Details of the Researcher

PHOTO

Ikuo Hirano
Section
Graduate School of Medicine
Job title
Senior Assistant Professor
Degree

  • 博士（医学）（東北大学）

  • 修士（医科学）（筑波大学）

Professional Memberships 2

  • 日本分子生物学会

  • 日本生化学会

Research Interests 7

  • 巨核球分化

  • 好酸球分化

  • Erythropoiesis

  • Erythropoietin

  • Hypoxia

  • GATA1

  • Leukemia

Research Areas 2

  • Life sciences / Tumor biology /

  • Life sciences / Medical biochemistry /

Awards 4

  1. 日本生化学会東北支部優秀論文賞

    2014/05/10　日本生化学会 東北支部

  2. 教育貢献賞

    2023/02　東北大学 医学部・医学系研究科

  3. 奨学賞A

    2020/01　東北医学会　腎臓エリスロポエチン産生制御機構の解明

  4. 第２回 低酸素研究会 YIA 最優秀賞

    2014/07/26　低酸素研究会

Papers 30

  1. Strain-dependent modifiers exacerbate familial leukemia caused by GATA1-deficiency. International-journal

    Ikuo Hirano, Kanako Abe, James Douglas Engel, Masayuki Yamamoto, Ritsuko Shimizu

    Experimental hematology & oncology　13　(1)　23-23　2024/02/26

    DOI： 10.1186/s40164-024-00491-w 　

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    GATA1 plays a critical role in differentiation, proliferation, and apoptosis during erythropoiesis. We developed a Gata1 knock-down allele (Gata1.05) that results in GATA1 expression at 5% of endogenous level. In female mice heterozygous for both the Gata1.05 and wild-type alleles, we observed a predisposition to erythroblastic leukemia three to six months after birth. Since no male Gata1.05 progeny survive gestation, we originally maintained heterozygous females in a mixed genetic background of C57BL/6J and DBA/2 strains. Around 30% of these mice reproducibly develop leukemia, but the other subset did not develop leukemia, even though they harbor a high number of preleukemic erythroblasts. These observations prompted us to hypothesize that there may be potential influence of genetic determinants on the progression of Gata1.05-driven hematopoietic precursors to full-blown leukemia. In an initial examination of Gata1.05/X mice backcrossed into C3H/He, BALB/c, DBA/2, C57BL/6J and 129X1/SvJ strains, we discerned that the backgrounds of C57BL/6J and 129X1/SvJ significantly expedited leukemia onset in Gata1.05/X mice. Conversely, backgrounds of C3H/He, BALB/c and DBA/2 did not substantially modify the effect of the Gata1 mutation. This indicates the existence of genetic modifiers that accentuate Gata1.05 leukemogenesis. Subsequent cohort studies evaluated Gata1.05/X mice within mix backgrounds of BALB/c:129X1/SvJ and BALB/c:C57BL/6J. In these settings, Gata1.05-driven leukemia manifested in autosomal dominant patterns within the 129X1/SvJ background and in autosomal recessive patterns within C57BL/6J background. To the best of our knowledge, this study provides the inaugural evidence of genetic modifiers that can reshape the outcome based on leukemia-associated gene signatures.

  2. The abundance of the short GATA1 isoform affects megakaryocyte differentiation and leukemic predisposition in mice. International-journal

    Daishi Ishihara, Atsushi Hasegawa, Ikuo Hirano, James Douglas Engel, Masayuki Yamamoto, Ritsuko Shimizu

