019
Muse Cells Are Endogenous Reparative Stem Cells. Peer-reviewed

Kushida Y, Wakao S, Dezawa M

Advances in experimental medicine and biology　1103　43-68　2018/12
Publisher: Springer Japan
DOI： 10.1007/978-4-431-56847-6_3 　

ISSN： 0065-2598

eISSN： 2214-8019
Protocols for Isolation and Evaluation of Muse Cells. Peer-reviewed

Tatsumi K, Kushida Y, Wakao S, Kuroda Y, Dezawa M

Advances in experimental medicine and biology　1103　69-101　2018/12
Publisher: Springer Japan
DOI： 10.1007/978-4-431-56847-6_4 　

ISSN： 0065-2598

eISSN： 2214-8019
Clinical Trials of Muse Cells. Peer-reviewed

Dezawa M

Advances in experimental medicine and biology　1103　305-307　2018/12

DOI： 10.1007/978-4-431-56847-6_17 　

ISSN： 0065-2598
Post-Infarct Administration of Human Xenograft Muse Cells Reduce the Myocardial Infarct Size and Improve the Cardiac Function and Remodeling in a Miniature Pig Model.

Yoshihisa Yamada, Shingo Minatoguchi, Shinya Baba, Sanae Shibata, Satoshi Takashima, Masanori Kawasaki, Atsushi Mikami, Shohei Wakao, Mari Dezawa, Shinya Minatoguchi

CIRCULATION　138　2018/11

ISSN： 0009-7322

eISSN： 1524-4539
Intracellular signaling similarity reveals neural stem cell-like properties of ependymal cells in the adult rat spinal cord. Peer-reviewed

Kitada M, Wakao S, Dezawa M

Development, growth & differentiation　60　(6)　326-340　2018/08

DOI： 10.1111/dgd.12546 　

ISSN： 0012-1592
Congress report: A report of the 16th Congress of the Japanese Society for Regenerative Medicine Peer-reviewed

Masaaki Kitada, Mari Dezawa

Regenerative Therapy　8　15-19　2018/06/01
Publisher: Japanese Society of Regenerative Medicine
DOI： 10.1016/j.reth.2018.01.001 　

ISSN： 2352-3204
Intravenously injected human multilineage-differentiating stress-enduring cells selectively engraft into mouse aortic aneurysms and attenuate dilatation by differentiating into multiple cell types Peer-reviewed

Katsuhiro Hosoyama, Shohei Wakao, Yoshihiro Kushida, Fumitaka Ogura, Kay Maeda, Osamu Adachi, Shunsuke Kawamoto, Mari Dezawa, Yoshikatsu Saiki

Journal of Thoracic and Cardiovascular Surgery　155　(6)　2301-2313.e4　2018/06/01
Publisher: Mosby Inc.
DOI： 10.1016/j.jtcvs.2018.01.098 　

ISSN： 1097-685X 0022-5223

eISSN： 1097-685X
Human Multilineage-differentiating Stress-Enduring Cells Exert Pleiotropic Effects to Ameliorate Acute Lung Ischemia-Reperfusion Injury in a Rat Model. Peer-reviewed

Yabuki H, Wakao S, Kushida Y, Dezawa M, Okada Y

Cell transplantation　27　(6)　979-993　2018/06
Publisher: SAGE Publications
DOI： 10.1177/0963689718761657 　

ISSN： 0963-6897

eISSN： 1555-3892

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Posttransplantation lung ischemia–reperfusion (IR) injuries affect both patient survival and graft function. In this study, we evaluated the protective effects of infused human multilineage-differentiating stress-enduring (Muse) cells, a novel, easily harvested type of nontumorigenic endogenous reparative stem cell, against acute IR lung injury in a rat model. After a 2-h warm IR injury induction in a left rat lung, human Muse cells, human mesenchymal stem cells (MSCs), and vehicle were injected via the left pulmonary artery after reperfusion. Functionality, histological findings, and protein expression were subsequently assessed in the injured lung. In vitro, we also compared human Muse cells with human MSCs in terms of migration abilities and the secretory properties of protective substances. The arterial oxygen partial pressure to fractional inspired oxygen ratio, alveolar-arterial oxygen gradient, left lung compliance, and histological injury score on hematoxylin–eosin sections were significantly better in the Muse group relative to the MSC and vehicle groups. Compared to MSCs, human Muse cells homed more efficiently to the injured lung, where they suppressed the apoptosis and stimulated proliferation of host alveolar cells. Human Muse cells also migrated to serum from lung-injured model rats and produced beneficial substances (keratinocyte growth factor [KGF], hepatocyte growth factor, angiopoietin-1, and prostaglandin E2) in vitro. Western blot of lung tissue confirmed high expression of KGF and their target molecules (interleukin-6, protein kinase B, and B-cell lymphoma-2) in the Muse group. Thus, Muse cells efficiently ameliorated lung IR injury via pleiotropic effects in a rat model. These findings support further investigation on the use of human Muse cells for lung IR injury.
S1P-S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction. International-journal Peer-reviewed

Yamada Y, Wakao S, Kushida Y, Minatoguchi S, Mikami A, Higashi K, Baba S, Shigemoto T, Kuroda Y, Kanamori H, Amin M, Kawasaki M, Nishigaki K, Taoka M, Isobe T, Muramatsu C, Dezawa M, Minatoguchi S

Circulation research　122　(8)　1069-1083　2018/04

DOI： 10.1161/CIRCRESAHA.117.311648 　

ISSN： 0009-7330

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RATIONALE: Multilineage-differentiating stress enduring (Muse) cells, pluripotent marker stage-specific embryonic antigen-3+ cells, are nontumorigenic endogenous pluripotent-like stem cells obtainable from various tissues including the bone marrow. Their therapeutic efficiency has not been validated in acute myocardial infarction. OBJECTIVE: The main objective of this study is to clarify the efficiency of intravenously infused rabbit autograft, allograft, and xenograft (human) bone marrow-Muse cells in a rabbit acute myocardial infarction model and their mechanisms of tissue repair. METHODS AND RESULTS: In vivo dynamics of Nano-lantern-labeled Muse cells showed preferential homing of the cells to the postinfarct heart at 3 days and 2 weeks, with ≈14.5% of injected GFP (green fluorescent protein)-Muse cells estimated to be engrafted into the heart at 3 days. The migration and homing of the Muse cells was confirmed pharmacologically (S1PR2 [sphingosine monophosphate receptor 2]-specific antagonist JTE-013 coinjection) and genetically (S1PR2-siRNA [small interfering ribonucleic acid]-introduced Muse cells) to be mediated through the S1P (sphingosine monophosphate)-S1PR2 axis. They spontaneously differentiated into cells positive for cardiac markers, such as cardiac troponin-I, sarcomeric α-actinin, and connexin-43, and vascular markers. GCaMP3 (GFP-based Ca calmodulin probe)-labeled Muse cells that engrafted into the ischemic region exhibited increased GCaMP3 fluorescence during systole and decreased fluorescence during diastole. Infarct size was reduced by ≈52%, and the ejection fraction was increased by ≈38% compared with vehicle injection at 2 months, ≈2.5 and ≈2.1 times higher, respectively, than that induced by mesenchymal stem cells. These effects were partially attenuated by the administration of GATA4-gene-silenced Muse cells. Muse cell allografts and xenografts efficiently engrafted and recovered functions, and allografts remained in the tissue and sustained functional recovery for up to 6 months without immunosuppression. CONCLUSIONS: Muse cells may provide reparative effects and robust functional recovery and may, thus, provide a novel strategy for the treatment of acute myocardial infarction.
Accelerating Cell Therapy for Stroke in Japan: Regulatory Framework and Guidelines on Development of Cell-Based Products. International-journal Peer-reviewed

Kiyohiro Houkin, Hideo Shichinohe, Koji Abe, Teruyo Arato, Mari Dezawa, Osamu Honmou, Nobutaka Horie, Yasuo Katayama, Kohsuke Kudo, Satoshi Kuroda, Tomohiro Matsuyama, Ichiro Miyai, Izumi Nagata, Kuniyasu Niizuma, Ken Sakushima, Masanori Sasaki, Norihiro Sato, Kenji Sawanobori, Satoshi Suda, Akihiko Taguchi, Teiji Tominaga, Haruko Yamamoto, Toru Yamashita, Toshiki Yoshimine

Stroke　49　(4)　e145-e152-e152　2018/04

DOI： 10.1161/STROKEAHA.117.019216 　

ISSN： 0039-2499
Cardiotrophic Growth Factor–Driven Induction of Human Muse Cells Into Cardiomyocyte-Like Phenotype Peer-reviewed

Mohamed Amin, Yoshihiro Kushida, Shohei Wakao, Masaaki Kitada, Kazuki Tatsumi, Mari Dezawa

Cell Transplantation　27　(2)　285-298　2018/02/01
Publisher: SAGE Publications Ltd
DOI： 10.1177/0963689717721514 　

ISSN： 1555-3892 0963-6897
Correction to: Basic Characteristics of Muse Cells. Peer-reviewed

Wakao S, Kushida Y, Dezawa M

Advances in experimental medicine and biology　1103　C1-C1　2018
Publisher: Springer Japan
DOI： 10.1007/978-4-431-56847-6_19 　

ISSN： 0065-2598

eISSN： 2214-8019
Mobilized muse cells after acute myocardial infarction predict cardiac function and remodeling in the chronic phase Peer-reviewed

Toshiki Tanaka, Kazuhiko Nishigaki, Shingo Minatoguchi, Takahide Nawa, Yoshihisa Yamada, Hiromitsu Kanamori, Atsushi Mikami, Hiroaki Ushikoshi, Masanori Kawasaki, Mari Dezawa, Shinya Minatoguchi

Circulation Journal　82　(2)　561-571　2018
Publisher: Japanese Circulation Society
DOI： 10.1253/circj.CJ-17-0552 　

ISSN： 1347-4820 1346-9843
Prolonged but non-permanent expression of a transgene in ependymal cells of adult rats using an adenovirus-mediated transposon gene transfer system Peer-reviewed

Jun-ichi Suzuki, Mari Dezawa, Masaaki Kitada

BRAIN RESEARCH　1675　20-27　2017/11

DOI： 10.1016/j.brainres.2017.08.033 　

ISSN： 0006-8993

eISSN： 1872-6240
Multilineage-differentiating stress enduring cellsを用いた新生児慢性肺疾患に対する新規治療法の開発

佐藤義朗, 鈴木俊彦, 田中雅人, 上田一仁, 田中亮, 三浦良介, 呉尚治, 浅田英之, 北瀬悠磨, 立花貴史, 見松はるか, 伊藤美香, 齊藤明子, 村松友佳子, 早川昌弘, 出澤真理, 串田良祐

日本新生児成育医学会雑誌　29　(3)　589-589　2017/10
Publisher: (公社)日本新生児成育医学会
ISSN： 2189-7549
新生児慢性肺疾患に伴う肺高血圧症に対するMultilineage-differentiating stress enduring cellsを用いた新規治療法の開発

鈴木俊彦, 佐藤義朗, 上田一仁, 田中雅人, 田中亮, 三浦良介, 呉尚治, 浅田英之, 北瀬悠磨, 立花貴史, 見松はるか, 伊藤美春, 齊藤明子, 村松友佳子, 早川昌弘, 出澤真理, 串田良祐

日本新生児成育医学会雑誌　29　(3)　611-611　2017/10
Publisher: (公社)日本新生児成育医学会
ISSN： 2189-7549
Allogeneic transplantation of MUSE cell ameliorates liver regenerations in large animal models of chronic liver injury. Peer-reviewed

Taketo Nishina, Shohei Wakao, Hiroaki Haga, Kazuo Okumoto, Tomohiro Katsumi, Kei Mizuno, Takafumi Saito, Mari Dezawa, Yoshiyuki Ueno

HEPATOLOGY　66　385A-385A　2017/10

ISSN： 0270-9139

eISSN： 1527-3350
Beneficial Effects of Systemically Administered Human Muse Cells in Adriamycin Nephropathy Peer-reviewed

Nao Uchida, Yoshihiro Kushida, Masaaki Kitada, Shohei Wakao, Naonori Kumagai, Yasumasa Kuroda, Yoshiaki Kondo, Yukari Hirohara, Shigeo Kure, Gregorio Chazenbalk, Mari Dezawa

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY　28　(10)　2946-2960　2017/10

DOI： 10.1681/ASN.2016070775 　

ISSN： 1046-6673

eISSN： 1533-3450
Genetically Engineered Multilineage-Differentiating Stress-Enduring Cells as Cellular Vehicles against Malignant Gliomas. International-journal Peer-reviewed

Tomohiro Yamasaki, Shohei Wakao, Hiroshi Kawaji, Shinichiro Koizumi, Tetsuro Sameshima, Mari Dezawa, Hiroki Namba

Molecular therapy oncolytics　6　45-56　2017/09/15

DOI： 10.1016/j.omto.2017.06.001 　

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Malignant glioma, the most common malignant brain tumor in adults, is difficult to treat due to its aggressive invasive nature. Enzyme/prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system is an efficient strategy for treating malignant gliomas. In the present study, we evaluated treatment with multilineage-differentiating stress-enduring (Muse) cells, which are endogenous non-tumorigenic pluripotent-like stem cells that are easily collectable from the bone marrow as SSEA-3+ cells, as carriers of the HSVtk gene. Human Muse cells showed potent migratory activity toward glioma cells both in vitro and in vivo. HSVtk gene-transduced Muse cells (Muse-tk cells) at a cell number of only 1/32 that of U87 human glioma cells completely eradicated U87 gliomas in nude mouse brains, showing a robust in vivo bystander effect. Pre-existing intracranial U87 gliomas in nude mouse brains injected intratumorally with Muse-tk cells followed by intraperitoneal GCV administration were significantly reduced in size within 2 weeks, and 4 of 10 treated mice survived over 200 days. These findings suggest that intratumoral Muse-tk cell injection followed by systemic GCV administration is safe and effective and that allogeneic Muse-tk cell-medicated suicide gene therapy for malignant glioma is clinically feasible.
ラット肺虚血再灌流障害モデルにおけるMuse細胞の有効性

矢吹皓, 若尾昌平, 串田良祐, 出澤真理, 岡田克典

移植　52　(総会臨時)　490-490　2017/08
Publisher: (一社)日本移植学会
ISSN： 0578-7947

eISSN： 2188-0034
アルドステロン産生腺腫における18-oxocortisol合成の意義

手塚雄太, 中村保宏, 北田容章, 祢津昌広, 小野美澄, 岩倉芳倫, 森本玲, 工藤正孝, 清治和将, 高瀬圭, 荒井陽一, 伊勢和恵, 山崎有人, 伊藤貞嘉, 出澤真理, 笹野公伸, 佐藤文俊

日本内分泌学会雑誌　93　(1)　297-297　2017/04
Publisher: (一社)日本内分泌学会
ISSN： 0029-0661

eISSN： 2186-506X
Neuro-regeneration therapy using human Muse cells is highly effective in a mouse intracerebral hemorrhage model Peer-reviewed

Norihito Shimamura, Kiyohide Kakuta, Liang Wang, Masato Naraoka, Hiroki Uchida, Shohei Wakao, Mari Dezawa, Hiroki Ohkuma

EXPERIMENTAL BRAIN RESEARCH　235　(2)　565-572　2017/02

DOI： 10.1007/s00221-016-4818-y 　

ISSN： 0014-4819

eISSN： 1432-1106
Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model Peer-reviewed

Hiroki Uchida, Kuniyasu Niizuma, Yoshihiro Kushida, Shohei Wakao, Teiji Tominaga, Cesario V. Borlongan, Mari Dezawa

STROKE　48　(2)　428-435　2017/02

DOI： 10.1161/STROKEAHA.116.014950 　

ISSN： 0039-2499

eISSN： 1524-4628
Therapeutic potential of multilineage-differentiating stress-enduring cells for osteochondral repair in a rat model Peer-reviewed

Elhussein Elbadry Mahmoud, Naosuke Kamei, Ryo Shimizu, Shohei Wakao, Mari Dezawa, Nobuo Adachi, Mitsuo Ochi

Stem Cells International　2017　2017
Publisher: Hindawi Limited
DOI： 10.1155/2017/8154569 　

ISSN： 1687-9678
The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation Peer-reviewed

Nicola Alessio, Servet Ozcan, Kazuki Tatsumi, Aysegul Murat, Gianfranco Peluso, Mari Dezawa, Umberto Galderisi

CELL CYCLE　16　(1)　33-44　2017

DOI： 10.1080/15384101.2016.1211215 　

ISSN： 1538-4101

eISSN： 1551-4005
Human Muse Cells, Nontumorigenic Pluripotent-Like Stem Cells, Have Liver Regeneration Capacity Through Specific Homing and Cell Replacement in a Mouse Model of Liver Fibrosis Peer-reviewed

Masahiro Iseki, Yoshihiro Kushida, Shohei Wakao, Takahiro Akimoto, Masamichi Mizuma, Fuyuhiko Motoi, Ryuta Asada, Shinobu Shimizu, Michiaki Unno, Gregorio Chazenbalk, Mari Dezawa

CELL TRANSPLANTATION　26　(5)　821-840　2017

DOI： 10.3727/096368916X693662 　

ISSN： 0963-6897

eISSN： 1555-3892
Therapeutic Potential of Multilineage-Differentiating Stress-Enduring Cells for Osteochondral Repair in a Rat Model Peer-reviewed

Elhussein Elbadry Mahmoud, Naosuke Kamei, Ryo Shimizu, Shohei Wakao, Mari Dezawa, Nobuo Adachi, Mitsuo Ochi

STEM CELLS INTERNATIONAL　2017　8154569　2017

DOI： 10.1155/2017/8154569 　

ISSN： 1687-966X

eISSN： 1687-9678
Muse細胞投与はマウス急性膵炎モデルを改善する

深瀬正彦, 坂田直昭, 串田良祐, 若尾昌平, 海野倫明, 出澤真理

移植　51　(総会臨時)　320-320　2016/09
Publisher: (一社)日本移植学会
ISSN： 0578-7947

eISSN： 2188-0034
再生医学における組織細胞化学的アプローチ

串田良祐, 出澤真理

組織細胞化学　2016　29-34　2016/07
Publisher: 日本組織細胞化学会
Regulation of DM-20 mRNA expression and intracellular translocation of glutathione-S-transferase pi isoform during oligodendrocyte differentiation in the adult rat spinal cord Peer-reviewed

Masaaki Kitada, Kazuya Takeda, Mari Dezawa

HISTOCHEMISTRY AND CELL BIOLOGY　146　(1)　45-57　2016/07

DOI： 10.1007/s00418-016-1421-z 　

ISSN： 0948-6143

eISSN： 1432-119X
Comparison of ASCs and BMSCs combined with atelocollagen for vocal fold scar regeneration Peer-reviewed

Nao Hiwatashi, Shigeru Hirano, Ryo Suzuki, Yoshitaka Kawai, Masanobu Mizuta, Yo Kishimoto, Ichiro Tateya, Shin-ichi Kanemaru, Tatsuo Nakamura, Mari Dezawa, Juichi Ito

LARYNGOSCOPE　126　(5)　1143-1150　2016/05

DOI： 10.1002/lary.25667 　

ISSN： 0023-852X

eISSN： 1531-4995
The expression of PLP/DM-20 mRNA is restricted to the oligodendrocyte-lineage cells in the adult rat spinal cord Peer-reviewed

Kazuya Takeda, Mari Dezawa, Masaaki Kitada

HISTOCHEMISTRY AND CELL BIOLOGY　145　(2)　147-161　2016/02

DOI： 10.1007/s00418-015-1384-5 　

ISSN： 0948-6143

eISSN： 1432-119X
Intratumoral heterogeneity of steroidogenesis in aldosterone-producing adenoma revealed by intensive double- and triple-immunostaining for CYP11B2/B1 and CYP17 Peer-reviewed

Yasuhiro Nakamura, Masaaki Kitada, Fumitoshi Satoh, Takashi Maekawa, Ryo Morimoto, Yuto Yamazaki, Kazue Ise, Celso E. Gomez-Sanchez, Sadayoshi Ito, Yoichi Arai, Mari Dezawa, Hironobu Sasano

MOLECULAR AND CELLULAR ENDOCRINOLOGY　422　(C)　57-63　2016/02

DOI： 10.1016/j.mce.2015.11.014 　

ISSN： 0303-7207
A Distinct Subpopulation of Bone Marrow Mesenchymal Stem Cells, Muse Cells, Directly Commit to the Replacement of Liver Components Peer-reviewed

H. Katagiri, Y. Kushida, M. Nojima, Y. Kuroda, S. Wakao, K. Ishida, F. Endo, K. Kume, T. Takahara, H. Nitta, H. Tsuda, M. Dezawa, S. S. Nishizuka

AMERICAN JOURNAL OF TRANSPLANTATION　16　(2)　468-483　2016/02

DOI： 10.1111/ajt.13537 　

ISSN： 1600-6135

eISSN： 1600-6143
Transplantation of Unique Subpopulation of Fibroblasts, Muse Cells, Ameliorates Experimental Stroke Possibly via Robust Neuronal Differentiation Peer-reviewed

Hiroki Uchida, Takahiro Morita, Kuniyasu Niizuma, Yoshihiro Kushida, Yasumasa Kuroda, Shohei Wakao, Hiroyuki Sakata, Yoshiya Matsuzaka, Hajime Mushiake, Teiji Tominaga, Cesario V. Borlongan, Mari Dezawa

STEM CELLS　34　(1)　160-173　2016/01

DOI： 10.1002/stem.2206 　

ISSN： 1066-5099

eISSN： 1549-4918
Muse Cells Provide the Pluripotency of Mesenchymal Stem Cells: Direct Contribution of Muse Cells to Tissue Regeneration Peer-reviewed

Mari Dezawa

CELL TRANSPLANTATION　25　(5)　849-861　2016

DOI： 10.3727/096368916X690881 　

ISSN： 0963-6897

eISSN： 1555-3892
Experimental model of small subcortical infarcts in mice with long-lasting functional disabilities Peer-reviewed

Hiroki Uchida, Hiroyuki Sakata, Miki Fujimura, Kuniyasu Niizuma, Yoshihiro Kushida, Mari Dezawa, Teiji Tominaga

BRAIN RESEARCH　1629　318-328　2015/12

DOI： 10.1016/j.brainres.2015.10.039 　

ISSN： 0006-8993

eISSN： 1872-6240
[Current status and future prospects of Muse cell research ]. Peer-reviewed

Wakao S, Dezawa M

Nihon yakurigaku zasshi. Folia pharmacologica Japonica　145　(6)　299-305　2015/06
Publisher: The Japanese Pharmacological Society
DOI： 10.1254/fpj.145.299 　

ISSN： 0015-5691
Astrocyte-Derived TGF-beta 1 Accelerates Disease Progression in ALS Mice by Interfering with the Neuroprotective Functions of Microglia and T Cells Peer-reviewed

Fumito Endo, Okiru Komine, Noriko Fujimori-Tonou, Masahisa Katsuno, Shijie Jin, Seiji Watanabe, Gen Sobue, Mari Dezawa, Tony Wyss-Coray, Koji Yamanaka

CELL REPORTS　11　(4)　592-604　2015/04

DOI： 10.1016/j.celrep.2015.03.053 　

ISSN： 2211-1247
Therapeutic Effects of Human Multilineage-Differentiating Stress Enduring (MUSE) Cell Transplantation into Infarct Brain of Mice Peer-reviewed

Tomohiro Yamauchi, Yasumasa Kuroda, Takahiro Morita, Hideo Shichinohe, Kiyohiro Houkin, Mari Dezawa, Satoshi Kuroda

PLOS ONE　10　(3)　e0116009　2015/03

DOI： 10.1371/journal.pone.0116009 　

ISSN： 1932-6203
Induction of Schwann Cells from Rat Bone Marrow Mesenchymal Stem Cells Peer-reviewed

Shohei Wakao, Masaaki Kitada, Mari Dezawa

Neural Stem Cell Assays　137-153　2015/01/30
Publisher: wiley
DOI： 10.1002/9781118308295.ch15 　
脳卒中再生医療脳梗塞をターゲットとした自己骨髄間質細胞の定位移植治療

黒田敏, 七戸秀夫, 宝金清博, 出澤真理

脳循環代謝　26　(1)　103-103　2014/11
Publisher: (一社)日本脳循環代謝学会
ISSN： 0915-9401

eISSN： 2188-7519
SUICIDE GENE THERAPY FOR GLIOMA USING MULTILINEAGE-DEFFERENTIATING STRESS ENDURING (MUSE) CELLS Peer-reviewed

Tomohiro Yamasaki, Shohei Wakao, Hiroshi Kawaji, Tomo Suzuki, Yoshinobu Kamio, Shinji Amano, Tetsuro Sameshima, Naoto Sakai, Tsutomu Tokuyama, Mari Dezawa, Hiroki Namba

NEURO-ONCOLOGY　16　2014/11

DOI： 10.1093/neuonc/nou255.64 　

ISSN： 1522-8517

eISSN： 1523-5866
Unique multipotent cells in adult human mesenchymal cell populations (vol 107, pg 8639, 2014) Peer-reviewed

Kuroda Yasumasa, Kitada Masaaki, Wakao Shohei, Nishikawa Kouki, Tanimura Yukihiro, Makinoshima Hideki, Goda Makoto, Akashi Hideo, Inutsuka Ayumu, Niwa Akira, Shigemoto Taeko, Nabeshima Yoko, Nakahata Tatsutoshi, Nabeshima Yo-ichi, Fujiyoshi Yoshinori, Dezawa Mari

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　111　(22)　8312　2014/06/03

DOI： 10.1073/pnas.1408449111 　

ISSN： 0027-8424
Human Adipose Tissue Possesses a Unique Population of Pluripotent Stem Cells with Nontumorigenic and Low Telomerase Activities: Potential Implications in Regenerative Medicine Peer-reviewed

Fumitaka Ogura, Shohei Wakao, Yasumasa Kuroda, Kenichiro Tsuchiyama, Mozhdeh Bagheri, Saleh Heneidi, Gregorio Chazenbalk, Setsuya Aiba, Mari Dezawa

