Details of the Researcher

PHOTO

Yoshiko Ikushima
Section
Institute of Medical Research
Job title
Senior Assistant Professor
Degree

  • 学士 (医学) (The University of Tokyo)

Research History 6

  • 2025 - Present
    Tohoku University　SiRIUS Institute of Medical Research　Distinguished Senior Assistant Professor

  • 2023 - 2025
    Japan Society for the Promotion of Science　JSPS overseas research fellowship (RRA)

  • 2021 - 2025
    The University of Edinburgh　University BHF Centre for Cardiovascular Science　Sponsored Researcher

  • 2015 - 2021
    国立国際医療研究センター研究所 糖尿病センター　分子糖尿病医学研究部　上級研究員

  • 2013 - 2015
    Keio University　School of Medicine

  • 2011 - 2013
    Japan Society for the Promotion of Science

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Education 2

  • Keio University

    2009 - 2013

  • The University of Tokyo　Faculty of Medicine　School of Medicine

    2003 - 2009

Research Areas 3

  • Life sciences / Pathobiochemistry / Bome marrow adipocytes (BMAds)

  • Life sciences / Pathobiochemistry /

  • Life sciences / Molecular biology /

Awards 4

  1. 若手研究奨励賞

    2019　第62回日本糖尿病学会

  2. 若手研究奨励賞

    2019　第33回日本糖尿病肥満動物学会

  3. Junior Investigator Poster Awards

    2012　10th Annual Meeting of International Society for Stem Cell Research (ISSCR)

  4. 奨励賞

    2012　第74回日本血液学会

Papers 16

  1. Adiponectin exerts sex-dependent effects on lipid, amino acid, and glucose metabolism during caloric restriction. International-journal

    Yoshiko M Ikushima, Kuan-Chan Chen, Richard J Sulston, Domenico Mattiucci, Eleanor J Brain, Stefanie A Fung Xin Zi, Karla J Suchacki, Benjamin J Thomas, Andrea Lovdel, Matthew Bennett, Hiroshi Kobayashi, Phillip D Whitfield, Keiyo Takubo, Andrew H Baker, Nicholas M Morton, Robert K Semple, William P Cawthorn

    PLoS biology　24　(6)　e3003821　2026/06

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1371/journal.pbio.3003821 　

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    ABSTRACT Adiponectin is the most abundant hormone in the circulation. Plasma adiponectin decreases in obesity but increases in leanness, including during caloric restriction (CR) in animals and humans. In obesity, adiponectin deficiency promotes cardiometabolic dysfunction. In contrast, the roles of adiponectin in CR, when it is at its highest, are largely unknown. To address this, we studied global adiponectin knockout (KO) in male and female mice fed eitherad libitum(AL) or a 30% CR diet from 9-13 weeks of age. We show that adiponectin KO did not alter CR effects on body mass, body composition, or energy expenditure. However, KO unexpectedly decreased blood glucose levels during CR, both on fasting and following an oral glucose challenge. This is opposite to the effects of adiponectin deficiency in the context ofad libitumdiet (AL) or obesity, and occurred without changes in insulin secretion or sensitivity. Moreover, adiponectin KO augmented CR-induced increases in plasma fatty acids in both sexes and, in males only, impaired systemic triglyceride clearance under CR. Indirect calorimetry further revealed that adiponectin KO alters the shifts between carbohydrate and lipid utilisation that occur during transitions between fed and fasted states. To determine potential molecular mechanisms, we investigated effects of adiponectin KO on the liver, a major adiponectin target that plays key roles entraining metabolism to nutritional state. Hepatic transcriptomics revealed that, in both sexes, adiponectin KO upregulates sterol and fatty acid synthesis genes under AL while increasing amino acid catabolic genes during CR. Together, our findings suggest that adiponectin tunes glucose, lipid, and amino acid metabolism during CR, in whole or in part through effects on the liver. The widely reported functions of adiponectin in pathological states, including obesity and insulin resistance, thus differ sharply from its roles during CR, with marked sexual dimorphism apparent for many of these functions.