    Experimental hematology & oncology　13　(1)　24-24　2024/02/26

    DOI： 10.1186/s40164-024-00492-9 　

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    Transcription factor GATA1 controls the delicate balance between proliferation, differentiation and apoptosis in both the erythroid and megakaryocytic lineages. In addition to full-length GATA1, there is an GATA1 isoform, GATA1s, that lacks the amino-terminal transactivation domain. Somatic GATA1 mutations that lead to the exclusive production of GATA1s appear to be necessary and sufficient for the development of a preleukemic condition called transient myeloproliferative disorder (TMD) in Down syndrome newborns. Subsequent clonal evolution among latent TMD blasts leads to the development of acute megakaryoblastic leukemia (AMKL). We originally established transgenic mice that express only GATA1s, which exhibit hyperproliferation of immature megakaryocytes, thus mimicking human TMD; however, these mice never developed AMKL. Here, we report that transgenic mice expressing moderate levels of GATA1s, i.e., roughly comparable levels to endogenous GATA1, were prone to develop AMKL in young adults. However, when GATA1s is expressed at levels significantly exceeding that of endogenous GATA1, the development of leukemia was restrained in a dose dependent manner. If the transgenic increase of GATA1s in progenitors remains small, GATA1s supports the terminal maturation of megakaryocyte progenitors insufficiently, and consequently the progenitors persisted, leading to an increased probability for acquisition of additional genetic modifications. In contrast, more abundant GATA1s expression compensates for this maturation block, enabling megakaryocytic progenitors to fully differentiate. This study provides evidence for the clinical observation that the abundance of GATA1s correlates well with the progression to AMKL in Down syndrome.

  3. Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice Peer-reviewed

    Ritsuko Shimizu, Ikuo Hirano, Atsushi Hasegawa, Mikiko Suzuki, Akihito Otsuki, Keiko Taguchi, Fumiki Katsuoka, Akira Uruno, Norio Suzuki, Akane Yumoto, Risa Okada, Masaki Shirakawa, Dai Shiba, Satoru Takahashi, Takafumi Suzuki, Masayuki Yamamoto

    Communications Biology　6　2023/08/25

    DOI： 10.1038/s42003-023-05251-w 　

  4. Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice. International-journal

    Taku Nakai, Yuma Iwamura, Koichiro Kato, Ikuo Hirano, Yotaro Matsumoto, Yoshihisa Tomioka, Masayuki Yamamoto, Norio Suzuki

    Blood advances　2023/05/05

    DOI： 10.1182/bloodadvances.2023009798 　

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    The erythroid growth factor erythropoietin (EPO) is mainly produced by the kidneys in adult mammals and induces expansion of erythroid cells and iron use for hemoglobin synthesis. The liver also produces EPO at a lower level than the kidneys. Renal and hepatic EPO production is fundamentally regulated by hypoxia-inducible transcription factors (HIFs) in a hypoxia/anemia-inducible manner. Recently, small compounds that activate HIFs and EPO production in the kidneys by inhibiting HIF-prolyl hydroxylases (HIF-PHIs) have been launched to treat EPO-deficiency anemia in patients suffering from kidney disease. However, the roles of the liver in the HIF-PHI-mediated induction of erythropoiesis and iron mobilization remain controversial. Here, to elucidate the liver contributions to the therapeutic effects of HIF-PHIs, genetically modified mouse lines lacking renal EPO-production ability were analyzed. In the mutant mice, HIF-PHI administration marginally increased plasma EPO concentrations and peripheral erythrocytes by inducing hepatic EPO production. The effects of HIF-PHIs on the mobilization of stored iron and on the suppression of hepatic hepcidin, an inhibitory molecule for iron release from iron-storage cells, were not observed in the mutant mice. These findings demonstrate that adequate induction of EPO mainly in the kidney is essential for achieving the full therapeutic effects of HIF-PHIs, which include hepcidin suppression. The data also show that HIF-PHIs directly induce the expression of duodenal genes related to dietary iron intake. Additionally, hepatic EPO induction is considered to partially contribute to the erythropoietic effects of HIF-PHIs but to be insufficient to compensate for the abundant EPO induction by the kidneys.

  5. Heterozygous variants in GATA2 contribute to DCML deficiency in mice by disrupting tandem protein binding

    Atsushi Hasegawa, Yuki Hayasaka, Masanobu Morita, Yuta Takenaka, Yuna Hosaka, Ikuo Hirano, Masayuki Yamamoto, Ritsuko Shimizu

    Communications Biology　5　(1)　2022/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-022-03316-w 　

    eISSN： 2399-3642

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    Abstract Accumulating lines of clinical evidence support the emerging hypothesis that loss-of-function mutations of GATA2 cause inherited hematopoietic diseases, including Emberger syndrome; dendritic cell, monocyte B and NK lymphoid (DCML) deficiency; and MonoMAC syndrome. Here, we show that mice heterozygous for an arginine-to-tryptophan substitution mutation in GATA2 (G2R398W/+), which was found in a patient with DCML deficiency, substantially phenocopy human DCML deficiency. Mice heterozygous for the GATA2-null mutation (G2-/+) do not show such phenotypes. The G2R398W protein possesses a decreased DNA-binding affinity but obstructs the function of coexpressed wild-type GATA2 through specific cis-regulatory regions, which contain two GATA motifs in direct-repeat arrangements. In contrast, G2R398W is innocuous in mice containing single GATA motifs. We conclude that the dominant-negative effect of mutant GATA2 on wild-type GATA2 through specific enhancer/silencer of GATA2 target genes perturbs the GATA2 transcriptional network, leading to the development of the DCML-like phenotype. The present mouse model provides an avenue for the understanding of molecular mechanisms underlying the pathogenesis of GATA2-related hematopoietic diseases.