STEM CELLS AND DEVELOPMENT　23　(7)　717-728　2014/04

DOI： 10.1089/scd.2013.0473 　

ISSN： 1547-3287

eISSN： 1557-8534
外科医と再生医学の最前線損傷肝修復に貢献するヒト骨髄間葉系幹細胞中の特定の細胞、Muse細胞に関する研究

片桐弘勝, 西塚哲, 串田良祐, 久米浩平, 遠藤史隆, 石田馨, 新田浩幸, 高原武志, 長谷川康, 板橋英教, 菅野将司, 石橋正久, 木村祐輔, 大塚幸喜, 肥田圭介, 佐々木章, 水野大, 出澤真理, 若林剛

日本外科学会雑誌　115　(臨増2)　218-218　2014/03
Publisher: (一社)日本外科学会
ISSN： 0301-4894
Muse cells, a novel type of non-tumorigenic pluripotent stem cells, that reside in human mesenchymal tissues. Peer-reviewed

Wakao S, Akashi H, Dezawa M

Spinal Surgery　28　(1)　17-23　2014

DOI： 10.1111/pin.12129 　
A New Age of Regenerative Medicine: Fusion of Tissue Engineering and Stem Cell Research Peer-reviewed

Teruo Okano, Mari Dezawa

ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY　297　(1)　4-5　2014/01

DOI： 10.1002/ar.22796 　

ISSN： 1932-8486

eISSN： 1932-8494
Mesenchymal Stem Cells and Their Subpopulation, Pluripotent Muse Cells, in Basic Research and Regenerative Medicine Peer-reviewed

Yasumasa Kuroda, Mari Dezawa

ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY　297　(1)　98-110　2014/01

DOI： 10.1002/ar.22798 　

ISSN： 1932-8486

eISSN： 1932-8494
Muse cells, newly found non-tumorigenic pluripotent stem cells, reside in human mesenchymal tissues Peer-reviewed

Shohei Wakao, Hideo Akashi, Yoshihiro Kushida, Mari Dezawa

PATHOLOGY INTERNATIONAL　64　(1)　1-9　2014/01

DOI： 10.1111/pin.12129 　

ISSN： 1320-5463

eISSN： 1440-1827
Transplantation of human bone marrow stromal cell-derived neuroregenrative cells promotes functional recovery after spinal cord injury in mice Peer-reviewed

Chikato Mannoji, Masao Koda, Koshiro Kamiya, Mari Dezawa, Masayuki Hashimoto, Takeo Furuya, Akihiko Okawa, Kazuhisa Takahashi, Masashi Yamazaki

ACTA NEUROBIOLOGIAE EXPERIMENTALIS　74　(4)　479-488　2014

ISSN： 0065-1400

eISSN： 1689-0035
Mesenchymal Stem Cells as a Source of Schwann Cells: Their Anticipated Use in Peripheral Nerve Regeneration Peer-reviewed

Shohei Wakao, Dai Matsuse, Mari Dezawa

CELLS TISSUES ORGANS　200　(1)　31-41　2014

DOI： 10.1159/000368188 　

ISSN： 1422-6405

eISSN： 1422-6421
Vasculogenesis in Experimental Stroke After Human Cerebral Endothelial Cell Transplantation Peer-reviewed

Hiroto Ishikawa, Naoki Tajiri, Kazutaka Shinozuka, Julie Vasconcellos, Yuji Kaneko, Hong J. Lee, Osamu Mimura, Mari Dezawa, Seung U. Kim, Cesar V. Borlongan

STROKE　44　(12)　3473-3481　2013/12

DOI： 10.1161/STROKEAHA.113.001943 　

ISSN： 0039-2499

eISSN： 1524-4628
Functional Regeneration of Laryngeal Muscle Using Bone Marrow-Derived Stromal Cells Peer-reviewed

Shin-ichi Kanemaru, Yoshiharu Kitani, Satoshi Ohno, Taeko Shigemoto, Tsuyoshi Kojima, Seiji Ishikawa, Masanobu Mizuta, Shigeru Hirano, Tatsuo Nakamura, Mari Dezawa

LARYNGOSCOPE　123　(11)　2728-2734　2013/11

DOI： 10.1002/lary.24060 　

ISSN： 0023-852X

eISSN： 1531-4995
Ischemic Stroke Brain Sends Indirect Cell Death Signals to the Heart Peer-reviewed

Hiroto Ishikawa, Naoki Tajiri, Julie Vasconcellos, Yuji Kaneko, Osamu Mimura, Mari Dezawa, Cesar V. Borlongan

STROKE　44　(11)　3175-3182　2013/11

DOI： 10.1161/STROKEAHA.113.001714 　

ISSN： 0039-2499

eISSN： 1524-4628
A Novel Approach to Collecting Satellite Cells From Adult Skeletal Muscles on the Basis of Their Stress Tolerance Peer-reviewed

Taeko Shigemoto, Yasumasa Kuroda, Shohei Wakao, Mari Dezawa

STEM CELLS TRANSLATIONAL MEDICINE　2　(7)　488-498　2013/07

DOI： 10.5966/sctm.2012-0130 　

ISSN： 2157-6564
Treatment with basic fibroblast growth factorincorporated gelatin hydrogel does not exacerbate mechanical allodynia after spinal cord contusion injury in rats Peer-reviewed

Takeo Furuya, Masayuki Hashimoto, Masao Koda, Atsushi Murata, Akihiko Okawa, Mari Dezawa, Dai Matsuse, Yasuhiko Tabata, Kazuhisa Takahashi, Masashi Yamazaki

Journal of Spinal Cord Medicine　36　(2)　134-139　2013/03

DOI： 10.1179/2045772312Y.0000000030 　

ISSN： 1079-0268 2045-7723
The Elite and Stochastic Model for iPS Cell Generation: Multilineage-Differentiating Stress Enduring (Muse) Cells are Readily Reprogrammable into iPS Cells Peer-reviewed

Shohei Wakao, Masaaki Kitada, Mari Dezawa

CYTOMETRY PART A　83A　(1)　18-26　2013/01

DOI： 10.1002/cyto.a.22069 　

ISSN： 1552-4922

eISSN： 1552-4930
Transplantation of bone marrow stromal cell-derived neural precursor cells ameliorates deficits in a rat model of complete spinal cord transection. International-journal Peer-reviewed

Misaki Aizawa-Kohama, Toshiki Endo, Masaaki Kitada, Shohei Wakao, Akira Sumiyoshi, Dai Matsuse, Yasumasa Kuroda, Takahiro Morita, Jorge J Riera, Ryuta Kawashima, Teiji Tominaga, Mari Dezawa

Cell transplantation　22　(9)　1613-25　2013

DOI： 10.3727/096368912X658791 　

ISSN： 0963-6897

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After severe spinal cord injury, spontaneous functional recovery is limited. Numerous studies have demonstrated cell transplantation as a reliable therapeutic approach. However, it remains unknown whether grafted neuronal cells could replace lost neurons and reconstruct neuronal networks in the injured spinal cord. To address this issue, we transplanted bone marrow stromal cell-derived neural progenitor cells (BM-NPCs) in a rat model of complete spinal cord transection 9 days after the injury. BM-NPCs were induced from bone marrow stromal cells (BMSCs) by gene transfer of the Notch-1 intracellular domain followed by culturing in the neurosphere method. As reported previously, BM-NPCs differentiated into neuronal cells in a highly selective manner in vitro. We assessed hind limb movements of the animals weekly for 7 weeks to monitor functional recovery after local injection of BM-NPCs to the transected site. To test the sensory recovery, we performed functional magnetic resonance imaging (fMRI) using electrical stimulation of the hind limbs. In the injured spinal cord, transplanted BM-NPCs were confirmed to express neuronal markers 7 weeks following the transplantation. Grafted cells successfully extended neurites beyond the transected portion of the spinal cord. Adjacent localization of synaptophysin and PSD-95 in the transplanted cells suggested synaptic formations. These results indicated survival and successful differentiation of BM-NPCs in the severely injured spinal cord. Importantly, rats that received BM-NPCs demonstrated significant motor recovery when compared to the vehicle injection group. Volumes of the fMRI signals in somatosensory cortex were larger in the BM-NPC-grafted animals. However, neuronal activity was diverse and not confined to the original hind limb territory in the somatosensory cortex. Therefore, reconstruction of neuronal networks was not clearly confirmed. Our results indicated BM-NPCs as an effective method to deliver neuronal lineage cells in a severely injured spinal cord. However, reestablishment of neuronal networks in completed transected spinal cord was still a challenging task.
Autologous mesenchymal stem cell-derived dopaminergic neurons function in parkinsonian macaques Peer-reviewed

Takuya Hayashi, Shohei Wakao, Masaaki Kitada, Takayuki Ose, Hiroshi Watabe, Yasumasa Kuroda, Kanae Mitsunaga, Dai Matsuse, Taeko Shigemoto, Akihito Ito, Hironobu Ikeda, Hidenao Fukuyama, Hirotaka Onoe, Yasuhiko Tabata, Mari Dezawa

JOURNAL OF CLINICAL INVESTIGATION　123　(1)　272-284　2013/01

DOI： 10.1172/JCI62516 　

ISSN： 0021-9738
Functional melanocytes are readily reprogrammable from multilineage- differentiating stress-enduring (muse) cells, distinct stem cells in human fibroblasts Peer-reviewed

Kenichiro Tsuchiyama, Shohei Wakao, Yasumasa Kuroda, Fumitaka Ogura, Makoto Nojima, Natsue Sawaya, Kenshi Yamasaki, Setsuya Aiba, Mari Dezawa

Journal of Investigative Dermatology　133　(10)　2425-2435　2013
Publisher: Nature Publishing Group
DOI： 10.1038/jid.2013.172 　

ISSN： 1523-1747 0022-202X
Isolation, culture and evaluation of multilineage-differentiating stress-enduring (Muse) cells Peer-reviewed

Yasumasa Kuroda, Shohei Wakao, Masaaki Kitada, Toru Murakami, Makoto Nojima, Mari Dezawa

Nature Protocols　8　(7)　1391-1415　2013
Publisher: Nature Publishing Group
DOI： 10.1038/nprot.2013.076 　

ISSN： 1750-2799 1754-2189
Morphologic and Gene Expression Criteria for Identifying Human Induced Pluripotent Stem Cells Peer-reviewed

Shohei Wakao, Masaaki Kitada, Yasumasa Kuroda, Fumitaka Ogura, Toru Murakami, Akira Niwa, Mari Dezawa

PLOS ONE　7　(12)　e48677　2012/12

DOI： 10.1371/journal.pone.0048677 　

ISSN： 1932-6203
Regenerative Effects of Mesenchymal Stem Cells: Contribution of Muse Cells, a Novel Pluripotent Stem Cell Type that Resides in Mesenchymal Cells. Peer-reviewed

Wakao S, Kuroda Y, Ogura F, Shigemoto T, Dezawa M

Cells　1　(4)　1045-1060　2012/11

DOI： 10.3390/cells1041045 　
Muse cells and induced pluripotent stem cell: implication of the elite model Peer-reviewed

Masaaki Kitada, Shohei Wakao, Mari Dezawa

CELLULAR AND MOLECULAR LIFE SCIENCES　69　(22)　3739-3750　2012/11

DOI： 10.1007/s00018-012-0994-5 　

ISSN： 1420-682X

eISSN： 1420-9071
A novel type of adult human pluripotent stem cells (Muse cells) that exist among mesenchymal tissues and their primary role in iPS cell generation. Peer-reviewed

Dezawa Mari

XXII INTERNATIONAL SYMPOSIUM ON MORPHOLOGICAL SCIENCES (ISMS)　27-32　2012
海外再生医療企業のトップに聞く : 再生医療産業成功のキーワード

畠賢一郎, 田畑泰彦, 出澤真理

再生医療 : 日本再生医療学会雑誌　11　(3)　206-219　2012/01
Publisher: メディカルレビュー社
ISSN： 1347-7919
Isolation of adult human pluripotent stem cells from mesenchymal cell populations and their application to liver damages Peer-reviewed

Shohei Wakao, Masaaki Kitada, Yasumasa Kuroda, Mari Dezawa

Methods in Molecular Biology　826　89-102　2012

DOI： 10.1007/978-1-61779-468-1_8 　

ISSN： 1064-3745
Parkinson's Disease and Mesenchymal Stem Cells: Potential for Cell-Based Therapy Peer-reviewed

Masaaki Kitada, Mari Dezawa

PARKINSONS DISEASE　2012　873706　2012

DOI： 10.1155/2012/873706 　

ISSN： 2090-8083
Functional Regeneration of Laryngeal Muscle Using Bone Marrow Derived Stromal Cells

KANEMARU Shin-ichi, KITANI Yoshiharu, OHONO Satoshi, KOJIMA Tsuyoshi, ISHIKAWA Seiji, HIRANO Shigeru, NAKAMURA Tatsuo, DEZAWA Mari

LARYNX JAPAN　23　(2)　66-70　2011/12/01
Publisher: THE JAPAN LARYNGOLOGICAL ASSOCIATION
DOI： 10.5426/larynx.23.66 　

ISSN： 0915-6127

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Bone marrow derived stromal cells (BSCs) which contain mesenchymal stem cells have great potential as therapeutic agents.Dezawa et al. reported a method for inducing skeletal muscle lineage cells from human and rat general adherent BSCs with 89% efficiency.Induced muscle progenitor cells (IMCs) were shown to differentiate into muscle fibers upon transplantation into degenerated muscles of rats and mdx-nude mice.However, the ability of regenerated muscle to restore skeletal muscle function in a large animal model such as canine has yet to be determined. <BR>In this study, we performed BSC⁄IMC transplantation into injured canine posterior cricoarytenoid muscles.We investigated the ability of BSC⁄IMC transplantation to promote functional regeneration of posterior cricoarytenoid muscles by fiberscopic analysis of vocal fold movement.As a control, a gelatin sponge scaffold without additional cells was transplanted into the injured area. <BR>Results indicated that auto-BSC⁄IMC transplantation effectively restored vocal fold movement, whereas scaffold alone or allo-BSC⁄IMC transplantation did not.Histological examination revealed that, in cases of good recovery, muscle regeneration occurred in the area of cell transplantation, while scar formation without muscle regeneration was observed under control conditions.
[Tissue repairing cells that exist among mesenchymal stem cells; their potential for cell-based therapy]. Peer-reviewed

Dezawa M

Nihon rinsho. Japanese journal of clinical medicine　69　(12)　2128-2135　2011/12
Publisher:
ISSN： 0047-1852
Bone Marrow Mesenchymal Cells: How Do They Contribute to Tissue Repair and Are They Really Stem Cells? Peer-reviewed

Yasumasa Kuroda, Masaaki Kitada, Shohei Wakao, Mari Dezawa

ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS　59　(5)　369-378　2011/10

DOI： 10.1007/s00005-011-0139-9 　

ISSN： 0004-069X
Combined Transplantation of Bone Marrow Stromal Cell-Derived Neural Progenitor Cells with a Collagen Sponge and Basic Fibroblast Growth Factor Releasing Microspheres Enhances Recovery After Cerebral Ischemia in Rats Peer-reviewed

Dai Matsuse, Masaaki Kitada, Fumitaka Ogura, Shohei Wakao, Misaki Kohama, Jun-ichi Kira, Yasuhiko Tabata, Mari Dezawa

TISSUE ENGINEERING PART A　17　(15-16)　1993-2004　2011/08

DOI： 10.1089/ten.tea.2010.0585 　

ISSN： 1937-3341
Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts Peer-reviewed

Shohei Wakao, Masaaki Kitada, Yasumasa Kuroda, Taeko Shigemoto, Dai Matsuse, Hideo Akashi, Yukihiro Tanimura, Kenichiro Tsuchiyama, Tomohiko Kikuchi, Makoto Goda, Tatsutoshi Nakahata, Yoshinori Fujiyoshi, Mari Dezawa

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　108　(24)　9875-9880　2011/06

DOI： 10.1073/pnas.1100816108 　

ISSN： 0027-8424
Transplantation of human bone marrow stromal cell-derived Schwann cells reduces cystic cavity and promotes functional recovery after contusion injury of adult rat spinal cord Peer-reviewed

Takahito Kamada, Masao Koda, Mari Dezawa, Reiko Anahara, Yoshiro Toyama, Katsunori Yoshinaga, Masayuki Hashimoto, Shuhei Koshizuka, Yutaka Nishio, Chikato Mannoji, Akihiko Okawa, Masashi Yamazaki

NEUROPATHOLOGY　31　(1)　48-58　2011/02

DOI： 10.1111/j.1440-1789.2010.01130.x 　

ISSN： 0919-6544
Lectins as a Tool for Detecting Neural Stem/Progenitor Cells in the Adult Mouse Brain Peer-reviewed

Masaaki Kitada, Yasumasa Kuroda, Mari Dezawa

ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY　294　(2)　305-321　2011/02

DOI： 10.1002/ar.21311 　

ISSN： 1932-8486
スナネズミ虚血脳に移植したヒト骨髄間質細胞由来神経細胞の細胞癒合能力の検討

徐海雁, 三木一徳, 石橋哲, 孫立元, 関矢一郎, 宗田大, 出澤真理, 水澤英洋

臨床神経学　50　(12)　1171-1171　2010/12

ISSN： 0009-918X
Transplantation of neuronal cells induced from human mesenchymal stem cells improves neurological functions after stroke without cell fusion

Haiyan Xu, Kazunori Miki, Satoru Ishibashi, Jun Inoue, Liyuan Sun, Shu Endo, Ichiro Sekiya, Takeshi Muneta, Joji Inazawa, Mari Dezawa, Hidehiro Mizusawa

Journal of Neuroscience Research　88　(16)　3598-3609　2010/12

DOI： 10.1002/jnr.22501 　

ISSN： 0360-4012 1097-4547
Transplantation of Neuronal Cells Induced From Human Mesenchymal Stem Cells Improves Neurological Functions After Stroke Without Cell Fusion Peer-reviewed

Haiyan Xu, Kazunori Miki, Satoru Ishibashi, Jun Inoue, Liyuan Sun, Shu Endo, Ichiro Sekiya, Takeshi Muneta, Joji Inazawa, Mari Dezawa, Hidehiro Mizusawa

JOURNAL OF NEUROSCIENCE RESEARCH　88　(16)　3598-3609　2010/12

DOI： 10.1002/jnr.22501 　

ISSN： 0360-4012

eISSN： 1097-4547
Human Umbilical Cord-Derived Mesenchymal Stromal Cells Differentiate Into Functional Schwann Cells That Sustain Peripheral Nerve Regeneration Peer-reviewed

Dai Matsuse, Masaaki Kitada, Misaki Kohama, Kouki Nishikawa, Hideki Makinoshima, Shohei Wakao, Yoshinori Fujiyoshi, Toshio Heike, Tatsutoshi Nakahata, Hidenori Akutsu, Akihiro Umezawa, Hideo Harigae, Jun-ichi Kira, Mari Dezawa

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY　69　(9)　973-985　2010/09

DOI： 10.1097/NEN.0b013e3181eff6dc 　

ISSN： 0022-3069
Long-term observation of auto-cell transplantation in non-human primate reveals safety and efficiency of bone marrow stromal cell-derived Schwann cells in peripheral nerve regeneration Peer-reviewed

Shohei Wakao, Takuya Hayashi, Masaaki Kitada, Misaki Kohama, Dai Matsue, Noboru Teramoto, Takayuki Ose, Yutaka Itokazu, Kazuhiro Koshino, Hiroshi Watabe, Hidehiro Iida, Tomoaki Takamoto, Yasuhiko Tabata, Mari Dezawa

EXPERIMENTAL NEUROLOGY　223　(2)　537-547　2010/06

DOI： 10.1016/j.expneurol.2010.01.022 　

ISSN： 0014-4886
Unique multipotent cells in adult human mesenchymal cell populations Peer-reviewed

Yasumasa Kuroda, Masaaki Kitada, Shohei Wakao, Kouki Nishikawa, Yukihiro Tanimura, Hideki Makinoshima, Makoto Goda, Hideo Akashi, Ayumu Inutsuka, Akira Niwa, Taeko Shigemoto, Yoko Nabeshima, Tatsutoshi Nakahata, Yo-ichi Nabeshima, Yoshinori Fujiyoshi, Mari Dezawa

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　107　(19)　8639-8643　2010/05

DOI： 10.1073/pnas.0911647107 　

ISSN： 0027-8424
Vision

Hiroto Ishikawa, Naohiro Ikeda, Sanae Kanno, Tomohiro Ikeda, Osamu Mimura, Mari Dezawa

Handbook of Physics in Medicine and Biology　10-10-20　2010/01/01
Publisher: CRC Press
DOI： 10.1201/9781420075250 　
Transplantation of cultured choroid plexus epithelial cells via cerebrospinal fluid shows prominent neuroprotective effects against acute ischemic brain injury in the rat Peer-reviewed

Naoya Matsumoto, Akihiko Taguchi, Hitoshi Kitayama, Yumi Watanabe, Masayoshi Ohta, Tomoyuki Yoshihara, Yutaka Itokazu, Mari Dezawa, Yoshihisa Suzuki, Hisashi Sugimoto, Makoto Noda, Chizuka Idel

NEUROSCIENCE LETTERS　469　(3)　283-288　2010/01

DOI： 10.1016/j.neulet.2009.09.060 　

ISSN： 0304-3940
局所脳虚血モデルに対するヒト骨髄間葉系幹細胞由来神経細胞の移植効果の検討

徐海雁, 三木一徳, 石橋哲, 関矢一郎, 宗田大, 出澤真理, 水澤英洋

臨床神経学　49　(12)　1036-1036　2009/12

ISSN： 0009-918X
Isolation and Characterization of Patient-derived, Toxic, High Mass Amyloid beta-Protein (A beta) Assembly from Alzheimer Disease Brains Peer-reviewed

Akihiko Noguchi, Satoko Matsumura, Mari Dezawa, Mari Tada, Masako Yanazawa, Akane Ito, Manami Akioka, Satoru Kikuchi, Michio Sato, Shouji Ideno, Munehiro Noda, Atsushi Fukunari, Shin-ichi Muramatsu, Yutaka Itokazu, Kazuki Sato, Hitoshi Takahashi, David B. Teplow, Yo-ichi Nabeshima, Akiyoshi Kakita, Kazutomo Imahori, Minako Hoshi

JOURNAL OF BIOLOGICAL CHEMISTRY　284　(47)　32895-32905　2009/11

DOI： 10.1074/jbc.M109.000208 　

ISSN： 0021-9258
Pancreatic cancer cells activate CCL5 expression in mesenchymal stromal cells through the insulin-like growth factor-I pathway Peer-reviewed

Hideki Makinoshima, Mari Dezawa

FEBS LETTERS　583　(22)　3697-3703　2009/11

DOI： 10.1016/j.febslet.2009.10.061 　

ISSN： 0014-5793
Committed neural progenitor cells derived from genetically modified bone marrow stromal cells ameliorate deficits in a rat model of stroke Peer-reviewed

Makoto Hayase, Masaaki Kitada, Shohei Wakao, Yutaka Itokazu, Kazuhiko Nozaki, Nobuo Hashimoto, Yasushi Takagi, Mari Dezawa

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM　29　(8)　1409-1420　2009/08

DOI： 10.1038/jcbfm.2009.62 　

ISSN： 0271-678X
Practical Induction System for Dopamine-Producing Cells from Bone Marrow Stromal Cells Using Spermine-Pullulan-Mediated Reverse Transfection Method Peer-reviewed

Kentaro Nagane, Masaaki Kitada, Shohei Wakao, Mari Dezawa, Yasuhiko Tabata

TISSUE ENGINEERING PART A　15　(7)　1655-1665　2009/07

DOI： 10.1089/ten.tea.2008.0453 　

ISSN： 1937-3341
【パーキンソン病基礎・臨床研究のアップデート】治療再生療法骨髄間葉系細胞を用いた自己細胞移植の可能性 Peer-reviewed

林拓也, 出澤真理

日本臨床　67　(増刊4 パーキンソン病)　429-434　2009/06
Publisher: (株)日本臨床社
ISSN： 0047-1852
Peripheral nerve regeneration by transplantation of BMSC-derived Schwann cells as chitosan gel sponge scaffolds Peer-reviewed

Namiko Ishikawa, Yoshihisa Suzuki, Mari Dezawa, Kazuya Kataoka, Masayoshi Ohta, Hirotomi Cho, Chizuka Ide

JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A　89A　(4)　1118-1124　2009/06

DOI： 10.1002/jbm.a.32389 　

ISSN： 1549-3296
Induction system of neural and muscle lineage cells from bone marrow stromal cells; a new strategy for tissue reconstruction in degenerative diseases Peer-reviewed

Masaaki Kitada, Mari Dezawa

HISTOLOGY AND HISTOPATHOLOGY　24　(5)　631-642　2009/05

DOI： 10.14670/HH-24.631 　

ISSN： 0213-3911

eISSN： 1699-5848
ヒト骨髄間質細胞由来神経細胞を用いた局所脳虚血モデルの移植治療

徐海雁, 三木一徳, 石橋哲, 関矢一郎, 宗田大, 出澤真理, 水澤英洋

臨床神経学　48　(12)　1181-1181　2008/12

ISSN： 0009-918X
Reduction of cystic cavity, promotion of axonal regeneration and sparing, and functional recovery with transplanted bone marrow stromal cell-derived Schwann cells after contusion injury to the adult rat spinal cord Peer-reviewed

Yukio Someya, Masao Koda, Mari Dezawa, Tomoko Kadota, Masayuki Hashimoto, Takahito Kamada, Yutaka Nishio, Ryo Kadota, Chikato Mannoji, Tomohiro Miyashita, Akihiko Okawa, Katsunori Yoshinaga, Masashi Yamazaki

JOURNAL OF NEUROSURGERY-SPINE　9　(6)　600-610　2008/12

DOI： 10.3171/SPI.2008.9.08135 　

ISSN： 1547-5654
[Neural repair]. Peer-reviewed

Kitada M, Dezawa M

Nihon rinsho. Japanese journal of clinical medicine　66　(5)　921-925　2008/05

ISSN： 0047-1852
Systematic neuronal and muscle induction systems in bone marrow stromal cells: the potential for tissue reconstruction in neurodegenerative and muscle degenerative diseases Peer-reviewed