  2. Caloric restriction exerts site-, sex-, and duration-dependent effects on skeletal structure and bone marrow adiposity. International-journal

    Kuan-Chan Chen, Richard J Sulston, Karla J Suchacki, Yoshiko M Ikushima, Benjamin J Thomas, Andrea Lovdel, Alex J Lafond, Sharon E Mitchell, John R Speakman, Nicholas M Morton, Robert K Semple, William P Cawthorn

    The Journal of endocrinology　269　(2)　2026/05/01

    DOI： 10.1530/JOE-25-0391 　

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    Bone marrow adipose tissue (BMAT) is a unique fat depot. It has distinct metabolic-endocrine functions and negatively correlates with bone mineral density, increasing with ageing and osteoporosis. Intriguingly, BMAT also expands during caloric restriction (CR), a lifespan-extending dietary intervention that also promotes bone loss; however, whether BMAT is a cause or consequence of this remains unclear. To address this, we studied 9-week-old male and female C57BL/6NCrl mice subjected to 30% CR for 1, 2, 4, or 6 weeks. Bone structure and BMAT volume were quantified by micro-computed tomography using a spatial method that precisely maps BMAT within bones. CR-induced BMAT expansion was site-specific, being greater in tibiae than femora and absent in humeri. Surprisingly, CR increased distal tibial BMAT despite prior suggestions that this BMAT region resists such environmental modulation. Expansion was also duration-dependent, plateauing after 4 weeks, and region-specific, particularly in the tibial metaphysis, femoral metaphysis, and the distal tibia. Similarly, CR altered trabecular and cortical bone in time-, region-, and sex-dependent ways, with BMAT levels more tightly associated with trabecular than cortical changes. CR also increased adiponectin, corticosterone, and ketones, while decreasing leptin, IGF-1, and insulin, in a sex- and/or duration-dependent manner. Metabolic phenotyping demonstrated that BMAT expansion was not associated with altered glucose tolerance, body mass, total fat mass, or fat percentage but correlated with energy deficit and systemic lipid mobilisation. Together, our findings highlight the complex interplay between BMAT expansion, skeletal remodelling, and metabolic homeostasis, providing new insights into BMAT formation and function and the health benefits of CR.

  3. Experimental analysis of bone marrow adipose tissue and bone marrow adipocytes: An update from the bone marrow adiposity society (BMAS). International-journal

    Michaela Tencerova, Biagio Palmisano, Stéphanie Lucas, Camille Attané, Kaisa K Ivaska, Léa Loisay, Yoshiko M Ikushima, Drenka Trivanovic, Alessandro Corsi, Adriana Roque, Hongshuai Li, Friederike Behler-Janbeck, Jeroen Geurts, Mara Riminucci, Izabela Podgorski, William P Cawthorn, Bram C J van der Eerden, André J van Wijnen

    Bone reports　26　101861-101861　2025/09

    DOI： 10.1016/j.bonr.2025.101861 　

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    Bone marrow adipose tissue (BMAT) is physiologically linked to bone and energy metabolism, endocrine regulation, hematopoiesis and cancer-related processes. A key challenge in the field is that methods for isolating BMAT or bone marrow adipocytes (BMAds) are variable because there are no widely adopted standardized protocols. To generate awareness of this challenge and to establish uniformity in experimental approaches requiring isolation, storage and characterization of BMAT and BMAds, the Biobanking Working Group of the international Bone Marrow Adiposity Society (BMAS) has previously recommended experimental standards. This paper provides an update on this effort and presents current state-of-the-art methods and technical considerations for isolation and characterization of BMAT and BMAds, including currently available high-throughput omics approaches. This review provides a reference point based on the consensus view of BMAS investigators to support studies on biomedical, biological, biochemical and biophysical questions associated with bone marrow adiposity.

  4. Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis Peer-reviewed

    Kotaro Soeda, Takayoshi Sasako, Kenichiro Enooku, Naoto Kubota, Naoki Kobayashi, Yoshiko Matsumoto Ikushima, Motoharu Awazawa, Ryotaro Bouchi, Gotaro Toda, Tomoharu Yamada, Takuma Nakatsuka, Ryosuke Tateishi, Miwako Kakiuchi, Shogo Yamamoto, Kenji Tatsuno, Koji Atarashi, Wataru Suda, Kenya Honda, Hiroyuki Aburatani, Toshimasa Yamauchi, Mitsuhiro Fujishiro, Tetsuo Noda, Kazuhiko Koike, Takashi Kadowaki, Kohjiro Ueki

    Nature Communications　14　(1)　2023/12

    DOI： 10.1038/s41467-023-42334-y 　

    eISSN： 2041-1723

  5. The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent Peer-reviewed

    Karla J Suchacki, Benjamin J Thomas, Yoshiko M Ikushima, Kuan-Chan Chen, Claire Fyfe, Adriana AS Tavares, Richard J Sulston, Andrea Lovdel, Holly J Woodward, Xuan Han, Domenico Mattiucci, Eleanor J Brain, Carlos J Alcaide-Corral, Hiroshi Kobayashi, Gillian A Gray, Phillip D Whitfield, Roland H Stimson, Nicholas M Morton, Alexandra M Johnstone, William P Cawthorn