  6. Esterification promotes the intracellular accumulation of roxadustat, an activator of hypoxia-inducible factors, to extend its effective duration. International-journal

    Taku Nakai, Daisuke Saigusa, Yuma Iwamura, Yotaro Matsumoto, Keiko Umeda, Koichiro Kato, Hayato Yamaki, Yoshihisa Tomioka, Ikuo Hirano, Seizo Koshiba, Masayuki Yamamoto, Norio Suzuki

    Biochemical pharmacology　197　114939-114939　2022/03

    DOI： 10.1016/j.bcp.2022.114939 　

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    Kidney injury often causes anemia due to a lack of production of the erythroid growth factor erythropoietin (EPO) in the kidneys. Roxadustat is one of the first oral medicines inducing EPO production in patients with renal anemia by activating hypoxia-inducible factors (HIFs), which are activators of EPO gene expression. In this study, to develop prodrugs of roxadustat with improved permeability through cell membrane, we investigated the effects of 8 types of esterification on the pharmacokinetics and bioactivity of roxadustat using Hep3B hepatoma cells that HIF-dependently produce EPO. Mass spectrometry of cells incubated with the esterified roxadustat derivatives revealed that the designed compounds were deesterified after being taken up by cells and showed low cytotoxicity compared to the original compound. Esterification prolonged the effective duration of roxadustat with respect to EPO gene induction and HIF activation in cells transiently exposed to the compounds. In the kidneys and livers of mice, both of which are unique sites of EPO production, a majority of the methyl-esterified roxadustat was deesterified within 6 h after drug administration. The deesterified roxadustat derivative was continuously detectable in plasma and urine for at least 48 h after administration, while the administered compound became undetectable 24 h after administration. Additionally, we confirmed that methyl-esterified roxadustat activated erythropoiesis in mice by inducing Epo mRNA expression exclusively in renal interstitial cells, which have intrinsic EPO-producing potential. These data suggest that esterification could lead to the development of roxadustat prodrugs with improvements in cell membrane permeability, effective duration and cytotoxicity.

  7. Blockade of the interaction between BMP9 and endoglin on erythroid progenitors promotes erythropoiesis in mice International-journal Peer-reviewed

    Ayami Yamaguchi, Ikuo Hirano, Shiho Narusawa, Kiyoshi Shimizu, Hiroyuki Ariyama, Kengo Yamawaki, Kenji Nagao, Masayuki Yamamoto, Ritsuko Shimizu

    Genes to Cells　26　(10)　782-797　2021/08/12

    Publisher: Wiley

    DOI： 10.1111/gtc.12887 　

    ISSN： 1356-9597

    eISSN： 1365-2443

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    Bone morphogenetic protein-9 (BMP9), a member of the transforming growth factor β (TGFβ) superfamily, plays important roles in the development and maintenance of various cell lineages via complexes of type I and type II TGFβ receptors. Endoglin is a coreceptor for several TGFβ family members, including BMP9, which is highly expressed in a particular stage of differentiation in erythroid cells as well as in endothelial cells. Although the importance of the interaction between BMP9 and endoglin for endothelial development has been reported, the contribution of BMP9 to endoglin-expressing erythroid cells remains to be clarified. To address this point, we prepared an anti-BMP9 antibody that blocks the BMP9-endoglin interaction. Of note, challenge with the antibody promotes erythropoiesis in wild-type mice but not in a mouse model of renal anemia in which erythropoietin (EPO) production in the kidneys is genetically ablated. While endoglin-positive erythroid progenitors are mainly maintained as progenitors when bone marrow-derived lineage-negative and cKit-positive cells are cultured in the presence of EPO and stem cell factor, the erythroid-biased accumulation of progenitors is impeded by the presence of BMP9. Our findings uncover an unrecognized role for BMP9 in attenuating erythroid differentiation via its interaction with endoglin on erythroid progenitors.