Mari Dezawa

MEDICAL MOLECULAR MORPHOLOGY　41　(1)　14-19　2008/03

DOI： 10.1007/s00795-007-0389-0 　

ISSN： 1860-1480
Peripheral nerve regeneration through the space formed by a chitosan gel sponge Peer-reviewed

N. Ishikawa, Y. Suzuki, M. Ohta, H. Cho, S. Suzuki, M. Dezawa, C. Ide

JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A　83A　(1)　33-40　2007/10

DOI： 10.1002/jbm.a.31126 　

ISSN： 1549-3296
Peripheral nerve regeneration by the in vitro differentiated-human bone marrow stromal cells with Schwann cell property Peer-reviewed

Satoshi Shimizu, Masaaki Kitada, Hiroto Ishikawa, Yutaka Itokazu, Shohei Wakao, Mari Dezawa

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　359　(4)　915-920　2007/08

DOI： 10.1016/j.bbrc.2007.05.212 　

ISSN： 0006-291X
Neuroprotective effect of bone marrow-derived mononuclear cells promoting functional recovery from spinal cord injury Peer-reviewed

Tomoyuki Yoshihara, Masayoshi Ohta, Yutaka Itokazu, Naoya Matsumoto, Mari Dezawa, Yoshihisa Suzuki, Akihiko Taguchi, Yumi Watanabe, Yasushi Adachi, Susumu Ikehara, Hisashi Sugimoto, Chizuka Ide

JOURNAL OF NEUROTRAUMA　24　(6)　1026-1036　2007/06

DOI： 10.1089/neu.2007.132R 　

ISSN： 0897-7151
[Insights into auto-transplantation--the unexpected discovery of transdifferentiation systems in bone marrow stromal cells and its application]. Peer-reviewed

Dezawa M

Brain and nerve = Shinkei kenkyu no shinpo　59　(5)　503-508　2007/05
Publisher:
ISSN： 1881-6096
Induction system of neuronal and muscle cells from bone marrow stromal cells and applications for degenerative diseases

DEZAWA Mari

Inflammation and Regeneration　27　(2)　96-101　2007/03/25
Publisher: The Japanese Society of Inflammation and Regeneration
DOI： 10.2492/inflammregen.27.96 　

ISSN： 1346-8022

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Bone marrow stromal cells (MSCs) have great potential as therapeutic agents since they are easily isolated and can be expanded from patients without serious ethical or technical problems. Recently, new methods for the highly efficient and specific induction of functional neuronal cells and skeletal muscle cells have been found in MSCs. These induced cells were transplanted into animal models of spinal cord injury, stroke, Parkinson's disease and muscle degeneration, resulting in the successful integration of transplanted cells and improvement in the behavior of the transplanted animals. Here I describe the discovery of these induction systems and focus on the potential use of MSC-derived cells for neuro- and muscle-degenerative diseases.
脳虚血病変に対する骨髄細胞と複製不能型VEGF産生HSV1vectorを用いた複合治療の可能性

三木義仁, 宮武伸一, 野々口直助, 趙明珠, 池田直廉, 古玉大介, 木村文治, Coffin R.S., 出澤真理, 黒岩敏彦

脳卒中　29　(2)　390-390　2007/03
Publisher: (一社)日本脳卒中学会
ISSN： 0912-0726

eISSN： 1883-1923
[Insights into auto-transplantation: the unexpected discovery of transdifferentiation systems in bone marrow stromal cells]. Peer-reviewed

Dezawa M

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　52　(2)　158-165　2007/02

ISSN： 0039-9450
Insights into autotransplantation: the unexpected discovery of specific induction systems in bone marrow stromal cells Peer-reviewed

M. Dezawa

CELLULAR AND MOLECULAR LIFE SCIENCES　63　(23)　2764-2772　2006/11

DOI： 10.1007/s00018-006-6191-7 　

ISSN： 1420-682X
Novel therapeutic strategy for stroke in rats by bone marrow stromal cells and ex vivo HGF gene transfer with HSV-1 vector Peer-reviewed

Ming-Zhu Zhao, Naosuke Nonoguchi, Naokado Ikeda, Takuji Watanabe, Daisuke Furutama, Daisuke Miyazawa, Hiroshi Funakoshi, Yoshinaga Kajimoto, Toshikazu Nakamura, Mari Dezawa, Masa-Aki Shibata, Yoshinori Otsuki, Robert S. Coffin, Wei-Dong Liu, Toshihiko Kuroiwa, Shin-Ichi Miyatake

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM　26　(9)　1176-1188　2006/09

DOI： 10.1038/sj.jcbfm.9600273 　

ISSN： 0271-678X

eISSN： 1559-7016
Effects of bone marrow stromal cell injection in an experimental glaucoma model Peer-reviewed

S Yu, T Tanabe, M Dezawa, H Ishikawa, N Yoshimura

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　344　(4)　1071-1079　2006/06

DOI： 10.1016/j.bbrc.2006.03.231 　

ISSN： 0006-291X
Effects of vibration and hyaluronic acid on activation of three-dimensional cultured chondrocytes Peer-reviewed

R Takeuchi, T Saito, H Ishikawa, H Takigami, M Dezawa, C Ide, Y Itokazu, M Ikeda, T Shiraishi, S Morishita

ARTHRITIS AND RHEUMATISM　54　(6)　1897-1905　2006/06

DOI： 10.1002/art.21895 　

ISSN： 0004-3591
Increase in bFGF-responsive neural progenitor population following contusion injury of the adult rodent spinal cord Peer-reviewed

Y Xu, M Kitada, M Yamaguchi, M Dezawa, C Ide

NEUROSCIENCE LETTERS　397　(3)　174-179　2006/04

DOI： 10.1016/j.neulet.2005.12.051 　

ISSN： 0304-3940
脳虚血病変に対する複製不能型HSV-1ベクターによるFGF-2遺伝子導入骨髄細胞の有用性

池田直廉, 宮武伸一, 野々口直助, 趙明珠, 三木義仁, 古玉大介, 木村文治, 出澤真理, Coffin R.S., 黒岩敏彦

脳卒中　28　(1)　210-210　2006/03
Publisher: (一社)日本脳卒中学会
ISSN： 0912-0726

eISSN： 1883-1923
脳虚血病変に対する骨髄細胞と複製不能型VEGF産生HSV1ベクターによる複合治療の可能性

三木義仁, 宮武伸一, 野々口直助, 趙明珠, 池田直廉, 古玉大介, 木村文治, Coffin R.S., 出澤真理, 黒岩敏彦

脳卒中　28　(1)　210-210　2006/03
Publisher: (一社)日本脳卒中学会
ISSN： 0912-0726

eISSN： 1883-1923
Choroid plexus ependymal cells host neural progenitor cells in the rat Peer-reviewed

Y Itokazu, M Kitada, M Dezawa, A Mizoguchi, N Matsumoto, A Shimizu, C Ide

GLIA　53　(1)　32-42　2006/01

DOI： 10.1002/glia.20255 　

ISSN： 0894-1491
Bone marrow stromal cells that enhanced fibroblast growth factor-2 secretion by herpes simplex virus vector improve neurological outcome after transient focal cerebral ischemia in rats Peer-reviewed

N Ikeda, N Nonoguchi, MZ Zhao, T Watanabe, Y Kajimoto, D Furutama, F Kimura, M Dezawa, RS Coffin, Y Otsuki, T Kuroiwa, SI Miyatake

STROKE　36　(12)　2725-2730　2005/12

DOI： 10.1161/01.STR.000019006.88896.d3 　

ISSN： 0039-2499

eISSN： 1524-4628
Behavioral and histological evaluation of a focal cerebral infarction rat model transplanted with neurons induced from bone marrow stromal cells Peer-reviewed

T Mimura, M Dezawa, H Kanno, Yamamoto, I

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY　64　(12)　1108-1117　2005/12

DOI： 10.1097/01.jnen.0000190068.03009.b5 　

ISSN： 0022-3069
Marrow stromal cells: Implications in health and disease in the nervous system Peer-reviewed

M Dezawa, M Hoshino, Y Nabeshima, C Ide

CURRENT MOLECULAR MEDICINE　5　(7)　723-732　2005/11

DOI： 10.2174/156652405774641070 　

ISSN： 1566-5240
Future views and challenges to the peripheral nerve regeneration by cell based therapy Peer-reviewed

Mari Dezawa

Clinical Neurology　45　(11)　877-879　2005/11

ISSN： 0009-918X
Potential of bone marrow stromal cells in applications for neuro-degenerative, neuro-traumatic and muscle degenerative diseases Peer-reviewed

Mari Dezawa, Hiroto Ishikawa, Mikio Hoshino, Yutaka Itokazu, Yo-Ichi Nabeshima

Current Neuropharmacology　3　(4)　257-266　2005/10

DOI： 10.2174/157015905774322507 　

ISSN： 1570-159X
The role of von Hippel-Lindau protein in the differentiation of neural progenitor cells under normoxic and anoxic conditions Peer-reviewed

Y Tanaka, H Kanno, M Dezawa, T Mimura, A Kubo, Yamamoto, I

NEUROSCIENCE LETTERS　383　(1-2)　28-32　2005/07

DOI： 10.1016/j.neulet.2005.03.056 　

ISSN： 0304-3940
Specific induction of neurons and Schwann cells from bone marrow stromal cells and application to neurodegenerative diseases Peer-reviewed

M Dezawa

NEUROLOGICAL SURGERY　33　(7)　645-649　2005/07

ISSN： 0301-2603
Bone marrow stromal cells generate muscle cells and repair muscle degeneration Peer-reviewed

M Dezawa, H Ishikawa, Y Itokazu, T Yoshihara, M Hoshino, S Takeda, C Ide, Y Nabeshima

SCIENCE　309　(5732)　314-317　2005/07

DOI： 10.1126/science.1110364 　

ISSN： 0036-8075
Conditioned medium of the primary culture of rat choroid plexus epithelial (modified ependymal) cells enhances neurite outgrowth and survival of hippocampal neurons Peer-reviewed

Y Watanabe, N Matsumoto, M Dezawa, Y Itokazu, T Yoshihara, C Ide

NEUROSCIENCE LETTERS　379　(3)　158-163　2005/05

DOI： 10.1016/j.neulet.2004.12.068 　

ISSN： 0304-3940
Neurogenesis in the ependymal layer of the adult rat 3rd ventricle Peer-reviewed

Y Xu, N Tamamaki, T Noda, K Kimura, Y Itokazu, N Matsumoto, M Dezawa, C Ide

EXPERIMENTAL NEUROLOGY　192　(2)　251-264　2005/04

DOI： 10.1016/j.expneurol.2004.12.021 　

ISSN： 0014-4886
Treatment of neurodegenerative diseases using adult bone marrow stromal cell-derived neurons Peer-reviewed

M Dezawa, M Hoshino, C Ide

EXPERT OPINION ON BIOLOGICAL THERAPY　5　(4)　427-435　2005/04

DOI： 10.1517/14712598.4.427 　

ISSN： 1471-2598
Effect of GDNF gene transfer into axotomized retinal ganglion cells using in vivo electroporation with a contact lens-type electrode Peer-reviewed

H Ishikawa, M Takano, N Matsumoto, H Sawada, C Ide, O Mimura, M Dezawa

GENE THERAPY　12　(4)　289-298　2005/02

DOI： 10.1038/sj.gt.3302277 　

ISSN： 0969-7128
Cell transplantation for neurodegenerative and neurotraumatic disorders. Peer-reviewed

Dezawa, M, Matsumoto, N, Ohta, M, Itokazu, Y, Suzuki, Y, Ide

Current Trends in Neurology　1　38-49　2005
Transplantation of bone marrow stromal cell-derived Schwann cells promotes axonal regeneration and functional recovery after complete transection of adult rat spinal cord Peer-reviewed

T Kamada, M Koda, M Dezawa, K Yoshinaga, M Hashimoto, S Koshizuka, Y Nishio, H Morlya, M Yamazaki

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY　64　(1)　37-45　2005/01

ISSN： 0022-3069
Novel heparin/alginate gel combined with basic fibroblast growth factor promotes nerve regeneration in rat sciatic nerve Peer-reviewed

M Ohta, Y Suzuki, H Chou, N Ishikawa, S Suzuki, M Tanihara, Y Suzuki, Y Mizushima, M Dezawa, C Ide

JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A　71A　(4)　661-668　2004/12

DOI： 10.1002/jbm.a.30194 　

ISSN： 0021-9304
Novel heparin/alginate gel combined with basic fibroblast growth factor promotes nerve regeneration in rat sciatic nerve. Peer-reviewed

Ohta M, Suzuki Y, Chou H, Ishikawa N, Suzuki S, Tanihara M, Suzuki Y, Mizushima Y, Dezawa M, Ide C

Journal of biomedical materials research. Part A　71　(4)　661-668　2004/12

DOI： 10.1002/jbm.a.30194 　

ISSN： 1549-3296
Peripheral nerve regeneration by transplantation of bone marrow stromal cell-derived Schwann cells in adult rats Peer-reviewed

T Mimura, M Dezawa, H Kanno, H Sawada, Yamamoto, I

JOURNAL OF NEUROSURGERY　101　(5)　806-812　2004/11

DOI： 10.3171/jns.2004.101.5.0806 　

ISSN： 0022-3085
Tlx, an orphan nuclear receptor, regulates cell numbers and astrocyte development in the developing retina Peer-reviewed

T Miyawaki, A Uemura, M Dezawa, RT Yu, C Ide, S Nishikawa, Y Honda, Y Tanabe, T Tanabe

JOURNAL OF NEUROSCIENCE　24　(37)　8124-8134　2004/09

DOI： 10.1523/JNEUROSCI.2235-04.2004 　

ISSN： 0270-6474
Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation Peer-reviewed

M Ohta, Y Suzuki, T Noda, Y Ejiri, M Dezawa, K Kataoka, H Chou, N Ishikawa, N Matsumoto, Y Iwashita, E Mizuta, S Kuno, C Ide

EXPERIMENTAL NEUROLOGY　187　(2)　266-278　2004/06

DOI： 10.1016/j.expneurol.2004.01.021 　

ISSN： 0014-4886
Implantation of neural stem cells via cerebrospinal fluid into the injured root Peer-reviewed

M Ohta, Y Suzuki, T Noda, K Kataoka, H Chou, N Ishikawa, M Kitada, N Matsumoto, M Dezawa, S Suzuki, C Ide

NEUROREPORT　15　(8)　1249-1253　2004/06

DOI： 10.1097/01.wnr.0000129998.72184.e1 　

ISSN： 0959-4965
Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation Peer-reviewed

M Dezawa, H Kanno, M Hoshino, H Cho, N Matsumoto, Y Itokazu, N Tajima, H Yamada, H Sawada, H Ishikawa, T Mimura, M Kitada, Y Suzuki, C Ide

JOURNAL OF CLINICAL INVESTIGATION　113　(12)　1701-1710　2004/06

DOI： 10.1172/JCI200420935 　

ISSN： 0021-9738
核内受容体Tlxの網膜発達制御機序の解析

宮脇貴也, 植村明嘉, 出澤真理, 田辺晶代

日本眼科学会雑誌　108　(臨増)　278-278　2004/03
Publisher: (公財)日本眼科学会
ISSN： 0029-0203
Study of drug effects of calcium channel blockers on retinal degeneration of rd mouse Peer-reviewed

Y Takano, H Ohguro, M Dezawa, H Ishikawa, H Yamazaki, Ohguro, I, K Mamiya, T Metoki, F Ishikawa, M Nakazawa

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　313　(4)　1015-1022　2004/01

DOI： 10.1016/j.bbrc.2003.12.034 　

ISSN： 0006-291X
「組織移植と細胞移植」－神経疾患の再生医療（その現状と将来）－ Invited

出澤真理, 松本直也, 井出千束

Clinical Neuroscience　21　(10)　1134-1138　2003/10
Transfer of the von Hippel-Lindau gene to neuronal progenitor cells in treatment for Parkinson's disease Peer-reviewed

H Yamada, M Dezawa, S Shimazu, M Baba, H Sawada, Y Kuroiwa, Yamamoto, I, H Kanno

ANNALS OF NEUROLOGY　54　(3)　352-359　2003/09

DOI： 10.1002/ana.10672 　

ISSN： 0364-5134
Increment of murine spermatogonial cell number by gonadotropin-releasing hormone analogue is independent of stem cell factor c-kit signal Peer-reviewed

M Ohmura, T Ogawa, M Ono, M Dezawa, M Hosaka, Y Kubota, H Sawada

BIOLOGY OF REPRODUCTION　68　(6)　2304-2313　2003/06

DOI： 10.1095/biolreprod.102.013276 　

ISSN： 0006-3363
Nilvadipine, a Ca2+ antagonist, effectively preserves photoreceptor functions in royal college of surgeons rat Peer-reviewed

H Yamazaki, H Ohguro, Maruyama, I, Y Takano, T Metoki, F Ishikawa, Y Miyagawa, K Mamiya, M Nakazawa, H Sawada, M Dezawa

NEURAL BASIS OF EARLY VISION　11　168-172　2003
The interaction between regenerating nerve axons and glial cells observed by electron microscopy

DEZAWA Mari

kenbikyo　37　(2)　141-144　2002/07/31
Publisher: The Japanese Society of Microscopy
DOI： 10.11410/kenbikyo1950.37.141 　

ISSN： 0417-0326
Rescue of axotomized retinal ganglion cells by BDNF gene electroporation in adult rats Peer-reviewed

XF Mo, A Yokoyama, T Oshitari, H Negishi, M Dezawa, A Mizota, E Adachi-Usami

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　43　(7)　2401-2405　2002/07

ISSN： 0146-0404
The role of c-fos in cell death and regeneration of retinal ganglion cells Peer-reviewed

T Oshitari, M Dezawa, S Okada, M Takano, H Negishi, H Horie, H Sawada, T Tokuhisa, E Adachi-Usami

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　43　(7)　2442-2449　2002/07

ISSN： 0146-0404
Preservation of retinal morphology and functions in Royal College Surgeons rat by nilvadipline, a Ca2+ antagonist Peer-reviewed

H Yamazaki, H Ohguro, T Maeda, Maruyama, I, Y Takano, T Metoki, M Nakazawa, H Sawada, M Dezawa

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　43　(4)　919-926　2002/04

ISSN： 0146-0404
Central and peripheral nerve regeneration by transplantation of Schwann cells and transdifferentiated bone marrow stromal cells. Peer-reviewed

Dezawa M

Anatomical science international　77　(1)　12-25　2002/03

DOI： 10.1046/j.0022-7722.2002.00012.x 　

ISSN： 1447-6959
Brain-derived neurotrophic factor enhances neurite regeneration from retinal ganglion cells in aged human retina in vitro Peer-reviewed

M Takano, H Horie, Y Iijima, M Dezawa, H Sawada, Y Ishikawa

EXPERIMENTAL EYE RESEARCH　74　(2)　319-323　2002/02

DOI： 10.1006/exer.2001.1118 　

ISSN： 0014-4835
Nilvadipine, a Ca2+ anatagonist, effectively preserves retinal morphology and functions in Royal College Surgeons rat Peer-reviewed

Hitoshi Yamazaki, Hiroshi Ohguro, Ikuyo Maruyama, Yoshiko Takano, Tomomi Metoki, Futoshi Ishikawa, Yasuhiro Miyagawa, Mitsuru Nakazawa, Hajime Sawada, Mari Dezawa

Keio Journal of Medicine　51　76-85　2002

DOI： 10.2302/kjm.51.supplement1_76 　

ISSN： 1880-1293 0022-9717
Gene transfer into retinal ganglion cells by in vivo electroporation: a new approach Peer-reviewed

M Dezawa, M Takano, H Negishi, XF Mo, T Oshitari, H Sawada

MICRON　33　(1)　1-6　2002

DOI： 10.1016/S0968-4328(01)00002-6 　

ISSN： 0968-4328
Protection of retinal ganglion cells from ischemia-reperfusion injury by electrically applied Hsp27 Peer-reviewed

A Yokoyama, T Oshitari, H Negishi, M Dezawa, A Mizota, E Adachi-Usami

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　42　(13)　3283-3286　2001/12

ISSN： 0146-0404
Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone-marrow stromal cells Peer-reviewed

M Dezawa, Takahashi, I, M Esaki, M Takano, H Sawada

EUROPEAN JOURNAL OF NEUROSCIENCE　14　(11)　1771-1776　2001/12

DOI： 10.1046/j.0953-816X.2001.01814.x 　

ISSN： 0953-816X
Optic nerve regeneration within artificial Schwann cell graft in the adult rat Peer-reviewed

H Negishi, M Dezawa, T Oshitari, E Adachi-Usami

BRAIN RESEARCH BULLETIN　55　(3)　409-419　2001/06

DOI： 10.1016/S0361-9230(01)00534-2 　

ISSN： 0361-9230
Effects of light and darkness on cell deaths in damaged retinal ganglion cells of the carp retina Peer-reviewed

M Dezawa, XF Mo, T Oshitari, M Takano, VB Meyer-Rochow, H Sawada, E Eguchi

ACTA NEUROBIOLOGIAE EXPERIMENTALIS　61　(2)　85-91　2001

ISSN： 0065-1400
Role of Schwann cells in retinal ganglion cell axon regeneration Peer-reviewed

M Dezawa, E Adachi-Usami

PROGRESS IN RETINAL AND EYE RESEARCH　19　(2)　171-204　2000/03

DOI： 10.1016/S1350-9462(99)00010-5 　

ISSN： 1350-9462
The0 interaction and adhesive mechanisms between axon and schwann cell during central and peripheral nerve regeneration Peer-reviewed

Mari Dezawa

Acta Anatomica Nipponica　75　(3)　255-265　2000

ISSN： 0022-7722
Increase in nucleoli after x-radiation of fibroblasts of patients with Gorlin syndrome Peer-reviewed

M Dezawa, K Fujii, K Kita, J Nomura, K Sugita, E Adachi-Usami, N Suzuki

JOURNAL OF LABORATORY AND CLINICAL MEDICINE　134　(6)　585-591　1999/12

DOI： 10.1016/S0022-2143(99)90097-5 　

ISSN： 0022-2143
Haemophilus influenzae has a GM1 ganglioside-like structure and elicits Guillain-Barre syndrome Peer-reviewed

M Mori, S Kuwabara, M Miyake, M Dezawa, E Adachi-Usami, H Kuroki, M Noda, T Hattori

NEUROLOGY　52　(6)　1282-1284　1999/04

ISSN： 0028-3878
Glial cells in degenerating and regenerating optic nerve of the adult rat Peer-reviewed

M Dezawa, K Kawana, H Negishi, E Adachi-Usami

BRAIN RESEARCH BULLETIN　48　(6)　573-579　1999/04

DOI： 10.1016/S0361-9230(99)00035-0 　

ISSN： 0361-9230
Putative gap junctional communication between axon and regenerating Schwann cells during mammalian peripheral nerve regeneration Peer-reviewed

M Dezawa, T Mutoh, A Dezawa, E Adachi-Usami

NEUROSCIENCE　85　(3)　663-667　1998/08

DOI： 10.1016/S0306-4522(98)00051-7 　

ISSN： 0306-4522
Immunohistochemical study of E-cadherin and ZO-1 in allergic nasal epithelium of the guinea pig Peer-reviewed

N Kobayashi, M Dezawa, H Nagata, S Yuasa, A Konno

INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY　116　(3)　196-205　1998/07

DOI： 10.1159/000023945 　

ISSN： 1018-2438
Effects of light and dark environment on regeneration of carp optic nerves Peer-reviewed

M Dezawa, A Ohtsuka, Y Shimoda, E Adachi-Usami, JD Steeves, E Eguchi

EXPERIMENTAL EYE RESEARCH　66　(5)　681-684　1998/05

DOI： 10.1006/exer.1998.0490 　

ISSN： 0014-4835
Abnormal DNA synthesis activity induced by X-rays in nevoid basal cell carcinoma syndrome cells Peer-reviewed

K Fujii, N Suzuki, S Ishijima, K Kita, T Sonoda, M Dezawa, K Sugita, H Niimi

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　240　(2)　269-272　1997/11

DOI： 10.1006/bbrc.1997.7603 　

ISSN： 0006-291X
A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice Peer-reviewed

M Hatano, T Aoki, M Dezawa, S Yusa, Y Iitsuka, H Koseki, M Taniguchi, T Tokuhisa

JOURNAL OF CLINICAL INVESTIGATION　100　(4)　795-801　1997/08

DOI： 10.1172/JCI119593 　

ISSN： 0021-9738
The role of Schwann cells during retinal ganglion cell regeneration induced by peripheral nerve transplantation Peer-reviewed

M Dezawa, K Kawana, E AdachiUsami

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　38　(7)　1401-1410　1997/06

ISSN： 0146-0404
Ncx, a Hox11 related gene, is expressed in a variety of tissues derived from neural crest cells Peer-reviewed

M Hatano, Y Iitsuka, H Yamamoto, M Dezawa, S Yusa, Y Kohno, T Tokuhisa

ANATOMY AND EMBRYOLOGY　195　(5)　419-425　1997/05

DOI： 10.1007/s004290050061 　

ISSN： 0340-2061
Compound eye fine structure in Paralomis multispina Benedict, an anomuran half-crab from 1200 m depth (Crustacea; Decapoda; Anomura) Peer-reviewed

E Eguchi, M Dezawa, VB MeyerRochow

BIOLOGICAL BULLETIN　192　(2)　300-308　1997/04

DOI： 10.2307/1542723 　

ISSN： 0006-3185
Selective UV-induced damage to short-wavelength receptor cells in the butterfly Papilio xuthus Peer-reviewed

M Wakakuwa, VB Meyer-Rochow, M Dezawa, T Kashiwagi, E Eguchi

PROTOPLASMA　200　(1-2)　112-115　1997

ISSN： 0033-183X
Normal human fibroblasts immortalized by introduction of human papillomavirus type 16 (HPV-16) E6-E7 genes Peer-reviewed