    eLife　12　2023/04/25

    Publisher: eLife Sciences Publications, Ltd

    DOI： 10.7554/elife.88080 　

    eISSN： 2050-084X

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    Caloric restriction (CR) reduces the risk of age-related diseases in numerous species, including humans. CR’s metabolic effects, including decreased adiposity and improved insulin sensitivity, are important for its broader health benefits; however, the extent and basis of sex differences in CR’s health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young females. Females’ resistance to fat loss was associated with decreased lipolysis, energy expenditure and fatty acid oxidation, and increased postprandial lipogenesis, compared to males. The sex differences in glucose homeostasis were not associated with differential glucose uptake but with altered hepatic ceramide content and substrate metabolism: compared to CR males, CR females had lower TCA cycle activity and higher blood ketone concentrations, a marker of hepatic acetyl-CoA content. This suggests that males use hepatic acetyl-CoA for the TCA cycle whereas in females it accumulates, stimulating gluconeogenesis and limiting hypoglycaemia during CR. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis similarly in both sexes. Finally, in a cohort of overweight and obese humans, CR-induced fat loss was also sex- and age-dependent: younger females (<45 years) resisted fat loss compared to younger males while in older subjects (>45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CR’s metabolic benefits. These findings have important implications for understanding the interplay between diet and health, and for maximising the benefits of CR in humans.

  6. An antisense transcript transcribed from Irs2 locus contributes to the pathogenesis of hepatic steatosis in insulin resistance International-journal Peer-reviewed

    Maya Matsushita, Motoharu Awazawa, Naoki Kobayashi, Yoshiko M Ikushima, Kotaro Soeda, Miwa Tamura-Nakano, Masafumi Muratani, Kenta Kobayashi, Matthias Blüher, Jens C. Brüning, Kohjiro Ueki

    Cell Chemical Biology　29　(4)　680-689.e6　2022/04

    Publisher: Elsevier BV

    DOI： 10.1016/j.chembiol.2021.12.008 　

    ISSN： 2451-9456

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    During insulin resistance, lipid uptake by the liver is promoted by peroxisome proliferator-activated protein (PPAR) γ upregulation, leading to hepatic steatosis. Insulin, however, does not directly regulate adipogenic gene expression in liver, and the mechanisms for its upregulation in obesity remain unclear. Here, we show that the Irs2 locus, a critical regulator of insulin actions, encodes an antisense transcript, ASIrs2, whose expression increases in obesity or after refeeding in liver, reciprocal to that of Irs2. ASIrs2 regulates hepatic Pparg expression, and its suppression ameliorates steatosis in obese mice. The human ortholog AL162497.1, whose expression is correlated with that of hepatic PPARG and the severity of non-alcoholic steatohepatitis (NASH), shows genomic organization similar to that of ASIrs2. We also identified HARS2 as a potential binding protein for ASIrs2, functioning as a regulator of Pparg. Collectively, our data reveal a functional duality of the Irs2 gene locus, where reciprocal changes of Irs2 and ASIrs2 in obesity cause insulin resistance and steatosis.

  7. MEK/ERK Signaling in β-Cells Bifunctionally Regulates β-Cell Mass and Glucose-Stimulated Insulin Secretion Response to Maintain Glucose Homeostasis Peer-reviewed

    Yoshiko M Ikushima, Motoharu Awazawa, Naoki Kobayashi, Sho Osonoi, Seiichi Takemiya, Hiroshi Kobayashi, Hirotsugu Suwanai, Yuichi Morimoto, Kotaro Soeda, Jun Adachi, Masafumi Muratani, Jean Charron, Hiroki Mizukami, Noriko Takahashi, Kohjiro Ueki

    Diabetes　70　(7)　1519-1535　2021/07

    Publisher: American Diabetes Association

    DOI： 10.2337/db20-1295 　

    ISSN： 0012-1797

    eISSN： 1939-327X

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    In diabetic pathology, insufficiency in β-cell mass, unable to meet peripheral insulin demand, and functional defects of individual β-cells in production of insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of db/db mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic β-cells through deletion of Mek1 and Mek2, glucose intolerance aggravates under high-fat diet–feeding conditions due to insufficient insulin production with lower β-cell proliferation and reduced β-cell mass, while in individual β-cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in β-cells for glucose homeostasis, i.e., in regulating β-cell mass as well as in controlling insulin exocytosis in individual β-cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.