  8. Defining the functionally sufficient regulatory region and liver-specific roles of the erythropoietin gene by transgene complementation Peer-reviewed

    Shun Yamazaki, Ikuo Hirano, Koichiro Kato, Masayuki Yamamoto, Norio Suzuki

    Life Sciences　269　119075-119075　2021/03

    Publisher: Elsevier BV

    DOI： 10.1016/j.lfs.2021.119075 　

    ISSN： 0024-3205

    eISSN： 1879-0631

  9. Nrf2 contributes to the weight gain of mice during space travel

    Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W. Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

    Communications Biology　3　(1)　2020/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-020-01227-2 　

    eISSN： 2399-3642

  10. An immortalized cell line derived from renal erythropoietin-producing (REP) cells demonstrates their potential to transform into myofibroblasts. International-journal Peer-reviewed

    Koji Sato, Ikuo Hirano, Hiroki Sekine, Kenichiro Miyauchi, Taku Nakai, Koichiro Kato, Sadayoshi Ito, Masayuki Yamamoto, Norio Suzuki

    Scientific reports　9　(1)　11254-11254　2019/08/02

    DOI： 10.1038/s41598-019-47766-5 　

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    The erythroid growth factor erythropoietin (Epo) is produced by renal interstitial fibroblasts, called REP (renal Epo-producing) cells, in a hypoxia-inducible manner. In chronic kidney disease (CKD), REP cells lose their Epo-production ability, leading to renal anaemia. Concurrently, REP cells are suggested to be transformed into myofibroblasts, which are the major player of renal fibrosis. Although establishment of cultured cell lines derived from REP cells has been a long-term challenge, we here successfully established a REP-cell-derived immortalized and cultivable cell line (Replic cells) by using a genetically modified mouse line. Replic cells exhibited myofibroblastic phenotypes and lost their Epo-production ability, reflecting the situation in renal fibrosis. Additionally, we found that cell-autonomous TGFβ signalling contributes to maintenance of the myofibroblastic features of Replic cells. Furthermore, the promoters of genes for Epo and HIF2α, a major activator of Epo gene expression, were highly methylated in Replic cells. Thus, these results strongly support our contention that REP cells are the origin of myofibroblasts in fibrotic kidneys and demonstrate that cell-autonomous TGFβ signalling and epigenetic silencing are involved in renal fibrosis and renal anaemia, respectively, in CKD. The Replic cell line is a useful tool to further investigate the molecular mechanisms underlying renal fibrosis.

  11. The Neural Crest as the First Production Site of the Erythroid Growth Factor Erythropoietin. Peer-reviewed

    Ikuo Hirano

    Frontiers in cell and developmental biology　7　105　2019/06/12

    DOI： 10.3389/fcell.2019.00105 　

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    While the neural crest is considered the fourth germ layer that originates a variety of tissues during mammalian development, we recently discovered that some neural crest cells and neuroepithelial cells play a unique role in secreting a vital hematopoietic hormone, erythropoietin (EPO), in mouse embryos. EPO production by the neural crest is transient in mid-stage embryos but essential for the first erythropoiesis in the yolk sac and for sufficient oxygen supply in the whole embryo growing in utero. The site of EPO production shifts from the neural crest to the liver in late embryonic stages, followed by interstitial fibroblasts of the kidneys in adults. Interestingly, the transition of EPO production sites synchronizes with the transition of erythropoietic sites during mouse development from the yolk sac and the fetal liver to the bone marrow. EPO produced by the neural crest and the neuroepithelium is first stored around the production sites and delivered to the yolk sac as an endocrine hormone for erythropoiesis after heartbeat activation. The fact that EPO is produced by some human cell lines derived from neuroblastoma, which mainly originates from the neural crest, provides evidence that the neural crest secretes EPO for primitive erythropoiesis not only in mouse but also in human embryos. Here, we introduce and discuss recent progress in studies on the mechanism of EPO production by the neural crest and its roles in erythropoietic development and in the fate of EPO-producing neural crest cells.