T Shiga, H Shirasawa, K Shimizu, M Dezawa, Y Masuda, B Simizu

MICROBIOLOGY AND IMMUNOLOGY　41　(4)　313-319　1997

ISSN： 0385-5600
Immunohistochemical localization of cell adhesion molecules and cell-cell contact proteins during regeneration of the rat optic nerve induced by sciatic nerve autotransplantation Peer-reviewed

M Dezawa, T Nagano

ANATOMICAL RECORD　246　(1)　114-126　1996/09

DOI： 10.1002/(SICI)1097-0185(199609)246:1<114::AID-AR13>3.0.CO;2-S 　

ISSN： 0003-276X
Tight junctions between the axon and Schwann cell during PNS regeneration Peer-reviewed

M Dezawa, T Mutoh, A Dezawa, T Ishide

NEUROREPORT　7　(11)　1829-1832　1996/07

ISSN： 0959-4965
CONTACTS BETWEEN REGENERATING AXONS AND THE SCHWANN-CELLS OF SCIATIC-NERVE SEGMENTS GRAFTED TO THE OPTIC-NERVE OF ADULT-RATS Peer-reviewed

M DEZAWA, T NAGANO

JOURNAL OF NEUROCYTOLOGY　22　(12)　1103-1112　1993/12

ISSN： 0300-4864
DISTRIBUTION OF ACTIN-FILAMENT BUNDLES IN MYOID CELLS, SERTOLI CELLS, AND TUNICA ALBUGINEA OF RAT AND MOUSE TESTES Peer-reviewed

M MAEKAWA, T NAGANO, K KAMIMURA, T MURAKAMI, H ISHIKAWA, M DEZAWA

CELL AND TISSUE RESEARCH　266　(2)　295-300　1991/11

ISSN： 0302-766X

Show all ︎Show first 5

Misc. 123

Muse細胞による消化器疾患治療

DEZAWA Mari

消化器疾患の最新医療　49　1-6　2018/08
An expect for paradigm shift of medical treatment by endogenous reparative Muse cells

DEZAWA Mari

ANTI-AGING MEDICINE　14　(2)　226-233　2018/04
Beneficial Pleiotropic Effects of Multilineage-Differentiating Stress Enduring Cells on Acute Lung Ischemia-Reperfusion Injury

H. Yabuki, S. Wakao, Y. Kushida, M. Dezawa, Y. Okada

JOURNAL OF HEART AND LUNG TRANSPLANTATION　36　(4)　S380-S380　2017/04

ISSN： 1053-2498

eISSN： 1557-3117
腸管出血性大腸菌感染マウスモデルおける再生医療(Muse細胞)を用いた急性脳症の治療効果(Effects of Muse cells on acute encephalopathy caused by Shiga toxin-producing E. coil infection in mice)

尾鶴亮, 若尾昌平, 松葉隆司, 磯部順子, 木全恵子, 綿引正則, 出澤真理, 藤井潤

日本細菌学雑誌　72　(1)　158-158　2017/02
Publisher: 日本細菌学会
ISSN： 0021-4930
急性膵炎モデルマウスの作成とその定量評価法の確立抗サイトカイン療法の実現へ向けての基礎実験

深瀬正彦, 坂田直昭, 川口桂, 若尾昌平, 串田良祐, 出澤真理, 海野倫明

日本腹部救急医学会雑誌　37　(2)　222-222　2017/02
Publisher: (一社)日本腹部救急医学会
ISSN： 1340-2242

eISSN： 1882-4781
脳内出血モデルおけるMultilineage-differentiateing Stress Enduring細胞による神経機能回復

嶋村則人, 角田聖英, 内田浩喜, 若尾昌平, 出澤真理, 大熊洋揮

再生医療　16　2017

ISSN： 1347-7919
Muse細胞静脈内投与は血管構成細胞再生によりマウス大動脈瘤拡大を抑制する

鷹谷紘樹, 細山勝寛, 若尾昌平, 串田良祐, 齋木佳克, 出澤真理

再生医療　16　2017

ISSN： 1347-7919
Sphingosine-1-phosphate mobilizes Muse cells, pluripotent stem cells, to replenish cardiomyocytes, reduce the infarct size, and recover the cardiac function after acute myocardial infarction

S. Minatoguchi, Y. Yamada, S. Wakao, Y. Kushida, M. Iwasa, H. Kanamori, M. Kawasaki, K. Nishigaki, M. Dezawa, S. Minatoguchi

EUROPEAN HEART JOURNAL　37　1167-1167　2016/08

ISSN： 0195-668X

eISSN： 1522-9645
Active cardiac-targeted delivery of sphingosine-1-phosphate attracts Muse cells to the infarcted region and replenishes cardiomyocytes to recover the cardiac function after myocardial infarction

S. Minatoguchi, Y. Yamada, S. Wakao, Y. Kushida, A. Mikami, H. Kanamori, M. Kawasaki, K. Nishigaki, M. Dezawa, S. Minatoguchi

EUROPEAN HEART JOURNAL　37　180-180　2016/08

ISSN： 0195-668X

eISSN： 1522-9645
MOUSE MODEL OF LACUNAR INFARCTS WITH LONG-LASTING FUNCTIONAL DISABILITIES

H. Uchida, K. Niizuma, H. Sakata, M. Fujimura, M. Dezawa, T. Tominaga

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM　36　215-215　2016/06

ISSN： 0271-678X

eISSN： 1559-7016
Muse細胞と再生治療

DEZAWA Mari

先進医療 NAVIGATOR　4　17-20　2016/04
ヒト多能性幹細胞(Muse細胞)における新規多能性制御因子とその機能

明石英雄, BAGHERI Mozhdeh, 若尾昌平, 黒田康勝, 柴田典人, 宮岸真, 北田容章, 藤吉好則, 田岡万悟, 磯辺俊明, 阿形清和, 出澤真理, 出澤真理

再生医療　15　2016

ISSN： 1347-7919
Transplantation of Unique, Newly Discovered Muse Cells May Lead to Promising Stroke Therapy

M. Dezawa

CELL TRANSPLANTATION　25　(4)　754-755　2016

ISSN： 0963-6897

eISSN： 1555-3892
Muse細胞と再生医療への実現性

DEZAWA Mari, KUSHIDA Yoshihir, WAKAO Shohei

THE LUNG perspectives　24　(2)　192-199　2016
Publisher: (株)メディカルレビュー社
ISSN： 0919-5742
Muse細胞が再生治療にもたらす新たな戦略

DEZAWA Mari

BIO Clinica　31　(10)　1032-1036　2016
Muse細胞を用いた再生医療の可能性

DEZAWA Mari

Orthopaedic Surgery and Traumatology　59　(13)　1749-1758　2016
Publisher: 金原出版
DOI： 10.18888/J00767.2017065308 　

ISSN： 0387-4095
細胞移植の新たな展開臍帯組織中に存在する多能性幹細胞Muse細胞の多能性の解析

串田良祐, 若尾昌平, 明石英雄, 西村範行, 岩谷壮太, 香田翼, 森岡一朗, 溝渕雅巳, 飯島一誠, 出澤真理

Organ Biology　22　(3)　43-43　2015/10
Publisher: (一社)日本臓器保存生物医学会
ISSN： 1340-5152

eISSN： 2188-0204
骨髄細胞中のMuse細胞は塩基性線維芽細胞増殖因子(bFGF)添加によって増加し軟骨分化能を維持する

目良恒, 若尾昌平, 玉村禎宏, 出澤真理, 脇谷滋之

日本整形外科学会雑誌　89　(8)　S1723-S1723　2015/09
Publisher: (公社)日本整形外科学会
ISSN： 0021-5325
Sphigosine-mono-phosphate (S1P) induces the migration of Muse cells but not non-Muse cells toward the rabbit post-infarct heart and contributes to the improvement of cardiac function and remodeling

Y. Yamada, S. Minatoguchi, H. Kanamori, K. Higashi, M. Kawasaki, K. Nishigaki, A. Mikami, S. Wakao, M. Dezawa, S. Minatoguchi

EUROPEAN HEART JOURNAL　36　868-868　2015/08

ISSN： 0195-668X

eISSN： 1522-9645
Post-infarct administration of multilineage-differentiating stress-enduring (Muse) cells regenerates cardiomyocytes and microvessels and improves cardiac function and remodeling in rabbits

Y. Yamada, S. Minatoguchi, K. Higashi, H. Kanamori, M. Kawasaki, K. Nishigaki, A. Mikami, S. Wakao, M. Dezawa, S. Minatoguchi

EUROPEAN HEART JOURNAL　36　946-946　2015/08

ISSN： 0195-668X

eISSN： 1522-9645
慢性腎臓病モデルに対するMuse細胞を用いた細胞治療の検討

内田奈生, 若尾昌平, 串田良祐, 熊谷直憲, 出澤真理, 呉繁夫, 根東義明

日本腎臓学会誌　57　(3)　601-601　2015/04
Publisher: (一社)日本腎臓学会
ISSN： 0385-2385

eISSN： 1884-0728
出血性脳損傷モデルに対するMultilineage-differentiateing Stress Enduring細胞を用いた神経再生治療

嶋村則人, 角田聖英, 若尾昌平, 内田浩喜, 出澤真理, 大熊洋揮

日本脳神経外傷学会プログラム・抄録集　38th　2015
プラナリアネオブラスト特異的抗体により同定された新規ヒト多能性制御因子とその機能

明石英雄, BAGHERI Mozhdeh, 若尾昌平, 黒田康勝, 柴田典人, 北田容章, 藤吉好則, 田岡万悟, 磯辺俊明, 阿形清和, 出澤真理

再生医療　14　2015

ISSN： 1347-7919
体性幹細胞とMuse細胞の位置づけ

WAKAO Shohei, DEZAWA Mari

膵島の再生医療　73-78　2015
生体内多能性幹細胞：Muse細胞

DEZAWA Mari

脳神経系の再生医学−発生と再生の融合的新展開−　19-26　2015/01
ヒトMuse細胞由来色素細胞を用いたヒト3次元培養皮膚の実用化

LAO Xintian, DEZAWA Mari, SUMITA Yoshihiro

COSMETIC STAGE　9　(5)　54-62　2015
Publisher: 技術情報協会
ISSN： 1881-4905
Multilineage-differentiating stress enduring (Muse) cells regenerate cardiomyocytes and microvessels and improve cardiac function and remodeling after myocardial infarction in rabbits

Y. Yamada, H. Kanamori, K. Higashi, S. Baba, S. Minatoguchi, M. Kawasaki, K. Nishigaki, S. Wakao, M. Dezawa, S. Minatoguchi

EUROPEAN HEART JOURNAL　35　112-112　2014/09

ISSN： 0195-668X

eISSN： 1522-9645
Experimental Model of Lacunar Infarcts in Mice with Long-Lasting Functional Disabilities

Hiroki Uchida, Hiroyuki Sakata, Miki Fujimura, Kuniyasu Niizuma, Mari Dezawa, Teiji Tominaga

CEREBROVASCULAR DISEASES　38　9-9　2014/09

ISSN： 1015-9770

eISSN： 1421-9786
Induction of melanocytes from multilineage-differentiating stress-enduring (Muse) cells derived from human adipose tissue

T. Yamauchi, K. Tsuchiyama, F. Ogura, S. Wakao, S. Koike, K. Yamasaki, M. Dezawa, S. Aiba

JOURNAL OF INVESTIGATIVE DERMATOLOGY　134　S122-S122　2014/05

ISSN： 0022-202X

eISSN： 1523-1747
Making three dimensional human colored skin by using Muse cells, a novel type of non-tumorigenic pluripotent stem cells

Mari Dezawa

FASEB JOURNAL　28　(1)　2014/04

ISSN： 0892-6638

eISSN： 1530-6860
Muse Cells, a Novel Type of Non-tumorigenic Puripotent Stem Cells, that Reside in Human Mesenchymal Tissues

WAKAO Shohei, AKASHI Hideo, DEZAWA Mari

脊髄外科 SPINAL SURGERY　28　(1)　17-23　2014/04

DOI： 10.2531/spinalsurg.28.17 　
Muse細胞研究の展望と課題

WAKAO Shohei, KUSHIDA Yoshihiro, DEZAWA Mari

最新医学　69　(3)　547-561　2014/03
プラナリアネオブラスト特異的抗体によるヒト成体多能性幹細胞因子の同定

明石英雄, MOZHDEH Bagheri, 若尾昌平, 黒田康勝, 柴田典人, 阿形清和, 田岡万悟, 礒辺俊明, 藤吉好則, 北田容章, 出澤真理

再生医療　13　2014

ISSN： 1347-7919
A New Age of Regenerative Medicine: Fusion of Tissue Engineering and Stem Cell Research

Kurt H. Albertine, Mari Dezawa

ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY　297　(1)　1-3　2014/01

DOI： 10.1002/ar.22811 　

ISSN： 1932-8486

eISSN： 1932-8494
グリオーマのHSVtk遺伝子治療におけるMuse細胞の有用性

難波宏樹, 山崎友裕, 川路博史, 天野慎士, 若尾昌平, 出澤真理

日本脳腫瘍学会プログラム・抄録集　32nd　101　2014
ARTIFICIAL CELL FATE REGULATION OF THE PROGENITOR CELLS IN THE ADULT SPINAL CORD

M. Kitada, J-I. Suzuki, M. Dezawa

GLIA　61　S148-S149　2013/07

ISSN： 0894-1491
ヒト生体に内在する新たな多能性幹細胞 Muse 細胞 : 細胞治療, 予後の診断, 創薬, 病態解析への展開の可能性

出澤真理

人工臓器　42　(1)　16-18　2013/06/15

ISSN： 0300-0818
ヒト線維芽細胞に存在する多能性幹細胞(Muse 細胞)とiPS細胞の関連性

若尾昌平, 北田容章, 黒田康勝, 出澤真理

日本生理学雜誌　75　(1)　34-35　2013/01/01

ISSN： 0031-9341
プラナリアネオブラスト特異的抗体により認識されるヒト多能性幹細胞因子の同定

明石英雄, MOZHDEH Bagheri, 若尾昌平, 黒田康勝, 柴田典人, 阿形清和, 田岡万悟, 磯部俊明, 藤吉好則, 北田容章, 出澤真理

日本解剖学会総会・全国学術集会講演プログラム・抄録集　118th　2013
Muse細胞をベクターとするグリオーマのHSVtk遺伝子細胞治療

難波宏樹, 山添知宏, 山崎友裕, 小泉慎一郎, 若尾昌平, 土山健一郎, 出澤真理

日本脳腫瘍学会プログラム・抄録集　31st　123　2013
他家移植へ向けたMuse細胞の可能性

黒田康勝, 繁本妙子, 出澤真理

日本解剖学会総会・全国学術集会講演プログラム・抄録集　118th　95　2013
成人ヒト間葉系細胞に内在する多分化能細胞の探索

黒田康勝, 北田容章, 若尾昌平, 西川幸希, 谷村幸宏, 合田真, 明石英雄, 繁本妙子, 藤吉好則, 出澤真理

再生医療　11　180　2012/05/16

ISSN： 1347-7919
パーキンソン病モデル霊長類動物における骨髄間質幹細胞由来A9ドーパミン神経細胞自家移植

林拓也, 若尾昌平, 光永佳奈枝, 北田正章, 合瀬恭幸, 渡部浩司, 松瀬大, 繁本妙子, 尾上浩隆, 田畑泰彦, 出澤真理

JSMI Report　5　(2)　99-99　2012/05
Publisher: 日本分子イメージング学会
ISSN： 1882-6490
神経再生研究の最前線−Muse細胞

DEZAWA Mari

脳神経外科速報　22　(5)　550-559　2012/05
Muse cells: a novel type of adult human pluripotent stem cells in mesenchymal tissues and their contribution to tissue repair

Mari Dezawa

FASEB JOURNAL　26　2012/04

ISSN： 0892-6638
ヒト皮膚由来線維芽細胞に存在する多能性幹細胞とiPS細胞の関連

若尾昌平, 北田容章, 黒田康勝, 繁本妙子, 明石英雄, 土山健一郎, 出澤真理

解剖学雑誌　87　(1)　5　2012/03/01

ISSN： 0022-7722
成体組織幹細胞の効率的な濃縮方法の確立:骨格筋を用いての検証

繁本妙子, 黒田康勝, 若尾昌平, 北田容章, 出澤真理

解剖学雑誌　87　(1)　4　2012/03/01

ISSN： 0022-7722
成人ヒト間葉系細胞に内在する新規多能性幹細胞の探索

黒田康勝, 北田容章, 若尾昌平, 谷村幸宏, 明石英雄, 繁本妙子, 出澤真理

解剖学雑誌　87　(1)　5　2012/03/01

ISSN： 0022-7722
プラナリア幹細胞特異的抗体を用いたヒト多能性幹細胞特異的因子の探索

明石英雄, 若尾昌平, 黒田康勝, 柴田典人, 阿形清和, 田岡万悟, 磯辺俊明, 藤吉好則, 北田容章, 出澤真理

再生医療　11　2012

ISSN： 1347-7919
Parkinson's disease and mesenchymal stem cells: Potential for cell-based therapy

Masaaki Kitada, Mari Dezawa

Parkinson's Disease　2012

DOI： 10.1155/2012/873706 　

ISSN： 2042-0080
ヒト生体由来多能性幹細胞Muse細胞−再生医学と生物学における意義

DEZAWA Mari

実験医学　30　(2)　180-188　2012
Human umbilical cord-derived mesenchymal stromal cells differentiate into the functional Schwann cells that sustain peripheral nerve regeneration

MATSUSE Dai, KITADA Masaaki, KOHAMA Misaki, NISHIKAWA Kouki, WAKAO Shohei, FUJIYOSHI Yoshinori, KIRA Jun-ichi, DEZAWA Mari

22　(2)　311-312　2011/12/01

ISSN： 0917-6772
生体由来の間葉系組織に内包されるMuse細胞の発見

DEZAWA Mari

実験医学　29　(19)　3077-3084　2011/12
iPS細胞リソースとしてのMuse細胞

WAKAO Shohei, KITADA Masaaki, DEZAWA Mari

医学のあゆみ　239　(14)　1326-1331　2011/12
Muse cells: a novel type of adult human pluripotent stem cells and their possible application to cell therapy

Mari Dezawa

FASEB JOURNAL　25　2011/04

ISSN： 0892-6638
成体組織幹細胞の効率的な単離方法の確立: 骨格筋を用いての検証

繁本妙子, 黒田康勝, 若尾昌平, 北田容章, 出澤真理

解剖学雑誌　86　(1)　10　2011/03

DOI： 10.1007/s12565-010-0095-1 　

ISSN： 0022-7722
皮膚由来線維芽細胞からのiPS細胞誘導における特定の幹細胞が寄与する可能性

若尾昌平, 北田容章, 黒田康勝, 繁本妙子, 松瀬大, 明石英雄, 谷村幸宏, 出澤真理

解剖学雑誌　86　(1)　10　2011/03

DOI： 10.1007/s12565-010-0095-1 　

ISSN： 0022-7722
成体脊髄に存在する新たなオリゴデンドロサイト系譜前駆細胞の同定

北田容章, 武田一也, 出澤真理

解剖学雑誌　86　(1)　10-10　2011/03
Publisher: (一社)日本解剖学会
DOI： 10.1007/s12565-010-0095-1 　

ISSN： 0022-7722
THE COMMENTARY 間葉系幹細胞の特性と再生医療における展開

黒田康勝, 出澤真理

再生医療　10　(1)　8-11　2011/02
Publisher: メディカルレビュー社
ISSN： 1347-7919
Mesenchymal stem cells and umbilical cord as sources for schwann cell differentiation: Their potential in peripheral nerve repair

Yasumasa Kuroda, Masaaki Kitada, Shohei Wakao, Mari Dezawa

Open Tissue Engineering and Regenerative Medicine Journal　4　(1)　54-63　2011

DOI： 10.2174/1875043501104010054 　

ISSN： 1875-0435
間葉系細胞に内在する多分化能細胞の探索

黒田康勝, 北田容章, 若尾昌平, 出澤真理

解剖学雑誌　85　(Supplement)　160-160　2010/03
Publisher: (一社)日本解剖学会
ISSN： 0022-7722
失われたグリア前駆細胞を求めて DM-20 mRNA発現細胞に着目して

北田容章, 武田一也, 出澤真理

解剖学雑誌　85　(Suppl.)　126-126　2010/03
Publisher: (一社)日本解剖学会
ISSN： 0022-7722
ラット脊髄損傷モデルに対する骨髄間質細胞由来誘導神経前駆細胞移植

小濱みさき, 北田容章, 松瀬大, 若尾昌平, 遠藤俊毅, 冨永悌二, 出澤真理

解剖学雑誌　85　(Suppl.)　170-170　2010/03
Publisher: (一社)日本解剖学会
ISSN： 0022-7722
筋ジストロフィーに対する治療研究を臨床に展開するための統括的研究 III.筋再生と幹細胞移植治療骨髄間葉系細胞からの有効な骨格筋誘導および筋変性モデルへの移植

出澤真理, 若尾昌平, 繁本妙子, 北田容章, 黒田康勝, 松瀬大, 金丸眞一, 中村達雄, 武田伸一

筋ジストロフィーに対する治療研究を臨床に展開するための統括的研究平成19-21年度総括研究報告書　60-63　2010
EFFECTS OF BFGF INCORPORATED GELATIN HYDROGEL AND BONE MARROW STROMAL CELL- DERIVED NEURAL PROGENITOR CELL TRANSPLANTATION IN A RAT SPINAL CORD CONTUSION MODEL

Masayuki Hashimoto, Takeo Furuya, Masao Koda, Koichi Hayashi, Atsushi Murata, Akihiko Okawa, Mari Dezawa, Yasuhiko Tabata, Kazuhisa Takahashi, Masashi Yamazaki

JOURNAL OF NEUROTRAUMA　26　(8)　A97-A97　2009/08

ISSN： 0897-7151
骨髄間葉系細胞の神経・骨格筋への分化転換におけるNotchの作用

黒田康勝, 若尾昌平, 北田容章, 出澤真理

解剖学雑誌　84　(Supplement)　253-253　2009/03
Publisher: (一社)日本解剖学会
ISSN： 0022-7722
カニクイザル骨髄間葉系細胞からのシュワン細胞誘導と末梢神経損傷への自己細胞移植 Peer-reviewed

若尾昌平, 林拓也, 高本智紹, 小濱みさき, 北田容章, 田畑泰彦, 出澤真理

第114回日本解剖学会総会・全国学術集会（2009.3.28－ 30 岡山）　2009
Insights into Autotransplantation : The Discovery of Specific Induction Systems in Bone Marrow Stromal Cells

DEZAWA M.