  8. Machine Learning of Hematopoietic Stem Cell Divisions from Paired Daughter Cell Expression Profiles Reveals Effects of Aging on Self-Renewal. International-journal Peer-reviewed

    Fumio Arai*, Patrick S Stumpf*, Yoshiko M Ikushima*, Kentaro Hosokawa, Aline Roch, Matthias P Lutolf, Toshio Suda, Ben D MacArthur

    Cell systems　11　(6)　640-652　2020/12/16

    DOI： 10.1016/j.cels.2020.11.004 　

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    Changes in stem cell activity may underpin aging. However, these changes are not completely understood. Here, we combined single-cell profiling with machine learning and in vivo functional studies to explore how hematopoietic stem cell (HSC) divisions patterns evolve with age. We first trained an artificial neural network (ANN) to accurately identify cell types in the hematopoietic hierarchy and predict their age from single-cell gene-expression patterns. We then used this ANN to compare identities of daughter cells immediately after HSC divisions and found that the self-renewal ability of individual HSCs declines with age. Furthermore, while HSC cell divisions are deterministic and intrinsically regulated in young and old age, they are variable and niche sensitive in mid-life. These results indicate that the balance between intrinsic and extrinsic regulation of stem cell activity alters substantially with age and help explain why stem cell numbers increase through life, yet regenerative potency declines.

  9. The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age Peer-reviewed

    Kentaro Hosokawa, Ben D. MacArthur, Yoshiko M Ikushima, Hirofumi Toyama, Yoshikazu Masuhiro, Shigemasa Hanazawa, Toshio Suda, Fumio Arai

    NATURE COMMUNICATIONS　8　(1)　804　2017/10

    DOI： 10.1038/s41467-017-00935-4 　

    ISSN： 2041-1723

  10. Nucleostemin is indispensable for the maintenance and genetic stability of hematopoietic stem cells Peer-reviewed

    Masayuki Yamashita, Eriko Nitta, Go Nagamatsu, Yoshiko M Ikushima, Kentaro Hosokawa, Fumio Arai, Toshio Suda

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　441　(1)　196-201　2013/11

    DOI： 10.1016/j.bbrc.2013.10.032 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  11. Enhanced Angpt1/Tie2 signaling affects the differentiation and long-term repopulation ability of hematopoietic stem cells Peer-reviewed

    Yoshiko M Ikushima, Fumio Arai, Yuka Nakamura, Kentaro Hosokawa, Yoshiaki Kubota, Masanori Hirashima, Hirofumi Toyama, Toshio Suda

    Biochemical and Biophysical Research Communications　430　(1)　20-25　2013/01/04

    DOI： 10.1016/j.bbrc.2012.11.002 　

    ISSN： 0006-291X 1090-2104

  12. Prostaglandin E2 regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells Peer-reviewed

    Yoshiko M Ikushima, Fumio Arai, Kentaro Hosokawa, Hirofumi Toyama, Keiyo Takubo, Tomoyuki Furuyashiki, Shuh Narumiya, Toshio Suda

    Blood　121　(11)　1995-2007　2013

    Publisher: American Society of Hematology

    DOI： 10.1182/blood-2012-06-437889 　

    ISSN： 1528-0020 0006-4971

  13. N-cadherin(+) HSCs in fetal liver exhibit higher long-term bone marrow reconstitution activity than N-cadherin(-) HSCs Peer-reviewed

    Hirofumi Toyama, Fumio Arai, Kentaro Hosokawa, Yoshiko M Ikushima, Toshio Suda

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　428　(3)　354-359　2012/11

    DOI： 10.1016/j.bbrc.2012.10.058 　

    ISSN： 0006-291X

  14. Role of N-cadherin in the regulation of hematopoietic stem cells in the bone marrow niche Peer-reviewed

    Fumio Arai, Kentaro Hosokawa, Hirofumi Toyama, Yoshiko Matsumoto, Toshio Suda

    HEMATOPOIETIC STEM CELLS VIII　1266　72-77　2012

    DOI： 10.1111/j.1749-6632.2012.06576.x 　

    ISSN： 0077-8923

  15. Isolation and characterization of endosteal niche cell populations that regulate hematopoietic stem cells Peer-reviewed

    Yuka Nakamura, Fumio Arai, Hiroko Iwasaki, Kentaro Hosokawa, Isao Kobayashi, Yumiko Gomei, Yoshiko Matsumoto, Hiroki Yoshihara, Toshio Suda

    BLOOD　116　(9)　1422-1432　2010/09

    DOI： 10.1182/blood-2009-08-239194 　

    ISSN： 0006-4971

  16. Diffuse-Type Gastric Carcinoma: Progression, Angiogenesis, and Transforming Growth Factor beta Signaling Peer-reviewed