  12. GATA2 hypomorphism induces chronic myelomonocytic leukemia in mice. Peer-reviewed

    Ikuo Hirano

    Cancer science　110　(4)　1183-1193　2019/02/23

    DOI： 10.1111/cas.13959 　

    ISSN： 1347-9032

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    The transcription factor GATA2 regulates normal hematopoiesis, particularly in- stem cell maintenance and myeloid differentiation. Various heteroallelic GATA2 gene mutations are associated with a variety of hematological neoplasms, including myelodysplastic syndromes and leukemias. Here, we report that impaired GATA2 expression induces myelodysplastic and myeloproliferative neoplasm development in elderly animals, and this neoplasm resembles chronic myelomonocytic leukemia in humans. GATA2 hypomorphic mutant (G2f GN / fGN ) mice that were generated by the germline insertion of a neocassette into the Gata2 gene locus avoided the early embryonic lethality observed in Gata2-null mice. However, adult G2f GN / fGN mice suffered from exacerbated leukocytosis concomitant with progressive anemia and thrombocytopenia and eventually developed massive granulomonocytosis accompanied by trilineage dysplasia. The reconstitution activity of G2f GN / fGN mouse stem cells was impaired. Furthermore, G2f GN / fGN progenitors showed myeloid lineage-biased proliferation and differentiation. Myeloid progenitor accumulation started at a younger age in G2f GN / fGN mice and appeared to worsen with age. G2f GN / fGN mice showed increased expression of transcripts encoding cytokine receptors, such as macrophage colony-stimulating factor receptor and interleukin-6 receptor, in granulocyte-monocyte progenitors. This increased expression could be correlated with the hypersensitive granulomonocytic proliferation reaction when the mice were exposed to lipopolysaccharide. Taken together, these observations indicate that GATA2 hypomorphism leads to a hyperreactive defense response to infections, and this reaction is attributed to a unique intrinsic cell defect in the regulation of myeloid expansion that increases the risk of hematological neoplasm transformation.

  13. 腎エリスロポエチン産生細胞(REP細胞)由来の細胞株は、細胞自律性TGFβ発現により筋線維芽細胞の形質を有する Peer-reviewed

    佐藤 浩司, 平野 育生, 関根 弘樹, 宮内 健一郎, 中井 啄, 加藤 幸一郎, 伊藤 貞嘉, 山本 雅之, 鈴木 教郎

    日本生化学会大会プログラム・講演要旨集　91回　[3T12m-019)]　2018/09

    Publisher: (公社)日本生化学会

  14. Induction of erythropoietin gene expression in epithelial cells by chemicals identified in GATA inhibitor screenings Peer-reviewed

    Hiroshi Kaneko, Takehide Katoh, Ikuo Hirano, Atsushi Hasegawa, Tadayuki Tsujita, Masayuki Yamamoto, Ritsuko Shimizu

    GENES TO CELLS　22　(11)　939-952　2017/11

    DOI： 10.1111/gtc.12537 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  15. Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements. International-journal Peer-reviewed

    Ikuo Hirano, Norio Suzuki, Shun Yamazaki, Hiroki Sekine, Naoko Minegishi, Ritsuko Shimizu, Masayuki Yamamoto

    Molecular and cellular biology　37　(4)　2017/02/15

    DOI： 10.1128/MCB.00451-16 　

    ISSN： 0270-7306

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    The erythropoietin (Epo) gene is under tissue-specific inducible regulation. Because the kidney is the primary EPO-producing tissue in adults, impaired EPO production in chronic kidney disorders results in serious renal anemia. The Epo gene contains a liver-specific enhancer in the 3' region, but the kidney-specific enhancer for gene expression in renal EPO-producing (REP) cells remains elusive. Here, we examined a conserved upstream element for renal Epo regulation (CURE) region that spans 17.4 kb to 3.6 kb upstream of the Epo gene and harbors several phylogenetically conserved elements. We prepared various Epo gene-reporter constructs utilizing a bacterial artificial chromosome and generated a number of transgenic-mouse lines. We observed that deletion of the CURE region (δCURE) abrogated Epo gene expression in REP cells. Although transgenic expression of the δCURE construct rescued Epo-deficient mice from embryonic lethality, the rescued mice had severe EPO-dependent anemia. These mouse lines serve as an elaborate model for the search for erythroid stimulatory activity and are referred to as AnRED (anemic model with renal EPO deficiency) mice. We also dissected the CURE region by exploiting a minigene harboring four phylogenetically conserved elements in reporter transgenic-mouse analyses. Our analyses revealed that Epo gene regulation in REP cells is a complex process that utilizes multiple regulatory influences.