120　(2)　173-175　2008/12/25
Publisher: 東北医学会
ISSN： 0040-8700
Effects of BFGF incorporated gelatin hydrogel transplantation in a rat spinal cord contusion model

Takeo Furuya, Masayuki Hashimoto, Masao Koda, Atsushi Murata, Akihiko Okawa, Masashi Yamazaki, Mari Dezawa, Dai Matsuse, Yasuhiko Tabata, Kazuhisa Takahashi

JOURNAL OF NEUROTRAUMA　25　(7)　922-922　2008/07

ISSN： 0897-7151
Identification of the glial progenitor cells and molecules involving their proliferation and differentiation in the adult spinal cord

Masaaki Kitada, Yutaka Itokazu, Chizuka Ide, Mari Dezawa

NEUROSCIENCE RESEARCH　61　S69-S69　2008

ISSN： 0168-0102
Notch-induced human bone marrow stromal cell grafts express neuronal phenotypic markers and reduce ischemic cell loss in tandem with behavioral recovery of transplanted stroke animals

M. M. Ali, M. Maki, T. Masuda, S. J. Yu, T. Yasuhara, K. Hara, M. McGrogan, M. Dezawa, K. Bankiewicz, C. Case, C. V. Borlongan

CELL TRANSPLANTATION　17　(4)　458-458　2008

ISSN： 0963-6897
急性期の脊髄損傷に対する骨髄由来単核球細胞移植の有効性について

吉原智之, 太田正佳, 糸数裕, 松本直也, 鈴木義久, 出澤真理, 田口明彦, 杉本壽, 井出千束

日本救急医学会雑誌　18　(8)　403-403　2007/08/15
Publisher: (一社)日本救急医学会
ISSN： 0915-924X
急性期の脊髄損傷に対する骨髄由来単核球細胞移植の有効性について

吉原智之, 太田正佳, 糸数裕, 松本直也, 鈴木義久, 出澤真理, 田口明彦, 杉本壽, 井出千束

日本救急医学会雑誌　18　(8)　366-366　2007/08/15
Publisher: (一社)日本救急医学会
ISSN： 0915-924X
Induction of neural and muscle lineage cells from bone marrow stromal cells

Regenerative medicine　6　(3)　251-257　2007/08
Publisher: メディカルレビュー社
ISSN： 1347-7919
Insights into auto-transplantation - The unexpected discovery of transdifferentiation systems in bone marrow stromal cells and its application

Mari Dezawa

Brain and Nerve　59　(5)　503-508　2007/05

ISSN： 0006-8969
幹細胞技術の現状と展望(6)胚葉をこえた多分化能と自己細胞移植治療への可能性

出澤真理

蛋白質核酸酵素　52　(2)　158-165　2007/02
Publisher: 共立出版
ISSN： 0039-9450
Exploring the glial progenitor cells in the intact adult spinal cord

Masaaki Kitada, Yutaka Itokazu, Chizuka Ide, Mari Dezawa

NEUROSCIENCE RESEARCH　58　S32-S32　2007

ISSN： 0168-0102
サブフェクション法を用いた骨髄由来間葉系幹細胞の神経誘導 Peer-reviewed

永根健太郎, 出澤真理, 田畑泰彦

第10 回日本組織工学会（2007.11.8－9．東京）　2007
Bone marrow stromal cells for auto-cell transplantation therapy : applications for neuro- and muscle-degenerative diseases

DEZAWA Mari

Microscopy　41　(3)　200-203　2006/11/30
Publisher: 日本顕微鏡学会
ISSN： 1349-0958
A challenge to auto-cell transplantation: Based on specific induction system of bone marrow stromal cells

Mari Dezawa

JOURNAL OF NEUROIMMUNOLOGY　178　27-27　2006/09

ISSN： 0165-5728
Novel Therapeutic Strategy for Ischemic Stroke by Bone Marrow Stromal Cells and Ex Vivo HGF and FGF2 Genes Transfer with Replication-Incompetent HSV-1 Vector

Naosuke Nonoguchi, Ming-Zhu Zhao, Naokado Ikeda, Yoshihito Miki, Daisuke Furutama, Fumiharu Kimura, Mari Dezawa, Hiroshi Funakoshi, Robert S. Coffin, Shin-ichi Miyatake, Toshihiko Kuroiwa

MOLECULAR THERAPY　13　S98-S98　2006/05

ISSN： 1525-0016

eISSN： 1525-0024
Transplantation of bone marrow stromal cell-derived Schwann cells promotes axonal regeneration and functional recovery after contusion injury of adult rat spinal cord

Y Someya, M Koda, M Dezawa, T Kamada, Y Nishio, A Okawa, K Yoshinaga, H Moriya, M Yamazaki

JOURNAL OF NEUROTRAUMA　23　(5)　785-786　2006/05

ISSN： 0897-7151
Specific induction of Schwann cells, neurons and skeletal muscle cells from bone marrow stromal cells and application for degenerative diseases

M Dezawa

FASEB JOURNAL　20　(4)　A19-A19　2006/03

ISSN： 0892-6638
急性期脊髄損傷に対する治療急性期の脊髄損傷に対する骨髄単核球細胞移植の有効性

吉原智之, 太田正佳, 糸数裕, 松本直也, 鈴木義久, 出澤真理, 田口明彦, 杉本壽, 井出千束

日本脳神経外科救急学会プログラム・抄録集　11回　68-68　2006/01
Publisher: (NPO)日本脳神経外科救急学会
Transplantation of bone marrow stromal cell-derived Schwann cells promotes axonal regeneration and functional recovery after contusion injury of adult rat spinal cord

Y Someya, A Koda, M Dezawa, T Kamada, Y Nishio, R Kadota, C Mannouji, T Miyashita, A Okawa, K Yoshinaga, M Yamazaki, H Moriya

JOURNAL OF NEUROTRAUMA　22　(10)　1175-1175　2005/10

ISSN： 0897-7151
急性期の脊髄損傷に対する骨髄単核球細胞移植の有効性

吉原智之, 太田正佳, 糸数裕, 松本直也, 出沢真理, 鈴木義久, 足立靖, 池原進, 田口明彦, 杉本寿, 井手千束

日本救急医学会雑誌　16　(8)　420-420　2005/08/15
Publisher: (一社)日本救急医学会
ISSN： 0915-924X
骨髄間質細胞から分化誘導したシュワン細胞を,キトサンを担体として移植した際の末梢軸索再生の観察

石川奈美子, 鈴木義久, 太田正佳, 片岡和哉, 出沢真理, 井出千束, 鈴木茂彦

日本形成外科学会基礎学術集会プログラム・抄録集　14th　72　2005
再生医療実用化への道―中枢神経・すい島―I. 中枢神経の機能再生―臨床応用へのbreakthrough―脊髄損傷の治療方法の開発(アルギン酸と骨髄間質細胞を用いた治療)

太田正佳, 鈴木義久, 片岡和哉, 張弘富, 大西克則, 谷原正夫, 橋本正, 出沢真理, 井出千束

再生医療　3　(4)　45-52　2004/11/01

ISSN： 1347-7919
脊髄損傷の神経修復脳脊髄液経由にニューロスフェアー,骨髄間質細胞を脊髄損傷部へ移植する新しい方法(Spinal cord injury and neural repair: A novel method for cell transplantation (neurosphere cells,bone marrow stromal cells) into damaged spinal cord via cerebrospinal fluid in rats)

鈴木義久, 張弘富, 太田正佳, 石川奈美子, 鈴木茂彦, 出澤真理, 井出千束

神経化学　43　(2-3)　348-348　2004/08
Publisher: 日本神経化学会
ISSN： 0037-3796
骨髄間質細胞からの神経細胞誘導法とパーキンソンモデルラットへの移植応用(Induction of neuronal cells from bone-marrow stromal cells and application for Parkinson's disease model rats)

出澤真理, 管野洋, 鈴木義久, 張弘富, 井出千束

神経化学　43　(2-3)　381-381　2004/08
Publisher: 日本神経化学会
ISSN： 0037-3796
Transplantation of Schwann cells derived from bone marrow stromal cells in rat spinal cord injury

KAMADA T.

15　(1)　360-360　2004/05/20

ISSN： 1346-4876
Transplantaion of bone marrow stromal cells to an experimental glaucoma model

S Yu, T Miyawaki, M Dezawa, H Chou, T Tanabe

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　45　U788-U788　2004/04

ISSN： 0146-0404
Tlx, an orphan nuclear receptor, is critical for the control of retinal cell numbers and glial development.

T Miyawaki, A Uemura, M Dezawa, T Tanabe

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　45　U634-U634　2004/04

ISSN： 0146-0404
VHL遺伝子導入による神経幹細胞の神経分化誘導と導入細胞の移植による脳梗塞の治療

菅野洋, 味村俊郎, 出澤真理, 山本勇夫

脳卒中　26　(1)　186-186　2004/03
Publisher: (一社)日本脳卒中学会
ISSN： 0912-0726
神経再生基礎と展望骨髄間質細胞から分化誘導したSchwann細胞を用いたラットの末梢神経再生

味村俊郎, 出澤真理, 菅野洋, 山本勇夫

日本神経外傷学会プログラム・抄録集　27回　98-98　2004/03
Publisher: (一社)日本脳神経外傷学会
II-C-06 脈絡叢上衣細胞初代培養の培養上清はラット海馬由来神経細胞の突起伸長と生存を促進する(細胞・神経,一般演題ポスター発表,第45回日本組織細胞化学会総会・学術集会)

渡邊裕美, 松本直也, 出澤真理, 糸数裕, 吉原智之, 井出千束

日本組織細胞化学会総会プログラムおよび抄録集　(45)　89-89　2004
Publisher: 日本組織細胞化学会
チューブ状に加工しないキトサンスポンジによるラットの末梢神経再生

石川奈美子, 鈴木義久, 太田正佳, 張弘富, 鈴木茂彦, 野田亨, 出沢真理, 井出千束

日本形成外科学会基礎学術集会プログラム・抄録集　13th　85　2004
脳脊髄液経路を利用した神経幹細胞移植による引き抜き損傷(硬膜内)の治療法の開発

太田正佳, 鈴木義久, 張弘富, 石川奈美子, 鈴木茂彦, 野田亨, 出沢真理, 井出千束

日本形成外科学会基礎学術集会プログラム・抄録集　13th　47　2004
脳脊髄液経由で細胞を脊髄損傷部へ移植できる

鈴木義久, 張弘富, 太田正佳, 片岡和哉, 鈴木茂彦, 出沢真理, 井出千束

炎症・再生　23　(6)　491-491　2003/11/20
Publisher: 日本炎症・再生医学会
ISSN： 1346-8022
骨髄間質細胞を脳脊髄形経由で投与することで脊髄損傷ラットの行動機能が回復する

太田正佳, 鈴木義久, 張弘富, 片岡和哉, 石川奈美子, 鈴木茂彦, 野田亨, 出沢真理, 井出千束

日本形成外科学会基礎学術集会プログラム・抄録集　12th　72　2003/10/09
骨髄間質細胞より分化させた神経細胞移植によるラット脊髄損傷治療の試み

張弘富, 鈴木義久, 太田正佳, 石川奈美子, 鈴木茂彦, 出沢真理, 井出千束

日本形成外科学会基礎学術集会プログラム・抄録集　12th　72　2003/10/09
骨髄間質細胞から分化誘導したシュワン細胞を用いたラットの末梢神経軸索の再生

石川奈美子, 鈴木義久, 張弘富, 太田正佳, 片岡和哉, 鈴木茂彦, 野田亨, 出沢真理, 井出千束

日本形成外科学会基礎学術集会プログラム・抄録集　12th　71　2003/10/09
Transplantation of Schwann cells derived from bone marrow stromal cells in rat spinal cord injury

T Kamada, M Koda, M Dezawa, M Yamazaki, K Yoshinaga, M Hashimoto, S Koshizuka, H Moriya

JOURNAL OF NEUROTRAUMA　20　(10)　1054-1054　2003/10

ISSN： 0897-7151
骨髄間質細胞から分化誘導したシュワン細胞及び人工材料用いたラットの末梢神経軸索の再生

石川奈美子, 鈴木義久, 張弘富, 太田正佳, 片岡和哉, 鈴木茂彦, 野田亨, 出沢真理, 井出千束

人工臓器(日本人工臓器学会)　32　(2)　S.125-S125　2003/09/15
Publisher: (一社)日本人工臓器学会
ISSN： 0300-0818
骨髄間質細胞による脊髄損傷治療の試み(ラットモデル)

太田正佳, 鈴木義久, 片岡和哉, 張弘富, 石川奈美子, 鈴木茂彦, 野田亨, 出沢真理, 井出千束

人工臓器(日本人工臓器学会)　32　(2)　S.124-S124　2003/09/15
Publisher: (一社)日本人工臓器学会
ISSN： 0300-0818
Schwann cell interactions with axons and CNS glial cells during optic nerve regeneration

Mari Dezawa

Advances in Molecular and Cell Biology　31　329-345　2003

DOI： 10.1016/S1569-2558(03)31015-X 　

ISSN： 1569-2558
Transdifferentiation of bone marrow stromal cells into neural cells, and application to model rats of Parkinson's disease

DEZAWA Mari

41　(2)　102-103　2002/12/25

ISSN： 1344-9699
VHL遺伝子導入神経幹細胞移植によるパーキンソン病治療

山田人志, 菅野洋, 出澤真理, 黒岩義之, 島津誠一郎

臨床神経学　42　(12)　1348-1348　2002/12
Publisher: (一社)日本神経学会
ISSN： 0009-918X
骨髄間質細胞の神経細胞への分化誘導及びパーキンソンモデルラットへの移植

出澤真理, 菅野洋, 山田人志, 澤田元

神経組織の成長・再生・移植研究会学術集会プログラム・予稿集　17回　36-36　2002/06
Publisher: 神経組織の成長・再生・移植研究会
VHL遺伝子導入による神経幹細胞のドーパミン産生ニューロンへの分化とそれを用いたパーキンソン病治療の可能性

菅野洋, 山田人志, 田中良英, 味村俊郎, 山本勇夫, 黒岩義之, 出澤真理, 澤田元, 馬場理也, 島津誠一郎

神経組織の成長・再生・移植研究会学術集会プログラム・予稿集　17回　30-30　2002/06
Publisher: 神経組織の成長・再生・移植研究会
Response of glial cell popukalion during the optic nerve regeneration induced by Schwann cell transplantation

DEZAWA Mari

35　462-462　2000/05/01

ISSN： 0417-0326
Direct gene transfer into retinal ganglion cells by usage of electroporation.

M Dezawa, H Negishi, T Oshitari, E Adachi-Usami

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　41　(4)　S396-S396　2000/03

ISSN： 0146-0404
Retinal ganglion cell regeneration into superior colliculus by usage of artificial Schwann cell graft.

E Adachi-Usami, H Negishi, T Oshitari, M Dezawa

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　41　(4)　S855-S855　2000/03

ISSN： 0146-0404
実験的脱髄性視神経症における免疫組織化学的,電気生理学的研究

谷合真理子, 伊藤彰, 出沢真理, 四倉次郎, 溝田淳, 安達惠美子

日本眼科学会雑誌　104　(臨増)　256-256　2000/03
Publisher: (公財)日本眼科学会
ISSN： 0029-0203
網膜神経節細胞の生存維持と分子メカニズム

忍足俊幸, 横山暁子, 出沢真理

神経眼科 = Neuro-ophthalmology Japan　16　(4)　402-412　1999/12/25

ISSN： 0289-7024
視神経のグリア細胞とその機能

出沢真理, 忍足俊幸

神経眼科 = Neuro-ophthalmology Japan　16　(1)　47-57　1999/03/25

ISSN： 0289-7024
Effects of light and dark environment on cell death and regeneration of carp retinal ganglion cells

M Dezawa, T Oshitari, H Negishi, E Adachi-Usami

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　40　(4)　S612-S612　1999/03

ISSN： 0146-0404
Optic nerve regeneration into the artificial Schwann cell graft in adults rats

H Negishi, M Dezawa, T Oshitari, E Adachi-Usami

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　40　(4)　S460-S460　1999/03

ISSN： 0146-0404
Effect of c-fos on retinal ganglion cell regeneration

T Oshitari, M Dezawa, H Negishi, E Adachi-Usami

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　40　(4)　S473-S473　1999/03

ISSN： 0146-0404
Glial cell response and optic nerve regeneration induced by transplantation of cultured Schwann cell grafts in adult rats

DEZAWA Mari, NEGISHI Hisanari, KAWANA Kouichirou, OSHITARI Toshiyuki, ADACHI USAMI Emiko

10　(1)　55-56　1998/06/06

ISSN： 0915-3896
Tight junctions between the axon and Schwann cell during PNS regeneration and CNS axonal elongation into PNS autograft.

M Dezawa, T Nagano

MOLECULAR BIOLOGY OF THE CELL　7　756-756　1996/12

ISSN： 1059-1524
Immunohistochemical localization of the cell adhesion molecules during regrowth in the rat optic nerve induced by peripheral nerve autotransplantation

DEZAWA M.

7　(1)　55-56　1995/06/02

ISSN： 0915-3896
ARRANGEMENT OF ACTIN-FILAMENT BUNDLES IN CELLS OF SEMINIFEROUS TUBULES - ELECTRON AND CONFOCAL LASER MICROSCOPIC STUDIES

T NAGANO, M MAEKAWA, K KAMIMURA, T MURAKAMI, H ISHIKAWA, M DEZAWA

JOURNAL OF ELECTRON MICROSCOPY　40　(4)　234-234　1991/08

ISSN： 0022-0744

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Books and Other Publications 10

Muse cells; Endogenous Reparative Pluripotent Stem Cells. Advances in Experimental Medicine and Biology

DEZAWA Mari

Springer　2018
Muse cells, non-tumorigenic endogenous pluripotent stem cells, as a source for generating functional melanocytes

DEZAWA Mari, TSUCHIYAMA Kenichiro, Yamazaki K, Aiba S

Springer International Publishing　2017
Muse cells

DEZAWA Mari

Springer Nature　2017
Vision

ISHIKAWA Hiroto, IKEDA Naohiro, KANNO Sanae, IKEDA Tomohiro, MIMURA Osamu, DEZAWA Mari

Taylor and Francis Publishing　2010
Regeneration (synopsis)

IDE Chizuka, DEZAWA Mari, MATSUMOTO Naoya, ITOKAZU Yutaka

Springer-Verlag　2009
Differentiation system of neural and muscle lineage cells from bone marrow stromal cells; a new strategy for tissue reconstruction in degenerative diseases

KITADA Masaaki, DEZAWA Mari

University of Murcia (Spain)　2009
Systematic neuronal and muscle induction systems in bone marrow stromal cells: the potential for tissue reconstruction in neurodegenerative and muscle degenerative diseases

DEZAWA Mari

Springer　2008
Transdifferentiation systems in bone marrow stromal cells and its application to muscle dystrophy

DEZAWA Mari, NABESHIMA Yoichi

Research Signpost　2008
Induction system of neuronal and muscle cells from bone marrow stromal cells and applications for degenerative diseases

DEZAWA Mari

Japanese Society of Inflammation and Regeneration　2007
Schwann cell interactions with the axon and with CNS glial cells during optic nerve regeneration

DEZAWA Mari

Elsevier　2004

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Presentations 170

Global Strategy of Muse Cells and Muse-exosomes:From Disease Treatment to Anti-aging Invited

Mari Dezawa

PPSSC2025　2025/05/24
脳機能回復へのMuse細胞治療の可能性 Invited

出沢真理

全国遷延性意識障害者・家族の会設立20周年記念講演会　2024/11/16
医療は新たなステージへ：HLA適合や免疫抑制剤を必要としないドナーMuse細胞による点滴治療 Invited

出沢真理

沖縄南部療育医療センター　2024/11/09
医療は新たなステージへ：HLA適合や免疫抑制剤を必要としないドナーMuse細胞による点滴治療 Invited

出沢真理

第59回日本脊髄障害医学会　2024/11/07
医療は新たなステージへ：HLA適合や免疫抑制剤を必要としないドナーMuse細胞の点滴治療 Invited

出沢真理

第67回日本脳循環代謝学会学術集会　2024/11/02
Cell replacement therapy harnessing the dead cell phagocytic activity of endogenous reparative Muse cells

MARI DEZAWA

Gordon Research Conference　2024/07/30
Cell Replacement Therapy Harnessing the Phagocytic Activity of Endogenous Reparative Macrophage-Like Pluripotent Muse Cells

MARI DEZAWA

Gordon Research Conference　2024/07/30
Multiple Organ Regeneration Using Muse Stem Cells Invited

MARI DEZAWA

Special Lecture at Colorado University　2024/07/26
Donor-Muse cell therapy is free from surgical treatment, gene manipulation, HLA-matching, and immunosuppressant. Invited

MARI DEZAWA

PPSSC2024　2024/06/15
医療は新たなステージへ：HLA適合や免疫抑制剤を必要としないドナーMuse細胞による点滴治療 Invited

出沢真理

第66回日本小児神経学会学術集会　2024/06/06
医療は新たなステージへ：HLA適合や免疫抑制剤を必要としないドナーMuse細胞の点滴治療 Invited

出沢真理

獨協医科大学「再生医療セミナー」　2024/05/09
医療は新たなステージへ：HLA適合や免疫抑制剤を必要としないドナーMuse細胞の点滴治療 Invited

出沢真理

第80回日本小児神経学会関東地方会　2024/03/03
医療は新たなステージへ：Muse細胞のもたらす未来の医療 Invited

出沢真理

第125回日本赤十字社院長連盟東部ブロック院長・事務部長会議　2024/02/21
A novel treatment strategy harnessing donor Muse cells that does not require HLA matching or immunosuppressants Invited

MARI DEZAWA

Special Lecture at Erciyes University　2024/01/16
A New Stage of Medicine:Future Medical care with Muse Cells Invited

MARI DEZAWA

第1回日本化粧品技術者会学術大会　2023/12/07
Muse cell treatment; Next-generation medical revolution compatible with the body's natural repair system Invited

MARI DEZAWA

JDDW 2023 第27回日本肝臓学会大会　2023/11/02
Donor-Muse cell therapy free from HLA-matching test and immunosuppressant treatment. Invited

MARI DEZAWA

第38回日本整形外科学会基礎学術集会　2023/10/19
Muse cell treatment:Next-generation medical revolution compatible with the 'body's natural repair systemus'

MARI DEZAWA

International Society Cell & Gene Therapy（ISCT）North America Regional Meeting　2023/09/09
Donor-Muse cell therapy for brain and spinal cord: free from surgical treatment, gene introduction, differentiation induction, HLA-matching and immunosuppressant.

MARI DEZAWA

Gordon Research Conference　2023/07/10
幹細胞・病的細胞を量子科学の視点から観る

DEZAWA MARI

2023/05/18
Muse細胞がリードする未来の医療と健康長寿社会の実現 Invited

出沢真理

第26回リウマチフォーラム　2023/02/04
Muse細胞のもたらす医療イノベーション Invited

出沢真理

第57回日本脊髄障害医学会　2022/11/17
生体に備わるMuse細胞の医療変革：アンチエージングへの貢献の可能性 Invited

出沢真理

第2回アンチエイジングセミナー in 仙台　2022/11/12
体内に備わる修復機構を活用した次世代のMuse細胞治療 Invited

出沢真理

第37回日本薬物動態学会　2022/11/08
体に内在する多能性修復幹細胞Muse細胞のもたらす医療変革 Invited

出沢真理

第49回⽇本臨床バイオメカニクス学会　2022/11/04
がん治療における臓器傷害からの復活：Muse細胞がリードする健康長寿社会の実現 Invited

出沢真理

世界がん撲滅サミット2022 in OSAKA　2022/11/03
体に内在する多能性修復幹細胞Muse細胞のもたらす医療変革 Invited

出沢真理

第58回日本移植学会　2022/10/15
Muse細胞のもたらす医療イノベーション Invited

出沢真理

第50回日本臨床免疫学会　2022/10/13
生体に備わるMuse細胞の医療変革：アンチエージングへの貢献の可能性 Invited

出沢真理

日本化粧品技術者会西日本支部第214回講演会　2022/09/30
体に内在する多能性修復幹細胞 Muse細胞のもたらす医療変革 Invited

出沢真理

第77回日本体力医学会　2022/09/23
体に内在する修復性多能性幹細胞 Muse細胞の拓く未来の医療 Invited

出沢真理

第36回新潟移植再生研究会　2022/09/05
Muse cell treatment: Next-generation medical revolution compatible with the ‘body’s natural repair systems’ Invited

MARI DEZAWA

PPSSC2022　2022/09/02
体に内在する修復性多能性幹細胞 Muse細胞の拓く未来の医療 Invited

出沢真理

LHS研究所「21世紀再生医療フォーラム」　2022/08/03
体に内在する多能性修復幹細胞Muse細胞のもたらす医療変革 Invited

出沢真理

東海地区遷延性意識障害者と家族の会「ひまわり」2022年度講演会　2022/07/31
Medical innovation by endogenous pluripotent Muse cells Invited

MARI DEZAWA

2022/07/01
Muse細胞のもたらす医療イノベーション Invited

出沢真理

第22回日本抗加齢医学会　2022/06/18
Muse細胞のもたらす医療イノベーション Invited

出沢真理

第37回日本脊髄外科学会　2022/06/16
Muse細胞のもたらす医療イノベーション Invited

出沢真理

第70回日本輸血・細胞治療学会総会　2022/05/28
Medical innovation by endogenous pluripotent Muse cells Invited

DEZAWA Mari

2022/05/18
Muse細胞のもたらす医療イノベーション Invited

出沢真理

LHS研究所設立１周年記念ウェビナー　2022/04/23
Muse細胞のもたらす医療イノベーション Invited

出沢真理

第42回日本臨床薬理学会学術集会　2021/12/10
Challenge to medical innovation by non-tumorigenic endogenous reparative Muse cells Invited

Mari Dezawa

Federation of Stem Cell Associations First International STEMNET MEETING　2021/09/23
Muse細胞のもたらす医療イノベーション Invited

出沢真理

第57回日本移植学会総会　2021/09/19
Medical innovation by endogenous pluripotent Muse cells; recent advances of basic research and clinical trials Invited

MARI DEZAWA

Pan Pacific Symposium on Stem Cells and Cancer Research（PPSSC）2021　2021/09/12
Muse細胞がもたらす未来の医療 Invited

出沢真理

2021薬物動態談話会セミナー　2021/08/26
Multilineage differentiating stress enduring (Muse) cells Invited

MARI DEZAWA

Regenerative Medicine and Tissue Engineering　2021/06/25
Medical innovation by non-tumorigenic reparative pluripotent Muse cells Invited

MARI DEZAWA

IANR XIII CONFERENCE　2021/05/26
Muse細胞のもたらす次世代の修復医療 Invited

出沢真理

第126回日本解剖学会総会・全国学術集会　2021/03/28
Muse細胞のもたらす新しい医療 Invited

出沢真理

第94回日本細菌学会総会　2021/03/25
Muse細胞のもたらす新しい医療 Invited

出沢真理

第20回日本再生医療学会学術総会　2021/03/11
Muse細胞を用いた医療イノベーションへの挑戦 Invited

出沢真理

第30回日本医療薬学会年会　2020/10/29
Muse細胞による医療イノベーションへの挑戦 Invited

出沢真理

第61回日本神経学会学術大会　2020/09/02
Muse細胞の作る未来の医療 Invited

出沢真理

21世紀先端医療コンソーシアム　2020/07/10
Muse細胞と臨床応用 Invited

Mari Dezawa

2020/05
Challenge to medical innovation by non-tumorigenic pluripotent Muse cells International-presentation Invited

DEZAWA Mari

Taiwan Healthcare Expo 2019　2019/12/06
Muse細胞を用いた医療イノベーションへの挑戦 Invited

出沢真理

第72回日本細菌学会中国・四国支部総会　2019/11/23
Aiming for a Medical Renaissance by Clinical Trials of Endogenous Reparative Pluripotent Muse cells International-presentation Invited

DEZAWA Mari

Health Span Hawaii Summit　2019/11/04
Challenge to medical innovation by Muse cells International-presentation Invited

DEZAWA Mari

The 3rd Vinmec Intl. Conference in Hanoi, Vietnam　2019/10/31
Muse細胞のもたらす医療イノベーションへの挑戦 Invited

出沢真理

第64回日本口腔外科学会総会学術大会　2019/10/27
Muse細胞を用いた新しい再生医療について Invited

出沢真理

第43回日本血液事業学会総会　2019/10/02
Muse細胞のもたらす新しい治療概念 Invited

出沢真理

第59回日本臨床化学会　2019/09/29
生体内修復幹細胞 Muse細胞による医療イノベーションへの挑戦 Invited

出沢真理

再生医療イノベーションフォーラム　2019/08/29
Muse細胞のもたらす新しい治療戦略：修復幹細胞治療 Invited

出沢真理

第92回日本整形外科学会学術総会　2019/05/12
Aiming for a Medical Renaissance by Clinical Trials of Endogenous Reparative Pluripotent Muse cells Invited

DEZAWA Mari

2019/05/09
Future of Regenerative Medicine and Immune Therapy for Cancer International-presentation Invited

MARI DEZAWA

Pan Pacific Symposium on Stem Cells and Cancer Research（PPSSC）2019　2019/05/04
Strategy for Clinical Trials of Muse Cells, Endogenous Reparative Pluripotent Stem Cells International-presentation Invited