    Akiyoshi Komuro, Masakazu Yashiro, Caname Iwata, Yasuyuki Morishita, Erik Johansson, Yoshiko Matsumoto, Akira Watanabe, Hiroyuki Aburatani, Hiroyuki Miyoshi, Kunihiko Kiyono, Yo-taro Shirai, Hiroshi I. Suzuki, Kosei Hirakawa, Mitsunobu R. Kano, Kohei Miyazono

    JOURNAL OF THE NATIONAL CANCER INSTITUTE　101　(8)　592-604　2009/04

    DOI： 10.1093/jnci/djp058 　

    ISSN： 0027-8874

    eISSN： 1460-2105

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Misc. 13

  1. 免疫細胞による摂食後の糖新生抑制メカニズム

    戸田郷太郎, 添田光太郎, 荒川直子, 升田紫, 生島芳子, 小林直樹, 正本庸介, 諏訪内浩紹, 粟澤元晴, 泉田欣彦, 黒川峰夫, 戸邉一之, 門脇孝, 植木浩二郎, 山内敏正

    日本体質医学会雑誌　83　(3)　160-160　2021/08

  2. 膵ホルモンの分泌シグナル-生理と病態 インスリン抵抗性状態での膵β細胞におけるMEK/ERKシグナル伝達の役割(Roles of MEK/ERK signaling in pancreatic β cells under insulin resistant status)

    生島 芳子, 粟澤 元晴, 小林 直樹, 遅野井 祥, 諏訪内 浩紹, 守本 祐一, 添田 光太郎, 足立 淳, 村谷 匡史, 水上 浩哉, 高橋 倫子, 植木 浩二郎

    糖尿病　64　(Suppl.1)　S6-6　2021/05

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  3. 膵β細胞の量と分泌能を制御するMEK/ERKシグナル

    生島 芳子, 小林 直樹, 粟澤 元晴, 諏訪内 浩紹, 添田 光太郎, 村谷 匡史, 足立 淳, 高橋 倫子, 植木 浩二郎

    糖尿病　63　(Suppl.1)　S-196　2020/08

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  4. 膵β細胞制御におけるMek/Erkシグナルの役割の解明

    生島 芳子, 小林 直樹, 粟澤 元晴, 諏訪内 浩紹, 添田 光太郎, 村谷 匡史, 高橋 倫子, 植木 浩二郎

    糖尿病　62　(Suppl.1)　S-105　2019/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  5. 心血管 心筋においてAktの果たす役割の解明

    添田 光太郎, 小林 直樹, 生島 芳子, 粟澤 元晴, 笹子 敬洋, 戸田 郷太郎, 中野 美和, 小山 千夏, 野田 哲生, 門脇 孝, 植木 浩二郎

    糖尿病合併症　32　(Suppl.1)　260-260　2018/10

    Publisher: (一社)日本糖尿病合併症学会

  6. 心筋におけるAktの役割の解明

    添田 光太郎, 小林 直樹, 生島 芳子, 戸田 郷太郎, 笹子 敬洋, 野田 哲生, 門脇 孝, 植木 浩二郎

    肥満研究　24　(Suppl.)　176-176　2018/09

    Publisher: (一社)日本肥満学会

    ISSN： 1343-229X

  7. 心筋におけるAktの役割の解明

    添田 光太郎, 小林 直樹, 生島 芳子, 戸田 郷太郎, 笹子 敬洋, 竹宮 聖一, 野田 哲生, 門脇 孝, 植木 浩二郎

    糖尿病　61　(Suppl.1)　S-405　2018/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

  8. Functional analysis of Protection of Telomeres 1a (Pot1a) in regulation of hematopoietic stem cell aging

    HOSOKAWA Kentaro, MACARTHUR Ben D, IKUSHIMA Yoshiko, TOYAMA Hirofumi, MASUHIRO Yoshikazu, HANAZAWA Shigemasa, SUDA Toshio, ARAI Fumio

    Rinsho Ketsueki　58　(8)　942-949　2017

    Publisher: The Japanese Society of Hematology

    DOI： 10.11406/rinketsu.58.942 　

    ISSN： 0485-1439

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    <p>Repeated cell divisions induce DNA damage accumulation, which impairs stem cell function during aging. However, the general molecular mechanisms by which this occurs remain unclear. Herein, we show that the expression of protection of telomeres 1a (Pot1a), a component of shelterin, is crucial for prevention of telomeric DNA damage response (DDR) and maintenance of hematopoietic stem cell (HSC) activity during aging. We observed that HSCs express high levels of Pot1a during development, and this expression declines with aging. Knockdown of Pot1a induced an age-related phenotype, characterized by increased telomeric DDR and reduced long-term reconstitution activity. In contrast, treatment with exogenous Pot1a protein prevented telomeric DDR, which decreased stem cell activity and partially rejuvenated HSC activity. These results highlight a general, reversible mechanism by which aging compromises mammalian stem cell activity, with widespread implications for regenerative medicine.</p>