  16. Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling. International-journal Peer-reviewed

    Tomokazu Souma, Masahiro Nezu, Daisuke Nakano, Shun Yamazaki, Ikuo Hirano, Hiroki Sekine, Takashi Dan, Kotaro Takeda, Guo-Hua Fong, Akira Nishiyama, Sadayoshi Ito, Toshio Miyata, Masayuki Yamamoto, Norio Suzuki

    Journal of the American Society of Nephrology : JASN　27　(2)　428-38　2016/02

    DOI： 10.1681/ASN.2014121184 　

    ISSN： 1046-6673

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    Erythropoietin (Epo) is produced by renal Epo-producing cells (REPs) in a hypoxia-inducible manner. The conversion of REPs into myofibroblasts and coincident loss of Epo-producing ability are the major cause of renal fibrosis and anemia. However, the hypoxic response of these transformed myofibroblasts remains unclear. Here, we used complementary in vivo transgenic and live imaging approaches to better understand the importance of hypoxia signaling in Epo production. Live imaging of REPs in transgenic mice expressing green fluorescent protein from a modified Epo-gene locus revealed that healthy REPs tightly associated with endothelium by wrapping processes around capillaries. However, this association was hampered in states of renal injury-induced inflammation previously shown to correlate with the transition to myofibroblast-transformed renal Epo-producing cells (MF-REPs). Furthermore, activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) selectively in Epo-producing cells reactivated Epo production in MF-REPs. Loss of PHD2 in REPs restored Epo-gene expression in injured kidneys but caused polycythemia. Notably, combined deletions of PHD1 and PHD3 prevented loss of Epo expression without provoking polycythemia. Mice with PHD-deficient REPs also showed resistance to LPS-induced Epo repression in kidneys, suggesting that augmented HIF signaling counterbalances inflammatory stimuli in regulation of Epo production. Thus, augmentation of HIF signaling may be an attractive therapeutic strategy for treating renal anemia by reactivating Epo synthesis in MF-REPs.

  17. Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes. International-journal Peer-reviewed

    Yutaka Tojo, Hiroki Sekine, Ikuo Hirano, Xiaoqing Pan, Tomokazu Souma, Tadayuki Tsujita, Shin-ichi Kawaguchi, Norihiko Takeda, Kotaro Takeda, Guo-Hua Fong, Takashi Dan, Masakazu Ichinose, Toshio Miyata, Masayuki Yamamoto, Norio Suzuki

    Molecular and cellular biology　35　(15)　2658-72　2015/08

    DOI： 10.1128/MCB.00161-15 　

    ISSN： 0270-7306

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    Erythropoietin (Epo) is produced in the kidney and liver in a hypoxia-inducible manner via the activation of hypoxia-inducible transcription factors (HIFs) to maintain oxygen homeostasis. Accelerating Epo production in hepatocytes is one plausible therapeutic strategy for treating anemia caused by kidney diseases. To elucidate the regulatory mechanisms of hepatic Epo production, we analyzed mouse lines harboring liver-specific deletions of genes encoding HIF-prolyl-hydroxylase isoforms (PHD1, PHD2, and PHD3) that mediate the inactivation of HIF1α and HIF2α under normal oxygen conditions. The loss of all PHD isoforms results in both polycythemia, which is caused by Epo overproduction, and fatty livers. We found that deleting any combination of two PHD isoforms induces polycythemia without steatosis complications, whereas the deletion of a single isoform induces no apparent phenotype. Polycythemia is prevented by the loss of either HIF2α or the hepatocyte-specific Epo gene enhancer (EpoHE). Chromatin analyses show that the histones around EpoHE dissociate from the nucleosome structure after HIF2α activation. HIF2α also induces the expression of HIF3α, which is involved in the attenuation of Epo production. These results demonstrate that the total amount of PHD activity is more important than the specific function of each isoform for hepatic Epo expression regulated by a PHD-HIF2α-EpoHE cascade in vivo.