MARI DEZAWA

Pan Pacific Symposium on Stem Cells and Cancer Research（PPSSC）2019　2019/05/04
Removing barriers of regenerative medicine and promoting innovation connections by discovery of human endogenous pluripotent Muse cells International-presentation Invited

MARI DEZAWA

the 2019 National Academy of Inventors Annual Meeting（NAI 8th Annual Meeting）　2019/04/11
Muse細胞を用いた臨床応用への取り組みと再生医療の実用化最前線 Invited

出沢真理

第18回日本再生医療学会　2019/03/22
Muse細胞による修復医療：基礎的研究から臨床応用まで Invited

出沢真理

第18回日本再生医療学会　2019/03/21
Muse細胞の発見と医療ルネッサンスへの挑戦 Invited

出沢真理

第53回糖尿病学の進歩　2019/03/02
Muse細胞の提示する新しい治療概念：修復医学 Invited

出沢真理

第80回日本臨床外科学会　2018/11/22
Muse細胞の発見と医療ルネッサンスへの挑戦！ International-presentation Invited

出沢真理

がん撲滅サミット2018　2018/11/18
Muse細胞の提示する新しい治療概念：修復医学 Invited

出沢真理

第45回日本臓器保存生物医学会　2018/11/10
新しい医療を切り開くMuse細胞の可能性 Invited

出沢真理

第21回日本IVF学会　2018/10/28
The Paradigm Shift of Stem Cell Therapy by Endogenous Reparative Pluripotent Muse Cells International-presentation Invited

MARI DEZAWA

Louisiana State University　2018/10/18
A novel type of stem cells, endogenous reparative pluripotent Muse cells, may revolutionize medical care International-presentation Invited

DEZAWA Mari

University of North Carolina　2018/10/16
新しい医療を切り開くMuse細胞の可能性 Invited

出沢真理

第33回日本整形外科学会・基礎講座　2018/10/11
Muse細胞による修復医療総論 Invited

出沢真理

日本脳神経外科学会第77回学術総会 JNS2018 in SENDAI　2018/10/10
Endogenous pluripotent Muse cells may revolutionize medical care International-presentation Invited

MARI DEZAWA

International Association of Neurorestoratology (IANR) 2018　2018/10/02
Muse細胞の提示する新しい治療概念：修復医学 Invited

出沢真理

第10回Acute Care Surgery学会　2018/09/15
医療の未来を切り開くMuse細胞 Invited

出沢真理

第28回日本臨床工学会　2018/05/26
Unique Reparative Mechanism of Muse Cells: Specific Homing by S1P-S1P Receptor System International-presentation Invited

MARI DEZAWA

The 11th Pan Pacific Symposium on Stem Cells and Cancer Research (PPSSC) 2018　2018/03/24
新しい医療を切り開くMuse細胞の特異性と可能性 Invited

出沢真理

第17回日本再生医療学会　2018/03/22
Endogenous reparative Muse cells may provide novel therapeutic approaches International-presentation Invited

DEZAWA Mari

Stem Cell Research 2018　2018/03/19
新しい医療を切り開くMuse細胞の可能性 Invited

出沢真理

第45回日本膵・膵島移植研究会　2018/03/02
Endogenous non-tumorigenic pluripotent Muse cells enable Reparative Medicine, a novel therapeutic concept International-presentation Invited

DEZAWA Mari

Cell Therapy of CNS Diseases Association of Polish Academy of Science　2017/12/08
新しい医療を切り開くMuse細胞の可能性 Invited

出沢真理

第52回日本脊髄障害医学会　2017/11/17
Muse細胞を活用する次世代医療：修復医学の可能性 Invited

出沢真理

第60回日本脳循環代謝学会学術集会　2017/11/04
Muse細胞：生体内修復機構を活用した新たな治療戦略 Invited

出沢真理

第63回日本病理学会秋期特別総会　2017/11/02
Endogenous reparative Muse cells may provide novel therapeutic approaches International-presentation Invited

DEZAWA Mari

The 8th meeting of Asian Cellular Therapy Organization（ACTO）　2017/10/28
生体に備わる修復幹細胞としての『Muse細胞』、新たな再生医療の世界 Invited

出沢真理

Bio Japan 2017　2017/10/11
Unique Newly Discovered Muse Cells May Lead to the Paradigm Shift of Stem Cell Therapy International-presentation Invited

DEZAWA Mari

Stem Cell Conference 2017　2017/08/07
Muse細胞：自然の修復機構を活用した新しい再生医学の可能性 Invited

出沢真理

京都コモンズ第20回セミナー　2017/07/26
医療の未来を切り開くMuse細胞 International-presentation Invited

DEZAWA Mari

The 10th KAITEKI FORUM　2017/07/11
Muse細胞：自然の修復機構を活用した新しい再生医療の可能性 Invited

出沢真理

第65回日本輸血・細胞治療学会総会　2017/06/23
Direct Contribution of Bone Marrow Cells to Tissue Regeneration International-presentation Invited

DEZAWA Mari

AMERICAN Transplant CONGRESS 2017　2017/05/01
Muse cells may contribute to tissue homeostasis by reparative function International-presentation Invited

DEZAWA Mari

テキサスA＆M大学研究打合せ・講義　2017/04/28
生体の修復を担うMuse細胞を活用した修復再生医学への展望 Invited

出沢真理

第8回日本ニューロリハビリテーション学会　2017/04/22
Human Muse cells reconstruct neuronal circuitry in rodent acute and subacute stroke models International-presentation Invited

DEZAWA Mari

The 10th Pan Pacific Symposium on Stem Cells and Cancer Research (PPSSC) 2017　2017/04/16
Muse細胞：自然の修復機構を活用した新しい再生医療の可能性 Invited

出沢真理

第16回日本再生医療学会総会（シンポジウム 17）　2017/03/08
成体に備わる修復幹細胞としてのMuse細胞：再生医療の一般普及を目指して Invited

出沢真理

第16回日本再生医療学会総会（会長講演）　2017/03/08
Muse細胞：自然の修復機構を活用した新しい再生医療の可能性 Invited

出沢真理

第14回日本免疫治療学研究会学術集会　2017/02/11
Unique Newly Discovered Muse Cells May Lead to the Paradigm Shift of Stem Cell Therapy Invited

出沢真理

日本研究皮膚科学会第41回年次学術大会・総会　2016/12/11
Unique Newly Discovered Muse Cells May Lead to the Paradigm Shift of Stem Cell Therapy International-presentation Invited

DEZAWA Mari

第9回アジア太平洋小児内分泌学会(APPES)　2016/11/19
多能性幹細胞Muse細胞による障がいの機能回復の展望 International-presentation Invited

DEZAWA Mari

スポーツ・文化・ワールド・フォーラム文部科学省主催スポーツダボス会議　2016/10/21
Unique Newly Discovered Muse Cells May Lead to the Paradigm Shift of Stem Cell Therapy International-presentation Invited

DEZAWA Mari

PACT Symposium: „Designer Cells Go Clinic“　2016/09/23
Muse cells as tissue repairing stem cells; a role of phagocytosis in their differentiation International-presentation Invited

DEZAWA Mari

Cell Symposium 100 Years of Phagocytes　2016/09/21
Unique mitochondrial metabolism in Muse cells International-presentation Invited

DEZAWA Mari

the 9th Pan Pacific Symposium on Stem Cells and Cancer Research (PPSSC) 2016　2016/05/13
Transplantation of Unique, Newly Discovered Muse Cells May Lead to Promising Stroke Therapy International-presentation Invited

DEZAWA Mari

The American Society for Neural Therapy and Repair (ASNTR) 2016　2016/04/29
Muse細胞：再生医療のおけるハードルの低い一般医療化を目指して Invited

出沢真理

第15回日本再生医療学会総会　2016/03/19
Muse細胞によるハードルの低い再生医療の一般化を目指して Invited

出沢真理

第15回再生心臓血管外科治療研究会　2016/02/15
生体内に存在する多能性幹細胞Muse細胞の体内動態と組織修復機構 Invited

出沢真理

第38回日本分子生物学会　2015/12/03
Muse細胞がもたらす医療革新 Invited

出沢真理

Nomura Investment Forum 2015　2015/12/01
生体内修復幹細胞としてのMuse細胞はどこまで脳梗塞を治せるのか Invited

出沢真理

第27回日本脳循環代謝学会総会　2015/10/30
Muse細胞発見のもたらす再生医療のパラダイムシフト Invited

出沢真理

テルモ科学技術振興財団特定研究成果報告会　2015/10/13
Muse細胞の発見：ハードルの高い再生医療の一般医療化を目指して Invited

出沢真理

第16回日本分子脳神経外科学会　2015/08/28
Muse細胞の発見によってもたらされる間葉系幹細胞移植のパラダイムシフト Invited

出沢真理

第5回細胞再生医療研究会特別講演Ⅱ　2015/07/26
Muse細胞の発見によってもたらされる間葉系幹細胞移植のパラダイムシフト Invited

出沢真理

日本耳鼻咽喉科学会東北連合学会特別講演　2015/07/18
Muse細胞の発見によってもたらされる間葉系幹細胞移植治療のパラダイムシフト Invited

出沢真理

第13回日本臨床腫瘍学会　2015/07/16
Discovery of Muse cells shift the paradigm of mesenchymal stem cells International-presentation Invited

DEZAWA Mari

AsiaCORD_AHA2015 MEETING in KOBE　2015/05/02
Muse細胞の発見がもたらす再生医療の新たな可能性 Invited

出沢真理

日本内分泌学会イブニングセミナー　2015/04/23
Discovery of Muse Cells shifts the Paradigm of Stem Cell Therapy International-presentation Invited

DEZAWA Mari

PPSSC 2015　2015/04/12
Muse cells and their possible application to both autologous and allogenic transplantation therapy International-presentation Invited

DEZAWA Mari

PPSSC 2015　2015/04/11
Discovery of Muse Cells shifts the Paradigm of Mesenchymal Stem Cells International-presentation Invited

DEZAWA Mari

Clinical Applications of Stem Cells　2015/02/27
Discovery of Muse Cells shifts the Paradigm of Mesenchymal Stem Cells International-presentation Invited

DEZAWA Mari

日仏再生医学シンポジウム　2014/11/20
Muse細胞の発見によってもたらされる間葉系幹細胞移植のパラダイムシフト Invited

出沢真理

第56回日本先天代謝異常学会　2014/11/14
Muse細胞の発見によってもたらされる間葉系幹細胞移植のパラダイムシフト Invited

出沢真理

未来医療開発プロジェクト（ＭＩＡＳＴ）シンポジウム　2014/08/08
腫瘍性の無い生体由来多能性幹細胞 Muse細胞の発見：ヒトは失われた機能を取り戻せるのか Invited

出沢真理

第14回日本外傷歯学会　2014/07/26
再生医療研究の現状とMuse細胞の将来展望 Invited

出沢真理

特許庁平成26年度先端技術研修　2014/06/20
骨髄と結合組織を足場とする多能性幹細胞 Muse細胞の担う生体内修復機能 Invited

出沢真理

第46回日本結合組織学会学術大会第61回マトリックス研究会大会合同学術集会　2014/06/06
Muse細胞発見のもたらす間葉系幹細胞のパラダイムシフト Invited

出沢真理

第55回日本神経学会　2014/05/24
Discovery of Muse cells, novel pluripotent stem cells that reside in human mesenchymal tissues: implications for new concepts of regenerative homeostasis and stem cell failure. International-presentation Invited

DEZAWA Mari

Seminar at Nelson Biological Labs in Rutgers　2014/04/30
Making three dimensional human colored skin by using Muse cells, a novel type of non-tumorigenic pluripotent stem cells International-presentation Invited

DEZAWA Mari

Stem Cells andTissue Injury Platform Session at EB 2014　2014/04/28
Discovery of Muse Cells, Novel Pluripotent Stem Cells That Reside in Human Mesenchymal Tissues: Implications for New Concepts of Regenerative Homeostasis and Stem Cell Failure International-presentation Invited

DEZAWA Mari

PPSSC 2014　2014/04/12
Discovery of intrinsic pluripotent stem cells, Muse cells, that reside in adult human mesenchymal tissues. International-presentation Invited

DEZAWA Mari

Small RNAs to Stem Cells & Epigenetic Reprogramming Asia-2013 Meeting　2013/11/26
ヒト生体に内在する新たな多能性幹細胞Muse細胞：組織修復恒常性の役割 Invited

出沢真理

第66回日本胸部外科学会定期学術集会　2013/10/19
Discovery of Muse cells, novel pluripotent stem cells that reside in human mesenchymal tissues: implications for new concepts of regenerative homeostasis and stem cell failure. International-presentation Invited

DEZAWA Mari

International Seminar Series of Norwegian Center for Stem Cell Research　2013/10/16
間葉系組織に存在する多能性幹細胞(Muse細胞)の可能性 Invited

出沢真理

BioJapan 2013　2013/10/10
生体内に内在する多能性幹細胞 Muse細胞とregenerative homeostasis Invited

出沢真理

第102回日本病理学会総会　2013/06/07
ヒト生体に内在する多能性幹細胞 Muse細胞：組織修復恒常性の役割 Invited

出沢真理

第28回日本脊髄外科学会　2013/06/06
Discovery of Muse cells, intrinsic pluripotent stem cells in human mesenchymal tissues; are they a major player of regenerative homeostasis in our body? International-presentation Invited

DEZAWA Mari

NIH－Tohoku University Intl. Symposium　2013/05/09
Intrinsic pluripotent stem cells, Muse cells, are a primary source of iPS cells in human fibroblasts International-presentation Invited

DEZAWA Mari

AAA's Annual Meeting at EB 2013　2013/04/22
新規に発見された組織恒常性を担う生体内多能性幹細胞：Muse細胞 Invited

出沢真理

日本医工学治療学会第29回学術大会　2013/04/20
Discovery of intrinsic pluripotent stem cells, Muse cells in human mesenchymal tissues; are they a major player of regenerative homeostasis in the body? International-presentation Invited

DEZAWA Mari

AsiaCORD meeting KOBE 2013　2013/04/19
ヒト生体に内在する新たな多能性幹細胞Muse 細胞：医療における様々な展開の可能性 Invited

出沢真理

第118回日本解剖学会総会・全国学術集会　2013/03/28
生体に内在する多能性幹細胞 Muse細胞：組織修復細胞としての機能と次世代の再生医療に向けて Invited

出沢真理

第12回日本再生医療学会総会　2013/03/21
The Possibility of Novel Adult Human Pluripotent Stem Cell Type, Muse Cell, for Regenerative Medicine Invited

出沢真理

第77回日本循環器学会学術集会　2013/03/16
新たに発見されたヒト生体内多能性幹細胞 Muse細胞の再生医療と組織再建への可能性 Invited

出沢真理

JAACT2012　2012/11/28
ヒト生体に内在する新たな多能性幹細胞Muse 細胞：細胞治療、予後の診断、創薬、病態解析への展開の可能性 Invited

出沢真理

第50回日本人工臓器学会大会　2012/11/23
ヒト生体由来多能性幹細胞 MUSE細胞の組織修復再生医療の可能性 Invited

出沢真理

第27回日本整形外科学会基礎学術集会　2012/10/27
新たに発見されたヒト生体由来の多能性幹細胞 Muse細胞：神経再生医療への可能性 Invited

出沢真理

第23回日本末梢神経学会　2012/09/01
Muse cells, a novel type of adult human pluripotent stem cells that reside in mesenchymal tissues: their great possibility for regenerative medicine International-presentation Invited

DEZAWA Mari

Dutch - Japanese Cross Debate Workshop on RM and Stem cells　2012/06/17
Muse cells, a novel type of adult human pluripotent stem cells that reside in mesenchymal tissues: their great possibility for regenerative medicine International-presentation Invited

DEZAWA Mari

IANR/GCNN/ISCITTsymposium　2012/05/05
A Novel Type of Adult Human Pluripotent Stem Cells (Muse Cells) that Exist Among Mesenchymal Tissues and Their Primary Role in iPS Cell Generation International-presentation Invited

DEZAWA Mari

Mayo Clinic　2012/04/30
Muse cells: A Great Potential of Muse Cells for Clinical Application to Neurodegenerative Diseases International-presentation Invited

DEZAWA Mari

APSNR＆PPSSC joint meeting　2012/04/15
ES細胞、iPS細胞に続く第三の多能性幹細胞Muse細胞：その再生医療へのポテンシャル Invited

出沢真理

第25回表皮細胞研究会　2011/10/29
Muse cells: a novel type of adult human pluripotent stem cells that exist in mesenchymal tissues International-presentation Invited

DEZAWA Mari

The 8th International Symposium on Minimal Residual Cancer　2011/09/23
A Novel Type of Adult Human Pluripotent Stem Cells (Muse cells) that reside in Mesenchymal Tissues International-presentation Invited

DEZAWA Mari

The 2nd Congress of Polish Biochemistry and Cell Biology　2011/09/08
ヒト成人生体由来の多能性幹細胞（Muse細胞）の発見と再生医療応用への可能性 Invited

出沢真理

第20回日本意識障害学会　2011/09/02
Muse細胞による再生治療、その臨床応用への展望と課題 Invited

出沢真理

日本再生医療学会主催エデュケーショナルセミナー　2011/08/02
ヒト生体の間葉系組織に存在する多能性幹細胞（Muse細胞）：生物学的意義と臨床応用への可能性 Invited

出沢真理

第30回分子病理学研究会　2011/07/23
新たなヒト生体由来多能性幹細胞の発見と再生医療への可能性 Invited

出沢真理

第54回日本腎臓学会学術総会　2011/06/15
ヒト間葉系組織に存在する新たな生体由来多能性幹細胞（Muse細胞）の発見 Invited

出沢真理

第116回日本解剖学会総会・全国学術集会　2011/03/29
Muse cells: a novel type of adult human pluripotent stem cells and their possible application to cell therapy International-presentation Invited

DEZAWA Mari

Experimental Biology 2011　2011/03/11
生体に存在する第三の多能性幹細胞：In situ stem cell therapyの可能性 Invited

出沢真理

第11回日本分子脳神経外科学会総会　2010/08/27
Muse細胞の発見：新たな生体由来のヒト多能性幹細胞の可能性 Invited

出沢真理

生物多様性学グローバルCOEプログラム　2010/07/26
Bone marrow stromal cells: A hope for auto-cell transplantation therapy for neuro- and muscle-degenerative diseases. International-presentation Invited

DEZAWA Mari

The Pan Pacific Symposium on Stem Cells Research　2010/04/18
未来の医療を変えるMuse細胞の発見と秘話：チャンスはどのように訪れるのか Invited

DEZAWA MARI

2023/06/17
Muse細胞のもたらす医療イノベーション Invited

DEZAWA MARI

2023/06/08
Muse細胞がリードする医療変革と健康長寿社会の実現 Invited

DEZAWA MARI

2023/03/03

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Industrial Property Rights 3

脳梗塞治療のための多能性幹細胞

吉田正順, 出沢真理, 富永俤二

Property Type: Patent
心筋梗塞の修復再生を誘導する多能性幹細胞

吉田正順, 湊口信也, 出沢真理

Property Type: Patent
生体組織から単離できる多能性幹細胞

出沢真理, 藤吉好則, 鍋島陽一, 若尾昌平

Property Type: Patent

Research Projects 63

Exploratory research for Muse cell function and epidemiology in diabetes patients

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Challenging Research (Exploratory)

Institution: Dokkyo Medical University

2023/06/30 - 2026/03/31
Basic research on Muse cell transplantation for Duchenne muscular dystrophy

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: National Center of Neurology and Psychiatry

2023/04/01 - 2026/03/31
正常細胞と病的細胞の光散乱・揺らぎ4次元解析：散乱透視学と医学の融合

出沢真理

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 学術変革領域研究(A)

Institution: 東北大学

2023/04/01 - 2025/03/31
急性心筋梗塞患者の末梢血で増加するMUSE細胞のプロファイル

佐久間理吏, 串田良祐, 井上晃男, 相馬良一, 出沢真理, 井上健一

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 基盤研究(C)

Institution: 獨協医科大学

2022/04/01 - 2025/03/31
The novel differentiation method in pluripotent stem cells without using gene introduction or cytokine stimulation.

Mari Dezawa

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2020/04 - 2024/03
Muse細胞の予防医学応用のための細胞組織疫学研究

小橋元, 内山浩志, 春山康夫, 出沢真理, 高倉聡, 井上健一

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 挑戦的研究(萌芽)

Institution: 獨協医科大学

2020/07/30 - 2023/03/31

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Multilineage-differentiating stress enduring (Muse)細胞は生体内に存在する多能性幹細胞である。骨髄から末梢血に動員されて各臓器に供給され、傷害や細胞死によって失われた細胞を分化によって置換・補充することで多様な臓器の修復に対応する。 Muse細胞は、胎盤の免疫抑制効果を担うHLA-Gを発現する性質と、傷害組織の細胞膜か出る警報シグナル(スフィンゴシン-1-リン酸；S1P)に対する受容体を持ち、傷害部位に特異的に集積する。本研究では、傷害組織の障害修復に関わるmuse細胞の予防医学への応用を目指して、健常者における予防医学的応用、さらには妊娠、胎児・乳幼児発達といった母子保健分野における応用の可能性を探る基礎資料を得ることを目的とするものであった。しかし、2020年からの新型コロナウイルス流行により、共同研究先の産科施設の妊婦検診の状況が大幅に変化したため、妊産婦のリクルートを行いその血液サンプルを解析するという当初の研究計画は大幅に遅れている。一方で、非妊婦集団を対象とした研究計画については、研究倫理審査委員会の承認を受け、共同研究先病院の糖尿病外来においてフォローアップを受けている男女患者（HbA1cレベルにて正常群、軽度耐糖能異常群、糖尿病群の３群に分類している）のリクルートがほぼ完了しつつある。血液サンプルからの単核球分離により行うmuse細胞のFACS解析、S1P測定、muse細胞における遺伝子発現解析等のデータは、次年度には解析を行い、その結果を学会等において報告していく予定である。当初の予定の一つであった周産期の血液サンプル解析に関しては、新型コロナウイルス流行の影響がやや収まりつつある次年度、臍帯血の採取と分析から開始できる予定であり、何とか当初計画した研究を再開し、有用な結果を得たいと考えている。
Muse cell transplantation for spinal cord injury in chronic phase

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: University of Tsukuba

2020/04/01 - 2023/03/31
Muse細胞を用いた急性心筋炎の病態解明および新規治療法確立

井上晃男, 串田良祐, 相馬良一, 出沢真理, 正和泰斗, 豊田茂, 井上健一

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 基盤研究(C)

Institution: 獨協医科大学

2020/04/01 - 2023/03/31

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基礎的研究：マウス心筋炎モデルを用いてMuse細胞の治療効果を検証するにあたり、現在外部施設においてウイルスおよび細胞の準備を行っており、今後マウス心筋炎モデル作成および治療効果を実証する予定である。臨床研究：劇症型急性心筋炎症例を対象に、経時的に末梢血を採取し遠心分離により単核球分画を分離しMuse細胞数を経時的に測定を行っている。。Muse細胞はフローサイトメトリーを用いてSSEA-3陽性細胞として検出し同時にS1Pの動態観察を行っている。これまでに7例の劇症型心筋炎患者から検討を行った。このうち1例は残念ながら治療の甲斐なく亡くなってしまったが、ご家族の同意が得られ病理解剖を行った。心臓の組織および全身の組織を東北大学出澤研究所へ持参し、Muse細胞の局在につき検討を行ったところ、血管周囲や心外膜・心内膜側にMuse細胞の集積が認められた。また肝臓・膵臓・大網・皮下脂肪においてMuse細胞が散在していた。この症例ではMuse細胞数は5日目にピークを迎えていた。更に急性心筋炎では急性期に心筋生検を右室中隔から施行するが、本症例における心臓組織においてMuse細胞の観察を行ったところ、剖検時に比べはるかに多いMuse細胞の集積が観察され、急性期炎症時により強くMuse細胞が集積することを初めて明らかにした。さらにこれまでに当院で施行した急性心筋炎生検標本17例分を同様に検討しており、データ分析して発表する予定である。またコントロールとしての健常心筋組織におけるMuse細胞が集積しないことの証明や、剖検例でのデータ集積を行っていく予定である。
Search for innovative organ transplantation without the need for relatives or HLA matching Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for challenging Exploratory Research

2019/04 - 2022/03
Platform for regenerative therapy of central nervous system using Muse cells

TOMINAGA TEIJI

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (A)

Institution: Tohoku University

2017/04/01 - 2020/03/31

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Cerebral infarction accounts for ~60% of the total stroke and the number of patients is increasing. Even with the current sophisticated treatments including thrombolysis and thrombectomy, more than half patients get disabled. Therefore, it is imperative to develop a new treatment to enhance recovery and restore the lost neurological functions. Multilineage-differentiating stress-enduring (Muse) cells are endogenous nontumorigenic stem cells with pluripotency and minimum safety concerns. Muse cells recognize the injured site, home preferentially into the tissue and spontaneously differentiate into tissue-compatible cells to replace the lost cells, and repair the tissue, delivering functional and structural regeneration. The purpose of this study is to develop Muse cell therapy for central nervous system disorders. If Muse cell treatment was successfully developed, the social and economic impact is unimaginable.
Development of sepsis treatment strategy using Muse cell as stress-tolerant pluripotent stem cells from mesenchymal stem cells

Kushimoto Shigeki, Sato Tetsuya

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Tohoku University

2016/04/01 - 2019/03/31

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Multilineage-differentiating stress-enduring (Muse) cells were recently discovered as stress-tolerant pluripotent stem cells from mesenchymal stem cells (MSCs) and fibroblasts, as well as from the adult human bone marrow mononucleated fraction. Although Muse cells have been demonstrated to play an important role in vivo as endogenous stem cells that contribute to tissue homeostasis through reparative maintenance and to tissue reconstruction following serious tissue damage, its presence and characteristics in the peripheral blood of healthy human have not evaluated yet. This study showed the novel subtype of “Peripheral Blood Muse cells” in human peripheral blood. While the cell has some different characteristics to the bone marrow MCS-Muse cells, they exhibit pluripotent and migrating capacity to S1P as target molecule, and reparative functions following focal administration to the damaged tissue.
Neuronal differentiation of MUSE cells mediated by neuronal differentiation control peptides and application to neuronal regeneration medicine