  9. 【再生医療-新たな医療を求めて-】 臨床応用を目指した基礎研究 体細胞研究 造血幹細胞

    生島 芳子, 小林 央, 須田 年生

    日本臨床　73　(増刊5 再生医療)　215-222　2015/06

    Publisher: (株)日本臨床社

    ISSN： 0047-1852

  10. POT1 REGULATES SELF-RENEWAL ACTIVITY OF CORD BLOOD HEMATOPOIETIC STEM CELLS

    Kentaro Hosokawa, Yoshiko Ikushima, Benjamin MacArthur, Toshio Suda, Fumio Arai

    EXPERIMENTAL HEMATOLOGY　42　(8)　S38-S38　2014/08

    ISSN： 0301-472X

    eISSN： 1873-2399

  11. PROSTAGLANDIN E2 REGULATES HEMATOPOIETIC STEM/PROGENITOR CELLS DIRECTLY THROUGH EP4 RECEPTOR AND INDIRECTLY BY MESENCHYMAL PROGENITOR CELLS

    Yoshiko Matsumoto, Fumio Arai, Toshio Sudo

    EXPERIMENTAL HEMATOLOGY　40　(8)　S49-S50　2012/08

    ISSN： 0301-472X

  12. [Regulation of hematopoietic stem cells in niche signaling].

    Matsumoto Y, Suda T

    Nihon rinsho. Japanese journal of clinical medicine　70 Suppl 2　133-138　2012/04

  13. Prostaglandin E2 Signaling Through the EP4 Receptor Regulates the Proliferation of Hematopoietic Stem/Progenitor Cells Under Stress Conditions

    Fumio Arai, Yoshiko Matsumoto, Toshio Suda

    BLOOD　118　(21)　1024-1025　2011/11

    ISSN： 0006-4971

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Presentations 16

  1. Adiponectin exerts unexpected effects on liver function, and glucose homeostasis during caloric restriction

    Ikushima YM, Chen KC, Sulston RJ, Mattiucci D., Brain EJ, Fung SA, Suchacki KJ, Thomas BJ, Lovdel A., Bennett M., Kobayashi H., Whitfield PD, Takubo K., Baker AH, Morton NM, Semple RK, Cawthorn WP

    8th International Meeting on Bone Marrow Adiposity　2024/09

  2. Investigating why females resist fat loss and hypoglycaemia during caloric restriction

    Ikushima YM, Chen KC, Suchacki KJ, Thomas BJ, Sulston RJ, Lovdel A., Woodward HJ, Mattiucci D., Brain EJ, Gray GA, Stimson RH, Morton NM, Cawthorn WP

    The 46th Meeting of the Adipose Tissue Discussion Group - Adipose Biology: Metabolic Buffering in an Obesogenic World -　2023/03

  3. MEK/ERKシグナルによるインスリン分泌制御のメカニズム

    The 64th Annual Meeting of Japanese Diabetes Society　2021/05

  4. Roles of MEK/ERK signaling in pancreatic β cells under insulin resistant status Invited

    Ikushima YM, Awazawa M, Kobayashi N, Osonoi S, Suwanai H, Morimoto Y, Soeda K, Adachi J, Muratani M, Mizukami H, Takahashi N, Ueki K

    The 64th Annual Meeting of Japanese Diabetes Society　2021/05

  5. 食後のインスリン・LPSシグナルによるマクロファージのIL-10発現を介した糖新生抑制メカニズム

    戸田 郷太郎, 添田 光太郎, 荒川 直子, 升田 紫, 小林 直樹, 生島 芳子, 粟澤 元晴, 正本 庸介, 諏訪内 浩紹, 泉田 欣彦, 黒川 峰夫, 戸邉 一之, 門脇 孝, 植木 浩二郎, 山内 敏正