Kanno Hiroshi, Dezawa Mari

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

2015/04/01 - 2019/03/31

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MUSE cells were sorted from skin-derived precursors with the MACS method. Neuronal differentiation of MUSE cells was induced by intracellular delivery of a VHL peptide composed of the BC-box motif [(A,P,S,T)LXXX (A,C) XXX(A,I,L,V)] corresponding to binding site of elongin BC. Neuronal differentiation mediated by the NDD was caused by the binding between it and elongin C followed by JAK2 ubiquitination of JAK2 and inhibition of the JAK2/STAT3 pathway. Then, we showed that different NDD peptide-delivered cells differentiated into different kinds of neuron-like cells. That is, dopaminergic neuron-like cells, cholinergic neuron-like cells, GABAnergic neuron-like cells or rhodopsin-positive neuron-like cells were induced by different NDD peptides. These novel findings might contribute to the development of a new method for promoting neuronal differentiation and shed further light on the mechanism of neuronal differentiation of somatic stem cells.
Effects of Multilineage-differentiating stress-enduring (Muse) cells on brain damages induced by Shiga toxin 2 in vivo and in vitro

Fujii Jun, DEZAWA Mari

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Tottori University

2015/10/21 - 2018/03/31

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Non-Muse cells are normal bone marrow mesenchymal stem cells minus Muse cells. NOD-SCID mice were infected with an injection directly into the stomach, with a bacterial suspension of STEC O111 1010 CFU (100% mortality). On day 2 after inoculation of STEC, bone marrow-derived Muse cells or non-Muse cells (bone marrow-MSCs other than Muse cells) were administered intravenously from the tail vein of the mouse model. An intravenous injection of human Muse cells had a strong effect in reducing the mortality rate (p<0.01) in the oral infection mouse model with STEC O111. In vitro experiment, reactivity of GFAP was maximized when 10 ng/ml of Stx2 and 1 µg/ml were exposed for a 12 h period. On greater observation many GFP-Muse cells were had attached to reactive astrocytes and some Muse cells surrounded astrocytes, and it seems that they may have killed the reactive astrocytes. In this microarray analysis, we discovered the factor X that may be involved in the reactive astrocytes.
Reconstruction of Neuronal Circuitry by Muse cell transplantation in lacunar stroke

Sakata Hiroyuki, TOMINAGA Teiji, DEZAWA Mari, Chan Pak H., WATANABE Mika, FUJIMURA Miki, NAKAGAWA Atsuhiro, NIIZUMA Kuniyasu

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Young Scientists (A)

Institution: Tohoku University

2015/04/01 - 2018/03/31

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Multilineage-differentiating stress-enduring (muse) cells, subpopulation of bone marrow-mesenchymal stem cells, are endogenous nontumorigenic stem cells with pluripotency. We transplanted Muse cells into the perilesion brain at 2 weeks after lacunar infarction in immunodeficient mice. Transplantation at the delayed subacute phase showed muse cells differentiated into neural cells, facilitated neural reconstruction, improved functions, and displayed solid safety outcomes over prolonged graft maturation period, indicating their therapeutic potential for lacunar stroke.
Treatment of Lung Ischemia-reperfusion injury by Muse cells

OKADA Yoshinori, DEZAWA Mari, YABUKI Hiroshi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Challenging Exploratory Research

Institution: Tohoku University

2015/04/01 - 2017/03/31

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Lung ischemia-reperfusion injury is a signify complication after lung transplantation. We examined the effect of Multi-lineage differentiating Stress Enduring cell (Muse cells) on ameliorating lung ischemia-reperfusion injury in a rat model. Human Muse cells (Muse group), human mesenchymal stem cells (MSC group) or PBS (Vehicle group) were infused into the left pulmonary artery after 2-hour ischemia and subsequent reperfusion. On days 3 and 5 after reperfusion, the Muse group showed the most favorable arterial blood gas, left lung compliance and histological scores for IR injury among 3 groups. The present study indicated that administration of Muse cells ameliorate lung ischemia-reperfusion injury in a rat model.
Analysis of the functions of MUSE in the lymphoma microenvironment.

Nakayama Takayuki, DEZAWA Mari

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Aichi Medical University

2014/04/01 - 2017/03/31

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The tumor microenvironment favors the tumor growth and enhanced the chemo-sensitivity of tumors. However, little is known about the mechanism what a kind cell forms the tumor microenvironment and where they come from so far. We found that multilineage-differentiating stress-enduring (Muse) cells reside in lymphoma tissues. Elevated expression of FGF2 has been reported in hematological malignancies, and is prognostically significant for malignant lymphoma. FGF2 significantly modulated expression of genes related to angiogenesis such as VEGF-A, Ang-1 in osteoblasts, a component of the tumor microenvironment, suggesting that FGF2 promotes angiogenesis. Migration assays showed that supernatants of lymphoma cells enhanced migration of MUSE cells. Thus, we concluded that MUSE cells migrate towards the lymphoma tumor via newly formed vasucularities by FGF2.
Genetically-engineered multilineage-differentiating stress-enduring cells as cellular vehicles against malignant gliomas

Namba Hiroki, DEZAWA MARI

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Hamamatsu University School of Medicine

2013/04/01 - 2017/03/31

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Suicide gene therapy based on the herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) is an efficient strategy for treating malignant gliomas. In the present study, we evaluated treatment with multilineage-differentiating stress-enduring (Muse) cells, endogenous non- tumorigenic pluripotent-like stem cells, as carriers of the HSVtk gene. HSVtk gene-transduced human Muse cells (Muse-tk cells) showed a potent in vivo bystander effect and migratory activity toward glioma cells. Intracranial U87 gliomas in nude mouse brains injected intratumorally with Muse-tk cells followed by intraperitoneal GCV administration were significantly reduced in size within 2 weeks. These findings suggest that intratumoral Muse-tk cell injection followed by systemic GCV administration is safe and effective, and that allogeneic Muse-tk cell-medicated suicide gene therapy for malignant glioma is clinically feasible.
腫瘍性を持たない多能性幹細胞 Muse細胞を用いた新たな肝再生治療 Competitive

DEZAWA Mari

Offer Organization: Japan Agency for Medical Research and Development

System: Research Program on Hepatitis

2015 - 2017
生体由来多能性幹細胞Ｍｕｓｅ細胞の発生学的起源の探索と組織恒常性維持における役割 Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for Scientific Research(B)

2014 - 2017
An analysis of the characteristics of Muse cells in mesenchymal cells obtained from umbilical cords, and the development of periodontal regenerative therapy applications

KANAZASHI Mikimoto, TABATA Yasuhiko, DEZAWA Mari

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Challenging Exploratory Research

Institution: Tsurumi University

2013/04/01 - 2016/03/31

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It has been reported that human stem tissues contain Muse cells, which have multilineage potential but do not have neoplasm generating characteristics. The purpose of this study is the development of tissue-engineering, periodontal regenerative therapy by using Muse cells in umbilical cord tissue, which is medical waste, and a gelatine hydrogel. As a result of sorting the cells, which were obtained from an umbilical cord by a method that we have reported on in the past, using SSEA-3, CD105 according to cytohistology protocols at the Graduate School of Medicine, Tohoku University, it was observed that the umbilical cord tissue had Muse cells with multilineage potential. In addition, the effectiveness of a gelatine hydrogel was confirmed as a result of human clinical studies. This study was performed under the authorization of the ethical review committee of the Faculty of Dentistry, Tsurumi University (receipt number: No.1203).
Basic and Clinical Aspects of MUSE Cells in Stroke Care

KURODA Satoshi, KUWAYAMA Naoya, HAYAKAWA Yumiko, DEZAWA Mari, KASHIWAZAKI Daina, AKIOKA Naoki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: University of Toyama

2013/04/01 - 2016/03/31

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Motor function recovery in BMSC and non-Muse groups became apparent at 21 days after transplantation, but reached the plateau thereafter. In Muse group, functional recovery was not observed for up to 28 days post-transplantation, but became apparent at 35 days post-transplantation. On immunohistochemistry, only Muse cells were integrated into peri-infarct cortex and differentiate into neurons, while negligible number of BMSCs and non-Muse cells remained in the peri-infarct area at 42 days post-transplantation. This study was aimed to prove the hypothesis that Muse cells are mobilized from bone marrow into peripheral blood in patients with ischemic stroke. This study included 29 patients with ischemic stroke. The number of Muse cells robustly increased within 24 hours after the onset, compared with the controls. Multivariate analysis revealed that smoking and alcohol intake significantly affect the increase in circulating Muse cells.
Muse細胞を用いた再生医療の実現に向けた製剤製造システムの研究開発 Competitive

DEZAWA Mari

Offer Organization: Japan Agency for Medical Research and Development

System: Project Focused on Developing Key Evaluation Technology: Manufacturing Technology for Industrialization in the Field of Regenerative Medicine

2015 - 2016
肝切除後組織修復に関わるMuse細胞の役割とその臨床応用に向けた基盤構築

若林剛, 出沢真理, 西塚哲, 八谷剛史

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 基盤研究(C)

Institution: 岩手医科大学

2013/04/01 - 2015/03/31

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先行実験からSCIDマウスの部分肝移植後にヒト骨髄由来のMuse細胞が肝切離断面に集積し、肝臓構成細胞に分化して肝組織修復および再生に寄与していることが明らかとなった。本研究では、(A)Muse細胞移植実験によって確認された確認された肝外性差肝組織修復細胞の誘導因子同定および(B)生体部分肝移植生検組織を用いた肝外由来細胞の局在同定を目的とし、肝外性細胞による組織修復を臨床的肝再生モニタリングの指標として用いる可能性を検証した。 (A)については、肝切離断面近傍で発現している遺伝子を網羅的に解析し切離後24時間では細胞接着、48時間ではMHC結合タンパク、72時間では細胞周期等に関する遺伝子発現が上昇していた。これらの結果からその上位シグナルを検証し誘導因子を同定する実験を開始した。(B)については、はじめにそのモデルとしてGFP導入Muse細胞を用いて、肝細胞(HepPar-1)、胆管細胞(CK19)、および類洞上皮細胞(Lyve-1)特異的タンパクの２重染色でその局在を同定し分化を確認した。さらに、レシピエントが男性、ドナーが女性の場合のグラフトからレシピエント由来（X染色体があるもの）細胞が各組織に分化していることを確認した。以上のことから、生体部分肝移植時のグラフト肝における肝外細胞由来の肝組織の存在が臨床的肝再生モニタリングの指標の一つになることが示された。一方、Muse細胞を用いた実験からは、肝外細胞の集積は肝切離面に比較的限局しており、切離面を避けて行う生検材料では情報が限定的になる可能性も考えられた。
Isolation of pluriptent somatic stem cells for neuronal regenerative medicine and neuronal differentiation peptide-mediated neuronal differentiation

KANNO Hiroshi, ITO Norihiko, DEZAWA Mari

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Yokohama City University

2011/04/01 - 2014/03/31

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We used neural stem cells and skin-derived mesenchymal stem cells as pluripotent somatic stem cells to neuronal lineage. Eleven BC-box proteins(SOCS1-7, ASB3, WSB2, LRR1, VHL)-derived functional peptides are delivered to those somatic stem cells. Each peptide induced to differentiate different type of neuron. VHL and socs7-derived peptides induced to differentiate dopaminergic and motor neurons, and SOCS5-derived peptide induced to differentiate retinal color epithelial cells and gultamate neuron. This mechanism of neuronal differentiation is suggested to be related to degeradation of Stat3, but is under investigation.
Suggested common mechanism underlying between human Muse cells and planarian neoblasts Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for challenging Exploratory Research

2013 - 2014
ヒト生体由来多能性幹細胞（Ｍｕｓｅ細胞）の再生医療への応用に向けた安全性・有効性の検証 Competitive

DEZAWA Mari

Offer Organization: Ministry of Health, Labour and Welfare

System: Health and Labor Sciences Research Grant

2012 - 2014
Development of a definitive therapy for degenerative neuromuscular diseases using autologous cells and cell banks Competitive

DEZAWA Mari

Offer Organization: National Institute of Biomedical Innovation

System: ＊

2010 - 2014
Muse細胞を用いた再生医療の実現に向けた製剤製造システムの研究開発 Competitive

DEZAWA Mari

Offer Organization: New Energy and Industrial Technology Development Organization

System: Project Focused on Developing Key Evaluation Technology: Manufacturing Technology for Industrialization in the Field of Regenerative Medicine

2014 -
Effects of bone marrow mesenchymal stem cells on encephalopathy caused by Shiga toxin 2c-producing Escherichia coli infection in mice

FUJII Jun, DEZAWA Mari

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

2011 - 2013

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We transplanted Mutilineage-differenting stress-enduring (Muse) cells or non-Muse cells intravenously to the mouse model that impaired blood brain barrier caused by an oral infection of Stx2c-producing E. coli (E32511). We investigated the effects of Muse and non-Muse cells on encephalopathy caused by E32511 infection. Only Muse cells engrafted in the pons and medulla and non-Muse cells did not engraft in any area of the whole brain. As the results, caspase-3 activation was statistically decrease in the mouse brain transplanted Muse cells in the E32511-infected mice. The water channel aquaporin 4 (AQP4) is located in the perivascular end-feet of astrocytes (ASTs) in the brain. Furthermore, reactive ASTs and down-regulation of AQP4were not detected in the brain transplanted Muse cells although reactive ASTs and down-regulation could be detectable in the brain transplanted non-Muse cells.
Characterization of Muse cells, non-tumorigenic intrinsic pluripotent stem cells, and their application to regenerative medicine. Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for Scientific Research(B)

2011 - 2013
Muse細胞の評価基盤技術開発に基づく、再生医療に向けた培養・評価装置の研究開発 Competitive

DEZAWA Mari

Offer Organization: New Energy and Industrial Technology Development Organization

System: ＊

2010 - 2013
Possibility of transplantation of human skin-derived pluripotent stem cells into the bone marrow Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for challenging Exploratory Research

Category: Grant-in-Aid for Challenging Exploratory Research

Institution: Tohoku University

2011 - 2012

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Human dermal fibroblast-derived Muse cells, a type of pluripotent stem cells (Kuroda et al., PNAS, 2010), were infused into X-ray irradiated SICD mouse via tail vein. Six months after, cells positive for human leukocyte, lymphocytes markers were detected in theperipheral blood of the mice. In the bone marrow, GFP-labeled Muse cells were suggested to be differentiated into pre-erythroblast marker CD235a-positive cells. Pluripotent Muse cells that can be harvested from mesenchymal tissues are suggested to be applicable to bone marrow transplantation.
Development of Technology to Manipulate the Biological Functions of Stem Cells for Cell Therapy of Next Generation

TABATA Yasuhiko, YAMAMOTO Masya, DEZAWA Mari, UMEZAWA Akihiko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (S)

Institution: Kyoto University

2008 - 2012

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A cationized gelatin of gene transfection was prepared by chemical introducing spermine to gelatin. Gelatin sponge scaffolds mechanically reinforced by ceramic granules incorporation were combined with growth factors and a complex of ca tionized gelatin and plasmid DNA. Bone marrow derived mesenchymal stem cells (MSC) were cultured for gene transfection in the sponge prepared. Comparing with the conventional gene transfection, a higher efficiency of MSC genetically engineering was observed. Upone combining with a bioreactor of culture medium circulating system, the engineering efficiency was further improved. This culture technology is applicable for small interfering DNA, and demonstrated to be a promising engineering technology of cell bioactivity.
間葉系組織に内包される多分化能細胞の探索 Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for challenging Exploratory Research

2009 - 2010
Identification of neural induction domain in stem cells and neuronal regenerative medicine using the peptide derived from the domain

KANNO Hiroshi, SAITO Tomoyuki, ITO Norihiko, MIZUKI Nobuhisa, DEZAWA Mari

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Yokohama City University

2008 - 2010

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We identified a neural induction domain for somatic stem cells at elonign BC binding site in the VHL protein, and show neuronal differentiation of the cells by transfer of the domain peptide linked to protein transduction domain (PTD). In addition, we show that the domain has the same function for the other somatic stem cells, and that BC-box motifs within SOCS-box proteins also have an ability to induce neuronal differentiation. Furthermore, when the domain peptide-transferred stem cells are grafted into recipient nervous tissue, the grafted cells differentiate to neurons and recovery of the neuronal symptom is recognized. Thus, the neuronal differentiation of pluripotent somatic stem cells is occurred by transfer of the neural induction domain peptide linked to PTD and would contribute to neuronal regenerative therapy.
Cell transplantation for the treatment of spinal cord injury in rats-morphological study and search for humoral effective factors-

IDE Chizuka, NAKANO Norihiko, YAMADA Yoshihiro, SUZUKI Yoshihisa, DEZAWA Mari, TAGUCHI Naoyuki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Aino University

2008 - 2010

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(1) Transplantation of bone marrow stromal cells (BMSCs) (a) Direct injection of BMSCs into the spinal cord lesion BMSCs (5×10^5) were injected into the spinal cord lesion 2 weeks after injury, and rats were observed for 4 weeks post-transplantation. Locomotion of rats was recovered up to about 10 points of BBB scale, with the control points of 4-5. Numerous regenerating axons extended through the lesion from the rostral to distal border. Electron microscopy showed that regenerating axons were surrounded by Schwann cells in the collagen fibril matrices. BMSCs disappeared within 2 weeks post transplantation, indicating that they were never incorporated into the spinal cord. (b) Transplantation through the cerebrospinal fluid (CSF) BMSCs (5×10^5) were injected into the 4^<th> ventricle 1, 2, and 4 weeks after spinal cord injury. Locomotion of cell-injected rats was recovered up to 10-13 points of BBB scale, while those of control remained at 0-4. Regenerating axons extended in bundles bridging the lesion between the rostral and distal margin. Regenerating axons extended through the collagen fibril matrices and were surrounded by Schwann cells. This shows that regenerating axons are in the same environment as peripheral nerves. Injected BMSCs disappeared from the spinal cord 2 weeks after injection, indicating that BMSCs exert their effects not by integration into the spinal cord, but probably by secreting some trophic factors in to the CSF. (2) Effective factors contained in the conditioned medium of BMSCs It was demonstrated that the conditioned medium (CM) contained IGF-1, HGF, VEGF, and TGF-β1. Cultured hippocampal neurons had receptors of IGF-1 and TGF-β1. They showed no changes in density by the treatment of CM. These trophic factors, when they were used single or in combination of 2, 3 and 4 factors to treat cultured hippocampal neurons in vitro, did not show the same effect level of cell viability and neurite extension as the case of CM. This suggests that the CM may contain some unidentified trophic factors.
神経・筋変性疾患における細胞移植システムの構築と自己細胞移植治療法の開発 Competitive

DEZAWA Mari

Offer Organization: Ministry of Health, Labour and Welfare

System: Health and Labor Sciences Research Grant

2007 - 2009
自己細胞移植による神経・筋肉変性疾患の根本的治療法の開発 Competitive

DEZAWA Mari

Offer Organization: National Institute of Biomedical Innovation

System: ＊

2005 - 2009
The mechanism of transdifferentiation in bone marrow stromal cells Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for Scientific Research(B)

Category: Grant-in-Aid for Scientific Research (B)

2007 - 2008
Neural induction of somatic stem cells / ES cells by VHL gene /peptide and application to regenerative medicine

KANNO Hiroshi, NAGASHIMA Yoji, YAMAMOTO Isao, DEZAWA Mari, SUGIMOTO Naoki, NAKANO Shuichi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Yokohama City University

2004 - 2007

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Several somatic stem cells have potential to differentiate to neurons, and they are hopeful to be used as grafted donor cells for neuronal regenerative therapy. However, the grated cells little survive and differentiate to functional neurons in recipient neural tissue. To overcome the problem, neural induction using neurotrophic factors or gene transfer has been employed before grafting, but neurotrophic factors do not occur specific neural induction, while gene transfer has risk of vector. If a neural induction domain for somatic stem cells exists in proteins to induce neural differentiation, its identification can contribute to neuronal regenerative therapy through neural induction of somatic stem cells using the neural induction domain. We previously demonstrated that von Hippel-Lindau tumor suppressor(VHL)protein has a function of neural induction in neural stem cells(NSCs)without any neurotrophic factors. Then, we hypothesized that a neural induction domain potentially exists in the VHL protein. Here we identify a neural induction domain for somatic stem cells in the VHL protein, and show neural induction of the cells by transfer of the domain peptide linked to protein transduction domain(PTD). The neural induction domain in the VHL protein contains BC-box motif[(A,P,S,T)XX(A,C)XXX(A,I,L,V)]corresponding to binding site of elongin BC, which is evolutionary conserved from virus to mammalian.Therefore, we proposed that other BC-box proteins also contain the neural induction domain, and subsequently show to identify the neural induction domains at amino-acid sequences encoded by BC-box motif within BC-box proteins responsible for neural induction of somatic stem cells. In addition, we show that the domain has the same function for other somatic stem cells except for neural stem cells. Furthermore, when the domain peptide-transferred stem cells are grafted into recipient nervous tissue in neuronal disease models, the grafted cells differentiate to neurons and neuronal repair for neuronal disease models is achieved. Thus, a neural induction domain is identified at BC-box motif in BC-box proteins. The neural induction of somatic stem cells is caused by intracellular delivery of the neural induction domain peptide linked to PTD, and would contribute to neuronal regenerative therapy.
The effects of transplantation of dopaminergic neuron induced from bone marrow stromal cells into amblyopia model through cerebrospinal fluid in rat

MIMURA Osamu, DEZAWA Mari, ISHIKAWA Hiroto

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Hyogo College of Medicine

2005 - 2006

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We showed the analysis of rat deprivation amblyopia in this research. In 2005, we made the amblyopia models, differentiation of bone marrow stromal cells (BMSc) to dopaminergic neuronal cells (DNc), and cell transplantation via cerebrospinal fluid to rat amblyopia models. In 2006, we analyzed these models using antibody array and PCR. Antibody array showed up-regulation of Tyrosine hydroxylase (Th) and down-regulation of signal proteins for apoptotic and MAP kinase signaling system in amblyopic brain. PCR study showed down-regulation of Th in amblyopic retina, and down-regulation signal proteins for apoptotic and MAP kinase signaling system in both amblyopic brain and retina. In the cell transplantation group, PCR study showed up-regulation of these proteins, neurofilament and GFAP. These results suggest that the BMSc derived DNc transplantation into rat amblyopia model is effective in up-regulation of Th, anti-apoptotic pathway and the survival of neuronal cells. In the future, there is a necessity for examining the effect of cell transplantation compared with the administration of Levodopa.
Bone marrow stromal cell transplantation as the treatment for glaucomatous optic neuropathy.