    日本糖尿病学会　2021

  6. 膵β細胞の量と分泌能を制御するMEK/ERKシグナル

    生島芳子, 小林直樹, 粟澤元晴, 諏訪内浩紹, 添田光太郎, 村谷匡史, 高橋倫子, 植木浩二郎

    2020/10

  7. MEK/ERKシグナルによる膵β細胞制御

    生島芳子, 小林直樹, 粟澤元晴, 諏訪内浩紹, 添田光太郎, 村谷匡史, 高橋倫子, 植木浩二郎

    2020/02

  8. 膵β細胞制御におけるMek/Erkシグナルの役割の解明

    生島芳子, 小林直樹, 粟澤元晴, 諏訪内浩紹, 添田光太郎, 村谷匡史, 高橋倫子, 植木浩二郎

    第62回日本糖尿病学会年次学術集会　2019/05

  9. Mek/Erkシグナルは膵β細胞の量と分泌能を制御する

    生島芳子, 小林直樹, 粟澤元晴, 竹宮聖一, 諏訪内浩紹, 添田光太郎, 守本祐一, 村谷匡史, 高橋倫子, 植木浩二郎

    第33回 日本糖尿病・肥満動物学会年次学術集会　2019/03

  10. 単一細胞レベルでの娘細胞解析に基づくAngpt1の造血幹細胞分裂パターン決定における作用について

    生島芳子, MacArthur BD, Stumpf PS, 細川健太郎, Roch A., Lutolf MP, 須田年生, 新井文用

    第76回 日本血液学会年次学術集会　2014/10

  11. 単一細胞レベルでの造血幹細胞の分裂パターン制御機構の解析

    生島芳子, MacArthur BD, 細川健太郎, Lutolf MP, 須田年生, 新井文用

    第75回 日本血液学会年次学術集会　2013/10

  12. Prostaglandin E2 directly and indirectly regulates hematopoietic stem/progenitor cells

    松元芳子, 新井文用, 細川健太郎, 外山弘文, 須田年生

    第74回 日本血液学会年次学術集会　2012/10

  13. Prostaglandin E2 Regulates Hematopoietic Stem/Progenitor Cells Directly through EP4 Receptor and Indirectly by Mesenchymal Progenitor Cells

    Matsumoto Y., Arai F., Hosokawa K., Toyama H., Suda T.

    41st Annual Scientific Meeting of Society for Hematology and Stem Cells (ISEH)　2012/08

  14. EP4 receptor-dependent direct and -independent indirect effects of prostaglandin E2 in the regulation of adult hematopoietic stem/progenitor cells

    Matsumoto Y., Arai F., Suda T.

    10th Annual Meeting of International Society for Stem Cell Research (ISSCR)　2012/05

  15. 造血幹細胞の分裂制御におけるTie2/Angiopoietin-1シグナルの機能解析

    松元芳子, 新井文用, MacArthur BD, 中村由香, 細川健太郎, 外山弘文, 須田年生

    第73回 日本血液学会年次学術集会　2011/10

  16. Function of Tie2/Angiopoietin-1 signaling in the regulation of long-term hematopoietic stem cell division patterns

    Matsumoto Y., Arai F., MacArthur BD, Nakamura Y., Hosokawa K., Toyama H., Suda T.

    40st Annual Scientific Meeting of Society for Hematology and Stem Cells (ISEH)　2011/08

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Research Projects 5

  1. 膵β細胞の量・機能を制御する細胞内シグナルの同定

    生島 芳子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 若手研究

    Category: 若手研究

    Institution: 国立研究開発法人国立国際医療研究センター

    2019/04 - 2022/03

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    研究者らは、膵β細胞特異的Mek1/2欠損マウスを用いたこれまでの解析で、MEK/ERKシグナルは膵β細胞の量だけでなく分泌能の制御にも重要であり、特にインスリン抵抗性の亢進によりインスリン需要の増大する肥満時には2型糖尿病発症の防波堤として機能している可能性を見出してきた。また、単離膵島および膵β細胞株を用いたリン酸化プロテオミクス解析の結果からは、MEK/ERKシグナルが開口放出関連因子や細胞骨格関連因子のリン酸化制御を介してインスリン顆粒の開口放出を制御している可能性が考えられた。さらに、剖検症例の解析を通じ、実際ヒトにおいても2型糖尿病の発症・進行と膵β細胞におけるMEK/ERKシグナルの活性化状況になんらかの因果関係がある可能性を見出した。今年度は、こうしたこれまでの一連の成果をまとめ論文発表した (Ikushima YM et al. Diabetes 2021)。また、リン酸化プロテオミクス解析を通じて見出された、MEK/ERK下流で制御されて開口放出制御に関与し得るいくつかのタンパク被リン酸化部位の候補について、インスリン顆粒の開口放出における実際の役割・寄与を検討するため、CRISPR-Cas9システムを利用した当該部位を含む遺伝子を欠損した膵β細胞株の作成、および、当該部位を含む遺伝子または当該部位をアラニン置換した同遺伝子の過剰発現に用いるAAVウイルスの準備を進めた。

  2. Role of MEK/ERK signaling in pancreatic beta cells - to develop a novel treatment strategy for type 2 diaetes

    Ikushima Yoshiko M, Kobayashi Naoki, Awazawa Motoharu, Suwanai Hirotsugu, Muratani Masafumi, Ueki Kohjiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: National Center for Global Health and Medicine

    2016/04 - 2019/03

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    To investigate the significance of MEK/ERK signaling in β cells, we generated β cell-specific Mek1/2 KO mice (DKO mice). These mice showed normoglycemia on normal chow diet. In contrast, when fed on high fat diet (HFD), DKO mice developed hyperglycemia. Islet areas in DKO mice were significantly smaller compared to those in controls when fed on HFD for long time. The inadequate insulin secretion based on the smaller islet area could be one cause of the hyperglycemia observed in HFD-fed DKO mice. We conclude that MEK/ERK signaling in β cells is especially important when the insulin demand increases, such as obesity.

  3. Analyses of hematopoietic stem cell division patterns in biomimetic culture conditions and optimization of culture condition for hematopoietic stem cells

    IKUSHIMA Yoshiko, ARAI Fumio, HOSOKAWA Kentaro, SUDA Toshio, MACARTHUR Ben D., STUMPF Patrich S, LUTOLF Matthias P.

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up

    Category: Grant-in-Aid for Research Activity Start-up

    2013/08 - 2015/03

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    We investigated hematopoietic stem cell (HSC) division patterns at the single cell level based on gene expression profiles of paired daughter cells (PDCs) derived from highly purified long-term HSCs. Also we analyzed the frequency of daughter stem cells with long-term bone marrow (BM) reconstitution activity in PDCs by limiting dilution competitive BM transplantation assays. We revealed that HSCs cultured on fibronectin-coated PEG hydrogel microwells with Angpt1 produce more daughter stem cells compared to HSCs cultured on fibronectin-coated normal cell culture dish without Angpt1. Our data indicated that biomimetic cell culture condition could maintain HSCs in vitro.

  4. Analysis of Niche Regulation for Cancer Stem Cells

    TOSHIO Suda, TAKUBO Keiyo, NAGAMATSU Go, IKUSHIMA Yoshiko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Keio University

    2010/04 - 2015/03

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    Stem cell maintenance in a haltered cell-cycle state (i.e., quiescence) has been proposed as a fundamental property of HSCs. Maintenance of quiescence protects HSCs from functional exhaustion and naturally producing extrinsic cellular insults to enable lifelong hematopoietic cell production. HSC quiescence is regulated through a complex network of cell intrinsic regulations along with extrinsic influences from the microenvironment. Normal HSCs maintain intracellular hypoxia, stabilize the hypoxia-inducible factor-1α (HIF-1α) protein and generate ATP by anaerobic metabolism. In HIF-1α deficiency, HSCs became metabolically aerobic, lost cell cycle quiescence, and finally exhausted.

  5. 単一細胞レベルでの造血幹細胞の対称・非対称分裂の制御機構の解明

    松元 芳子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特別研究員奨励費

    Category: 特別研究員奨励費

    Institution: 慶應義塾大学

    2011 - 2012

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    本研究は、造血幹細胞および造血幹細胞が分裂して生じるペアとなった娘細胞(Paired Daughter Cells(PDCs)を対象に単一細胞での網羅的定量PCR解析を行い、その結果から、造血幹細胞の分裂パターン制御に寄与する分子・遺伝子を特定することを目的としている。昨年度までの解析結果からは、Tie2/Angpt1シグナルが造血幹細胞の自己複製を伴う対称分裂を促している可能性が示唆された。 本年度は、遺伝子発現プロファイルの解析手法に高度な学習モデルであるSupport Vector Machine(SVM)classifierを取り入れた。この手法では、まずSVM classifierに造血幹細胞および前駆細胞の遺伝子発現プロファイルを入力してその特徴を学習させる。その上で娘細胞の遺伝子発現プロファイルを入力すると、親細胞の遺伝子発現プロファイルとの比較により、各々の娘細胞を「幹細胞」か「前駆細胞」のいずれかに分類することができる。SVMC Classifierによる解析の結果、培養液にAngpt1が添加されていることで、造血幹細胞が「娘幹細胞」を2つ生じる対称分裂を行う割合が増えることが明らかとなった。さらに今年度は、プラスチック細胞培養プレートに比べ柔らかく保水性に優れた、Polyethylene glycol(PEG)hydrogel microwell上で造血幹細胞を培養しPDCアッセイを行った。そして娘細胞の遺伝子発現プロファイルについてSVM classifierによる解析を進めたところ、PEG hygdrogel microwell上で培養された造血幹細胞は、「娘幹細胞」を2つ生じる対称分裂をする割合が高く、この割合は培養メディウムにAngpt1を添加することでさらに上昇することが明らかとなった。以上の結果は、培養条件を骨髄ニッチに近づけることで、造血幹細胞増幅できる可能性を示唆している。