TANABE Teruyo, YOSHIMURA Nagahisa, DEZAWA Mari

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

2005 - 2006

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To know if the transplantation of bone marrow stromal cells(BMSCs) could be beneficial for reconstructing or protecting glaucomatous eyes, we investigated if transplanted BMSCs in glaucoma model eye could survive, differentiate into retinal ganglion cells(RGCs), and also prevent the reduction of RGC in host glaucoma retina. Glaucoma was induced in the right eye of adult rat by ligating episcleral veins and the left eye was sham operated and used as a control. The GFP-expresssing BMSCs(GFP-BMSCs) or phosphate buffered saline(PBS) were injected into the vitreous body of both the control and the glaucoma eyes at various stages. One week after transplantation, GFP-BMSCs were mostly present along with inner limiting membrane(ILM) and a few cells were integrated into the ganglion cell layer(GCL). No cells were integrated into the optic disc. The transplanted cells expressed CD54, the marker of mesenchymal cells, however the expression of neuronal or glial markers were not observed. The analysis of RGC number by fluorogold retrogradely labeling at 4 weeks after injection revealed less reduction in the number of RGCs in BMSC injected glaucoma eyes compared with the PBS injected glaucoma eyes. At 2 or 4 weeks after transplantation, GFP-BMSCs were observed to express various trophic factors by immunohistochemistry. The quantative assessment by real-time PCR demonstrated that the expression of of bFGF and CNTF in BMSC transplanted glaucoma eyes is significantly increased compared with the PBS injected glaucoma eyes. In conclusion, BMSCs could survive and express trophic factors in glaucoma eyes and the decrease in the number of RGC was prevented in BMSCs transplanted glaucoma retina. BMSCs transplantation may be worthy as a neuroportective tool to treat glaucoma.
Regeneration of neurons and vessels using bone marrow cells and gene delivery

KUROIWA Toshihiko, MIYATAKE Shinichi, KAJIMOTO Yoshinaga, NONOGUCHI Naosuke, DEZAWA Mari

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Osaka Medical College

2005 - 2006

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We preliminarily intravenously implanted bone marrow cells from young mouse to old senescence accelerated mouse (SAM). We evaluate the memory function by water maze, however, no improvement in memory function was observed. Therefore, intravenous administration of young bone marrow has little effect on preventing aging and further enhanced treatment such as useful gene induction and targeting administration to the brain or bone marrow. Then we examined the effects of neurological improvement after transient middle cerebral artery occlusion (MCAO) in rats by a novel therapeutic strategy with FGF-2 gene-transferred mesenchymal stromal cells (MSCs) by the herpes simplex virus type 1 (HSV-1) vector. The stroke animals receiving FGF-2-modified MSCs demonstrated significant functional recovery compared with the other groups. Fourteen days after the MCAO, there was a significant reduction in infarction volume only in FGF-2-modified MSC-treated group. FGF-2 production in the FGF-2-modified MSC-treated brain was significantly higher compared with the other groups at 3 and 7 days after MCAO. Administrated FGF-2-modified MSCs strongly expressed the FGF-2 protein, which was proven by ELISA. In conclusion these datum suggested that the FGF-2 gene-modified MSCs with the HSV-1 vector can contribute to remarkable functional recovery after stroke compared with MSCs transplantation alone. The hepatocyte growth factor (HGF) is also one of the useful gene for tissue restoration. we introduce a new strategy combining MSCs and ex vivo HGF gene transferring with a multimutated HSV-1 vector in a rat transient MCAO model. The significant difference of infarction areas on day was detected only between the MSC-HGF group and the PBS group with the superacute treatment, but was detected among each group on day 14 with both transplantations. After the superacute transplantation, we detected abundant expression of HGF protein in the ischemic brain of the MSC-HGF group compared with others on day 1 after treatment, and it was maintained for at least 2 weeks. Furthermore, we determined that the increased expression of HGF was derived from the transferred HGF gene in gene-modified MSCs. The percentage of apoptosis-positive cells in the ischemic boundary zone (IBZ) was significantly decreased, while that of remaining neurons in the cortex of the IBZ was significantly increased in the MSC-HGF group compared with others. The present study shows that combined therapy is more therapeutically efficient than MSC cell therapy alone, and it may extend the therapeutic time window from superacute to acute phase. Following these experiments, the improving effect is mainly due to anti-apoptotic and neuron-protective effects and there were no evidence for neuron-generation. Another effective methods such as intra-bone marrow injection of bone marrow cell should be examined in the future.
Promotion of brain-and spinal-cord regeneration by transplantation of somatic cells(bone marrow stromal cells and choroid plexus ependymal cells)-mechanisms of rescuing injured neural cells, and perspectives for clinical applications-

IDE Chizuka, SUZUKI Yoshihisa, DEZAWA Mari, MATSUMOTO Naoya

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Aino University

2005 - 2006

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We studied spinal cord regeneration by cell transplantation using those cells that are potentially available for clinical application, such as bone marrow stromal cells (BMSCs) and choroid plexus ependymal cells (CPECs). 1. BMSCs Autogeneous BMSCs were injected by lumbar puncture to a patient with spinal cord injury (C4,5) on March 23, 2006. This is the first clinical case of spinal cord injury in which BMSCs were transplanted through cerebrospinal fluid (CSF). The patient has as yet had no harmful side effect, while showing a sign of functional improvement. Next, we studied transplantation of bone marrow-derived mononuclear cells in the rat to explore the possibility of cell therapy without any cell culture process for spinal cord-injured patients immediately after admission to the hospital. The rat showed the reduced cavity formation in the spinal cord, and improved locomotion. HGF was high, and TNF-α was low in concentration in the CFS. A large number of blood vessels and nerve fibers were seen in the cavity wall. These regenerative effects are considered due to trophic factors secreted from mononuclear cells. Next, we discovered that many skeletal muscle cells develop from cultured BMSCs. 2. CPECs We showed that conditioned medium of CPEC culture promotes the survival of neurons, and neurite extension in vitro. The same effects were seen with the conditioned medium of BMSCs. Next, it was revealed that the choroid plexus ependymal cell layer contains neural stem cells. Similarly, the third ventricle ependymal cell layer contains a large number of neural stem cells. 3. Others We showed that a large number of neural stem cells are generated mainly from central canal following crush injury to the spinal cord. At the same time, bFGF production was promoted in the lesion. The question of why these changes of spinal cord do not contribute to the spinal cord regeneration remains to be resolved.
骨髄間質細胞からの神経・骨格筋幹細胞の効率町誘導と自己再生システムの開発 Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: ＊

2005 - 2006
Specific induction of functional neurons and skeletal muscle cells from bone marrow stromal cells and their application for auto-cell transplantation therapy in neuro-and muscle degenerative diseases Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for Scientific Research(C)

Category: Grant-in-Aid for Scientific Research (C)

Institution: Kyoto University

2005 - 2006

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Bone marrow stromal cells (MSCs) have the capability under specific conditions to differentiate into various cell types, such as osteocytes, chondrocytes and adipocytes. Here we demonstrate a highly efficient and specific induction of Schwann cells (peripheral glial cells), neurons and skeletal muscle cells from both rat and human MSCs. Neuronal induction could be achieved by NICD transfection followed by trophic factor administration of bFGF+ CNTF + forskolin. MSCs expressed markers related to neural stem cell and neuronal progenitor cells after transfection with NICD, and subsequent administration of trophic factors induced post-mitotic neurons without differentiation of glial cells. Some of induced cells showed action potentials compatible with characteristics of functional neurons. Further treatment of the neurons with GDNF increased the proportion of dopamine-producing cells and transplantation of these neurons showed improvement in rat model of Parkinson's disease. Highly efficient skeletal muscle induction could also be achieved by the administration of a combination of cytokines followed by NICD transfection. Induced cells differentiate into muscle fibers upon transplantation into degenerated muscles. Since induced cells contained satellite-like cells, they contributed to subsequent regeneration upon repetitive damage without additional transplantation of cells. Since our induction system does not depend on a rare stem cell population, but can utilize the general population of MSCs which can be easily isolated and expanded, functional Schwann cells, neurons and skeletal muscle cells can be obtained on a therapeutic scale. Our MSC differentiation system may contribute substantially to a major advance toward eventual cell-based therapies for neurodegenerative and muscle degenerative diseases.
骨髄間質細胞からの神経並びに筋細胞の選択的誘導とパーキンソン病・筋ジストロフィーへの自家移植治療法の開発 Competitive

DEZAWA Mari

Offer Organization: Ministry of Health, Labour and Welfare

System: ＊

2004 - 2006
Transplantation of human bone marrow stromal cell-derived Schwann cell for contusive spinal cord injury of adult rats

YOSHINAGA Katsunori, YAMAZAKI Masashi, OKAWA Akihiko, DEZAWA Mari

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Chiba University

2004 - 2005

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Objective : The aim of this study was to evaluate whether transplantation of human bone marrow stromal cell-derived. Schwann cells (hBMSC-SC) promotes functional recovery after contusive spinal cord injury of adult rats. Materials and Methods : Human bone marrow stromal cells (hBMSC) were cultured from bone marrow of adult human patient and induced into Schwann cells in vitro. Nine-weeks-old male Wistar rats were laminectomized and their spinal cords were contused using NYU impactor (10g,25mm). Nine days after injury, mixture of Matrigel and hBMSC-SC (hBMSC-SC group), Matrigel and hBMSC (hBMSC group) or Matrigel alone (MG group) was injected into the lesioned site. Histological examination, immunohistochemistry, electron microscopy and functional assessment were performed. Results and Discussion : Five weeks after transplantation, cresyl-violet staining revealed that the area of cystic cavity was smaller in the hBMSC and hBMSC-SC groups than that in the MG group. Immunohistochemstry revealed that the number of GAP-43-positive nerve fibers was significantly larger in the hBMSC-SC group than that in the other groups and the number of tyrosine hydroxylase- or serotonin-positive fibers was significantly larger at lesion epicenter and caudal level in the hBMSC and hBMSC-SC groups than that in the MG group. Electron microscopy revealed that peripheral type myelin formation near the lesion epicenter in the hBMSC-SC transplanted rats. Hind limb function recovered significantly in the hBMSC and hBMSC-SC groups compared with the MG group. In conclusion, transplantation of hBMSC-SC is potentially useful treatment for spinal cord injury.
ラット脊髄損傷モデルに対する骨髄間質細胞由来シュワン細胞移植の有用性の検討

山崎正志, 大河昭彦, 出澤真里

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 萌芽研究

Institution: 千葉大学

2003 - 2004

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[目的]骨髄間質細胞をin vitroでSchwann細胞に分化させた細胞(骨髄間質細胞由来Schwann細胞:Dezawa, Eur J Neurosci, 2001)をラット脊髄損傷モデルに移植し、その効果につき検討すること。 [方法]1)成ラット大腿骨より骨髄を採取し付着性細胞を培養して、骨髄間質細胞を得た。 2)1)の細胞をβ-メルカプトエタノール処理した後、all-transレチノイン酸を3日間加え、さらにフォルスコリン、bFGF,PDGF-AA,heregulinβ-1を加え1週間培養し、骨髄間質細胞由来Schwann細胞が得られた。 3)ラット脊髄損傷モデルを作成した。8週齢雄Wistarラットを全身麻酔下に第7・第8胸椎椎弓切除し、その部分で脊髄を約4mm長の欠損ができるように切断して、脊髄完全損傷モデルとした。 4)限外濾過膜を直径約2.2mm、5mm長の円筒形に成型したチューブに、骨髄間質細胞由来Schwann細胞をMatrigelに混和したものまたはMatrigelのみをそれぞれ充填し、脊髄欠損部に架橋状に移植した。 5)移植後時間経過を追って、BBB locomotor scale (Basso et al. 1995)を用いて行動学的評価を行った。 6)組織標本につき各種線維に対する抗体を用いた免疫染色にて移植したチューブ内への軸索の伸展を評価した。 8)行動学的評価・組織学的評価につき両群間で比較し、骨髄間質細胞由来シュワン細胞の脊髄損傷モデルに対する有効性を検討した。 [結果]骨髄間質細胞由来Schwann細胞を移植した群では移植後5週(損傷後6週)の時点で平均スコアが約7点と、コントロールの平均スコア3点と比較して有意な回復が観察された。免疫染色ではneurofilament陽性の神経線維が骨髄間質細胞由来Schwann細胞移植群でチューブ内に多く見られた。Tyrosine hydroxylase陽性の下降性線維が骨髄間質細胞由来Schwann細胞移植群でチューブ内に多く見られた。Serotonin陽性線維数calcitonin gene related peptide陽性線維数は両群間で有意差がなかった。また、骨髄間質細胞由来Schwann細胞移植群で機能回復が見られたもののうち2匹に対し、移植後5週時、移植チューブの再切断を行ったところ、回復した機能はすべて失われその後も回復しなかった。 [考察]骨髄間質細胞由来Schwann細胞移植は軸索再生を促進し、後肢機能を有意に回復させた。骨髄間質細胞由来Schwann細胞は、採取の容易さ・自己移植可能であることなどから、脊髄損傷に対する細胞治療の細胞ソースの候補として有望である。
表皮細胞を神経細胞に分化転換させる方法の開発-自己再生を目指して-

井出千束, 出澤真理, 菅野洋, 松本直也

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 萌芽研究

Institution: 京都大学

2003 - 2004

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皮膚細胞は採取がもっとも容易な体細胞であり、倫理上の問題が無く、また患者本人から採取可能である。我々はNotch遺伝子を用いた骨髄間質細胞からの神経分化やVHL遺伝子による神経幹細胞からの神経誘導を行ってきたが、今回新たに別種の細胞である皮膚細胞に着目し、選択的に神経細胞に分化転換する技術開発を試みた.皮膚細胞は神経組織と同じく外胚様由来であるために、神経系細胞への文化転換が期待できると考えたからである。ラットおよびヒトのメラノサイト(いずれもBiotWhittakerより購入)、またラット胎児の表皮細胞を培養した。これらの細胞に、以下の二つの方法を試みた。 1)アデノウイルスに組み込んだVHL遺伝子(von Hippel Lindau (VHL)腫瘍抑制遺伝子)をこれらの細胞に導入し、cAMPの上昇作用をもたらすForskolin, basic FGFの因子を組み合わせて同時投与を行った. 2)Notch細胞質ドメイン(Notch intracellular domain)をpCI-neo vecterに組み込み、lipofectionによって導入する。その後G418を用いて導入された細胞を選択し、増殖の回復を待ってから60%conflucencyに継代培養し、Forskolin, basic FGFを投与する。特定の遺伝子(von Hippel Lindau(VHL)腫瘍抑制遺伝子)を導入することによって、神経細胞が誘導出来ることを確認している。これらの結果、2)の方法では皮膚細胞の形態的な変化は認められなかった。しかし1)によってメラノサイトからは突起伸長などの神経様の形態変化が見られた。また神経マーカーであるMAP2, neurofilamentの発現が認められた。しかしbetaa 3-tubulinやNeuNの発現は検出できなかった。Brd-U取り込み実験ではpost-mitotic neuronである確証は取れなかった。皮膚細胞は高度に分化し、生体において特定の機能を果たしている細胞である。この細胞を機能的な神経細胞に分化転換させるには、エピジェネチックな制御を含めたアプローチが必要であると推察される。
Establishment of adult rat-derived stem cells, and histological/functional reconstruction of spinal cord by auto- and allo-grafting of those stem cells

IDE Chizuka, SUZUKI Yoshihisa, DEZAWA Mari, MATSUMOTO Naoya

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Kyoto University Graduate School of Medicine

2003 - 2004

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Based on the early experiments, we recognized that there are big barriers for neural stem cells to be clinically applied : those are ethical problems concerning the use of fetus and inevitable allergenic transplantation. On the other hand, bone marrow stromal cells (BMSCs) have great advantages in being autogenic for clinical application. In experiments, BMSCs were injected into the cerebrospinal fluid (CSF) through the 4^th ventricle of the rat. Many injected BMSCs were attached to the spinal cord surface, and some of them further invaded the lesion. Based on the BBB scale, cell-graft rats showed 14 15 and 11 points in locomotion, while the controls were 10 and 8 points, in the mild and strong spinal cord crush, respectively. The size of spinal cord cavity was ca. 1/2 smaller in the cell-graft rats than the controls. Less proliferation of astrocytes was observed, and a larger amount of neural components was preserved in the cell-graft rats than in the controls. Injected cells disappeared from the spinal cord within 4-5 weeks after injection. This implies that injected BMSCs exerted their effects not by being integrated into the host tissue, but by releasing some trophic factors into the CSF. The in vitro experiments also supported this hypothesis. BMSCs function not as stem cells, but as ordinary somatic cells derived from adult animals. It is considered that BMSCs suppress the degenerative processes, and at the same time promote the survival, of injured cells at the early stage of degeneration. We confirmed the safety of BMSC injection into the CSF in the monkey by injecting autogenic BMSCs through lumbar puncture. We provided a complete protocol for clinical application, and the Ethic Committee of Kansai University approved this cell transplantation to patients with spinal cord therapy by BMSC transplantation to patients with spinal cord injury on July 1^<st> 2005. We are now ready for the BMSC transplantation therapy to patients matched to the protocol. In parallel with this study, we also examined the effects of choroid plexus ependymal (epithelial) cells to the ischemic brain injury, and clarified that the injection of cultured choroid plexus ependymal cells have a great effect on the recovery of brain tissue from ischemic damages. This finding might open a new horizon for the therapy of ischemic brain injury.
The reset and transdifferentiation of bone marrow stromal cells and developmental research for organ regeneration Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for Scientific Research(C)

Category: Grant-in-Aid for Scientific Research (C)

Institution: Kyoto University

2003 - 2004

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Bone marrow stromal cells (MSCs) have the capability under specific conditions to differentiate into other cell types. In this study, we demonstrate a highly efficient and specific induction of cells with neuronal, Schwann cells and skeletal muscle characteristics. Neurons : MSCs were transfected with Notch intracellular domain(NICD) followed by cytokine treament. (bFGF+CNTF+forskolin). Induced neuronal cells expression neuronal markers, and showed voltage-gated fast sodium and action potentials. Glial markers could not be detected. Further treatment of the induced neuronal cells with GDNF increased the proportion of tyrosine hydroxylase (TH)-positive cells. Transplantation of these GDNF-treated cells showed improvement in apomorphine-induced rotational behavior, following intrastriatal implantation in a 6-hydroxy dopamine rat model of Parkinson's disease. Schwann cells : Cells were treated with beta-mercaptoethanol and retinoic acid, followed by treatment with cytokines of bFGF, FSK, PDGF and neuregulin. MSCs changed their morphology after treatment with expression of Schwann cell markers of p75, GFAP, S-100 and P0. Transplantation of induced cells improved the function of spinal cord contusion injury model rats. Skeletal muscle cells : MSCs were treated with cytokines (FSK+bFGF+PGDF+neuregulin) followed by NICD transfection. Induced cells expressed MyoD, Myogenin and other skeletal muscle markers and Pax7, c-MetR satellite cell markers, and formed multinuclear skeletal muscle cells. After intravenous transplantation of induced cell, muscle regeneration and integration of induced cells could be observed in mdx-mice (muscle dystrophy model mice). MSCs have a great potential as therapeutic agents against neurological diseases since they can be readily obtained through a well-established clinical procedure and are easy to isolate and expand for autotransplantation with no risk of rejection. This study shows that a population of neuronal cells can be specifically generated from MSCs and that induced cells may allow for a neuroreconstructive approach.
The mechanism of the induction of differentiation of bone marrow stromal stem cells and its application

SAWADA Hajime, KANNO Hiroshi, DEZAWA Mari, YAMADA Hitoshi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Yokohama City University

2002 - 2004

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By transfection of the cytoplasmic domain of Notch gene and stimulation by cytokines such as basic FGF, bone marrow stromal cells differentiated into neurons. By the present method most of the cells differentiated into neurons and few glial cells were formed. Electrophysiologically these neurons exhibit neuronal phenotype and shown to be functioning. Further stimulation of these cells by GDNF and other cytokines, these neurons restrict their developmental direction to dopaminergic neurons. When these cells were transplanted into the brain of model rats for Parkinson's disease, their symptoms were alleviated. These results seemed to open the way for the clinical treatment of Parkinson's disease. The bone marrow stromal cells were shown to have another repertoire of differentiation. When a clone from bone marrow stromal cells were treated with a tumor promoter TPA, they changed to multinuclear giant cells. The cells exhibit markers of osteoclasts such as tartrate-resistant acid phosphatase, and this case is a rare phenomenon that bone marrow stromal cells were induced to differentiate into cells of hematopoietic lineage. Since there is a hypothesis that bone marrow stromal cells exhibit multipotentiality by fusing with differentiated cells in the transplanted area, we tested the possibility of cell fusion. When marker genes such as CFP or GFP were introduced in to the cells and the cells with distinct markers were mixed and stimulated by TPA, cells with multiple markers appeared indicating that the cell fusion contributes to the appearance of multinuclear cells, although the possibility of endomitosis (cell division without nuclear division) cannot be excluded. Osteoclasts are known to develop through the action of RANK/RANKLor M-CSF/c-fms signal transductions, but in the present case none of these pathways was shown to be working indicating a possibility of contribution of new pathways.
合成蛋白質導入による骨髄間質細胞の選択的神経細胞誘導と神経変性疾患への応用 Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: ＊

2004 -
VHL遺伝子による神経幹細胞・ES細胞の神経分化メカニズムの解明とその応用

菅野洋, 出澤真理, 味村俊郎

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 萌芽研究

Institution: 横浜市立大学

2002 - 2003

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神経幹細胞や骨髄細胞などの中枢神経系内への移植によって、神経機能を回復させ、神経難病を治療しようとする神経再生医療の研究が注目されている。これまで、研究代表者らは、神経幹細胞や胚性幹細胞を一定方向(神経細胞へ)に分化を誘導する可能性について検討を行い、その結果、腫瘍抑制遺伝子の一種であるvon Hippel-Lindau腫瘍抑制遺伝子(VHL遺伝子)を導入することによって、神経幹細胞を特異的に神経細胞へ分化誘導しうることを見出した。VHL遺伝伝子導入により、神経細胞へ分化誘導された細胞は、神経特異的マーカーであるNeurofilament、Neuropeptide Y,MAP-2などの陽性が確認できたばかりでなく、神経としても電気生理学的機能に関しても、パッチクランプ法で高位のNa-K電流を確認できた。さらにVHL遺伝子をアデノウイルスベクターで導入した神経幹細胞を6-OHDHを脳内へ注入して作成したパーキンソンモデルラットの脳内へ移植を試みると、神経症状の改善を認め、脳内で高率に生着し、高率に神経細胞(ニューロン)へ分化していることが確認できた。また、この神経分化はVHL遺伝子のアンチセンスで完全に抑制され、変異型のVHL遺伝子導入でも抑制された。コントロールとして、無処理の神経幹細胞を移植しても、症状の改善は得られなかっただけでなく、移植内で大部分は神経膠細胞(グリア)へ分化していた。VHL遺伝子を導入することで神経幹細胞がどうして神経細胞へ分化するか、そのメカニズムに関しては、10,000種類の遺伝子発現をマイクロアレイ法で網羅的に解析した。その結果、神経分化に関与する因子の遺伝子発現の上昇をみとめ、グリア細胞へ分化誘導する因子群の遺伝子発現の抑制を認めた。このことから、VHL遺伝子は神経幹細胞から神経細胞(ニューロン)への分化において、極めて重要な役割を演じていることが示された。また、ES細胞においては、VHL遺伝子導入のみでは分化誘導されず、神経栄養因子の存在が必要であった。
骨髄間質細胞からの選択的な神経細胞誘導法の確立とパーキンソンモデルへの移植応用 Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: ＊

2003 -
神経-シュワン細胞間に形成されるタイトおよびギャップ結合の再生における役割 Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for Young Scientists(B)

2001 - 2002
骨髄間質細胞の神経系細胞への分化誘導並びに神経損傷・パーキンソンモデルへの応用 Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: ＊

2002 -
遺伝子導入シュワン細胞を用いた人工移植片開発による視神経再生 Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for Encouragement of Scientists

1999 - 2000
Optic nerve regeneration by usage of artificial Schwann cell graft

ADACHI Emiko, TSUYAMA Yoshihiko, MIZOTA Atsushi, FUJIMOTO Naoya

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (A).

Institution: Chiba University

1998 - 2000

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We investigate whether the graft made by cultured Schwann cell can provide a substrate enabling regrowth of injured optic nerve, and assess the effect of neurotrophic factors for the induction of optic nerve regeneration. Cultured Schwann cells were purified from dorsal root ganglions of newborn rats (Wistar strain). Approximately 106 Schwann cells/ml were suspended in an extracellular matrix containing neurotrophic factors either of NGF, BDNF or NT4, and then transferred into a silicon tube or a hollow fiber. The grafts were transplanted to the retinal stump of the transected adult optic nerve (Wistar strain). The degree of optic nerve regeneration was evaluated by counting the number of diI labeled retinal ganglion cells (RGCs). The degree of surviving RGCs was 2±1.01 % only with the extracellular matrix. The combination with BDNF or CNTF intravitreous injection resulted in an increase of 30.28±16.97 % or 54.32±8.005 %. As the second step, we elicited the regrowth of transected optic nerve fibers into superior colliculus by this artificial graft. The grafts linked the left eye and the right superior colliculus along a extracranial course in adult rats (Wistar strain). Three months after operation, diI retrograde labeling (injected into the superior colliculus) showed that 18.1±0.11 % of retinal ganglion cell axons penetrated the superior colliculus. Furthermore, we evaluated the in vivo electroporation as a delivery method in RGCs, efficiency, cell specificity, stability and tissue damage were investigated by using green fluorescent protein gene as the genetic marker. The results showed that approximately 40 % of total ganglion cells in the entire electroinjected area were GFP positive by 7th day.
近視化初期における眼球形態形成及び神経回路網による制御機能の解析

池尻充哉, 出沢真理, 溝田淳

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 萌芽的研究

Institution: 千葉大学

1998 - 1999

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遮蔽近視群の眼球形態、網膜視機能の評価を実施した。白色レグホンヒヨコを用い明暗12時間サイクルで飼育した。生後2日目屈折度を検影法で測定、孵化後14日目に屈折度を検影法で測定後暗順応ERGを測定、a-波、b-波の振幅、潜時を検討した。その結果、潜時に遮蔽の影響は見られないが近視眼でb-波振幅の増大が見られた。(第7回国際近視学会:H10年11月19日、台北で発表) 孵化後9日目にヒヨコ遮蔽眼のERGを9時、21時の2回測定し非遮蔽眼のERGと比較した。その結果ERG振幅は朝に大きく夜に小さくなる生体リズムが存在し、しかも遮蔽眼では非遮蔽眼と比較してその変動幅が増大することが観察された。(The Association for Research Vision and Ophthalmology H11年5月13日、Frolida、USAで発表) 孵化後2日のヒヨコ右眼にAPB(ON反応抑制剤)、キヌレニン酸(OFF反応遮断剤)および対照としてBSSをそれぞれ硝子体に注入。孵化後9日目散瞳後、麻酔下でERG測定後潅流固定、眼軸長を測定した。それぞれの左眼を被操作眼として対照とした。孵化後2および9日の屈折度は散瞳後検影法で決定し、摘出眼球から網膜の光顕、電顕標本を作成した。その結果、ERGはAPB注入眼で顕著にb波の、キヌレニン酸注入眼で顕著にa波の源弱を示した。孵化後9日目、コントロール群は、ほぼ正視で眼軸長9.1mmとなりAPB注入眼で遠視化(単眼軸長、8.9mm)、キヌレニン酸注入眼で近視化(長眼軸長、9.45mm)が認められた。光顕、電顕観察では、APBおよびキヌレニン酸注入眼で内顆粒層の細胞群、特に水平細胞、双極細胞に細胞内小器官の膨化、崩壊がみられた。本実験よりヒヨコ網膜で、オン反応伝達経路遮断が遠視化の、オフ反応経路遮断が近視化の機構に関連することが示唆され引き続き検討予定である。
培養シュワン細胞移植による損傷視神経の再生促進手段の開発 Competitive

DEZAWA Mari

Offer Organization: Ministry of Education, Culture, Sports, Science and Technology

System: Grant-in-Aid for Encouragement of Scientists

1997 - 1998
PERIPHERAL NERVE REGENERATION IN MAGNETIC STIMULATION

DEZAWA Akira, DEZAWA Mari, YAMANE Tomojiro

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: TEIKYO UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF ORTHOPAEDIC SURGERY

1996 - 1998

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Gap junctions are intercellular channels which mediate the traffic of ions and a variety of molecular messengers between contiguous cells. Here, we report on the possibility that atypical gap junctions develop between heterologous tissues, that is the regenerating nerve axon and Schwann cell, during peripheral nerve regeneration of adult rats. After a complete transection and subsequent regeneration in the rat sciatic nerve distal segment, a small scale of gap junction-like structure was observed between the regenerating axon and adjoining Schwann cell. One of the gap junctional protein, connexln32, located at a small region of contact site between the axon and Schwann cell in an immunoelectrori microscopyy. The intercellular coupling was examined by evidence that blocytin, a dye of small molecular weight, was transported from regenerating axons into adjoining Schwann cells. The present findings suggest that regenerating axons communicate directly with adjacent Schwann cells through small gap junctions, which may play a role in the mechanism of regeneration following nerve transection,

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Teaching Experience 4

Macroscopic anatomy　Tohoku University
Histology　Tohoku University
解剖学　東北大学
組織学　東北大学