  18. [Identification of erythropoietin producing cells and erythropoietin gene regulation]. Peer-reviewed

    Yamamoto M, Hirano I

    [Rinsho ketsueki] The Japanese journal of clinical hematology　55　(10)　1785-1794　2014/10

    ISSN： 0485-1439

  19. Nrf2 Enhances Cholangiocyte Expansion in Pten-Deficient Livers Peer-reviewed

    Keiko Taguchi, Ikuo Hirano, Tohru Itoh, Minoru Tanaka, Atsushi Miyajima, Akira Suzuki, Hozumi Motohashi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　34　(5)　900-913　2014/03

    DOI： 10.1128/MCB.01384-13 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  20. Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis Peer-reviewed

    Norio Suzuki, Ikuo Hirano, Xiaoqing Pan, Naoko Minegishi, Masayuki Yamamoto

    NATURE COMMUNICATIONS　4　2902　2013/12

    DOI： 10.1038/ncomms3902 　

    ISSN： 2041-1723

  21. Plasticity of Renal Erythropoietin-Producing Cells Governs Fibrosis Peer-reviewed

    Tomokazu Souma, Shun Yamazaki, Takashi Moriguchi, Norio Suzuki, Ikuo Hirano, Xiaoqing Pan, Naoko Minegishi, Michiaki Abe, Hideyasu Kiyomoto, Sadayoshi Ito, Masayuki Yamamoto

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY　24　(10)　1599-1616　2013/10

    DOI： 10.1681/ASN.2013010030 　

    ISSN： 1046-6673

    eISSN： 1533-3450

  22. HIF-3αによるエリスロポエチン遺伝子発現の抑制的制御 Peer-reviewed

    牧野 塁, 潘 小青, 山嵜 瞬, 平野 育生, 山本 雅之, 鈴木 教郎

    日本生化学会大会プログラム・講演要旨集　86回　2P-337　2013/09

    Publisher: (公社)日本生化学会

  23. A mouse model of adult-onset anaemia due to erythropoietin deficiency Peer-reviewed

    Shun Yamazaki, Tomokazu Souma, Ikuo Hirano, Xiaoqing Pan, Naoko Minegishi, Norio Suzuki, Masayuki Yamamoto

    NATURE COMMUNICATIONS　4　1950　2013/06

    DOI： 10.1038/ncomms2950 　

    ISSN： 2041-1723

  24. Isolation and Characterization of Renal Erythropoietin-Producing Cells from Genetically Produced Anemia Mice Peer-reviewed

    Xiaoqing Pan, Norio Suzuki, Ikuo Hirano, Shun Yamazaki, Naoko Minegishi, Masayuki Yamamoto

    PLOS ONE　6　(10)　e25839　2011/10

    DOI： 10.1371/journal.pone.0025839 　

    ISSN： 1932-6203

  25. HEMATOPOIESIS - CYTOKINES, SIGNAL TRANSDUCTION, APOPTOSIS AND CELL CYCLE REGULATION POSTER I

    Pan, Xiaoqing, Suzuki, Norio, Hirano, Ikuo, Yamazaki, Shun, Yamashita, Toshiharu, Ohneda, Osamu, Minegishi, Naoko, Yamamoto, Masayuki

    BLOOD　116　(21)　656-656　2010/11

    Publisher: AMER SOC HEMATOLOGY

    ISSN： 0006-4971

  26. Isolation and Characterization of Renal Erythropoietin-Producing Cells: Contribution of HIF3 alpha In Vivo

    Pan, Xiaoqing, Suzuki, Norio, Hirano, Ikuo, Yamazaki, Shun, Yamashita, Toshiharu, Ohneda, Osamu, Minegishi, Naoko, Yamamoto, Masayuki

    BLOOD　116　(21)　656-656　2010/11

    Publisher: AMER SOC HEMATOLOGY

    ISSN： 0006-4971

  27. Caffeine and Taurine Enhance Endurance Performance Peer-reviewed

    T. F. Imagawa, I. Hirano, K. Utsuki, M. Horie, A. Naka, K. Matsumoto, S. Imagawa

    INTERNATIONAL JOURNAL OF SPORTS MEDICINE　30　(7)　485-488　2009/07

    DOI： 10.1055/s-0028-1104574 　

    ISSN： 0172-4622

  28. β-globin LCR luciferaseトランスジェニックマウスを用いた造血シグナルの解析とドーピング物質検出への応用 Peer-reviewed

    堀江 正樹, 中, 彩乃, 松本, 健, 平野, 育生, 山本, 雅之, 今川 重彦

    日本臨床スポーツ医学会誌　17　(2)　239-246　2009/04

    Publisher:

    ISSN： 1346-4159

  29. 2-oxoglutarateを用いた実験腫瘍モデルマウスにおける腫瘍血管新生および増殖の抑制効果 Peer-reviewed

    松本 健, 堀江, 正樹, 平野, 育生, 中, 彩乃, 小原, 直, 今川 重彦

    医学のあゆみ　225　(6)　547-548　2008/05

    Publisher:

    ISSN： 0039-2359

  30. Detection of hypoxia-inducible gene manipulation Peer-reviewed

    Imagawa Shigehiko, Horie Masaki, Matsumoto Ken, Hirano Ikuo, Suzuki Norio, Yamamoto Masayuki

    BLOOD　110　(11)　1069A　2007/11/16

    ISSN： 0006-4971

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Misc. 12

  1. 【巨核球造血と血小板産生の新知見】 巨核球造血の転写制御機構

    平野 育生, 清水, 律子

    血液フロンティア　27　(6)　821-826　2017/05

  2. 【酸素生物学から考える医療】 低酸素ストレスに対する生体応答機構

    平野 育生, 山本, 雅之

    ファルマシア　53　(3)　201-205　2017/03

    Publisher: 公益社団法人 日本薬学会

    DOI： 10.14894/faruawpsj.53.3_201 　

  3. エリスロポエチン遺伝子の腎特異的転写制御領域の解析と腎性貧血モデルマウスの樹立

    平野育生, 鈴木教郎, 祢津昌広, 関根弘樹, 相馬友和, 峯岸直子, 清水律子, 山本雅之

    日本生化学会大会(Web)　88th　4T5L-10(3P0698) (WEB ONLY)-10(3P0698)]　2015/12

    Publisher: (公社)日本生化学会

  4. 【CKD治療の新たな標的分子】 酸化・低酸素ストレスと腎臓

    平野 育生, 山本, 雅之

    腎と透析　74　(2)　240-245　2013/02

  5. トランスジェニックマウスを利用したエリスロポエチン遺伝子エンハンサーの探索

    平野育生, 鈴木教郎, 山崎瞬, 峯岸直子, 山本雅之, 清水律子

    日本分子生物学会年会プログラム・要旨集(Web)　36th　1P-0195 (WEB ONLY)　2013

  6. 神経堤細胞におけるエリスロポエチン遺伝子発現

    平野育生, 鈴木教郎, PAN Xiaoqing, 峯岸直子, 山本雅之

    日本生化学会大会(Web)　85th　3T09-04 (WEB ONLY)-04　2012/12

    Publisher: (公社)日本生化学会

  7. Erythropoietin production in neural crest cells

    Ikuo Hirano, Norio Suzuki, Xiaoqing Pan, Shun Yamazaki, Naoko Minegishi, Masayuki Yamamoto

    AMERICAN JOURNAL OF HEMATOLOGY　87　(10)　E100-E100　2012/10

    ISSN： 0361-8609

  8. 胎仔期神経細胞,神経堤細胞によるエリスロポエチン産生

    平野育生, 鈴木教郎, PAN Xiaoqing, 山崎瞬, 峯岸直子, 山本雅之

    生化学　84回　ROMBUNNO.3T14A-3-3　2011/09

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  9. 成獣における誘導的エリスロポエチン遺伝子破壊の造血に与える影響

    山嵜瞬, 峯岸直子, 鈴木教郎, 小原直, PAN Xiaoqing, 平野育生, 寺社下浩一, 本田紅里穂, 山本雅之

    生化学　83回・33回　ROMBUNNO.1P-0304-0304　2010/12

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  10. 単離腎臓Erythropoietin産生細胞を用いたErythropoietin遺伝子制御機構の解明

    平野育生, PAN Xiaoqing, 鈴木教郎, 山崎瞬, 小原直, 峯岸直子, 山本雅之

    生化学　83回・33回　ROMBUNNO.1P-0690-0690　2010/12

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  11. Rescue of Erythropoietin-Deficient Mice From Anemia by Complementation with BAC Transgene.

    Shun Yamazaki, Norio Suzuki, Naoshi Obara, Xiaoqing Pan, Ikuo Hirano, Kou-ichi Jishage, Kurisu Honda, Naoko Minegishi, Masayuki Yamamoto

    BLOOD　114　(22)　1397-1397　2009/11

    ISSN： 0006-4971

  12. Epo遺伝子欠失マウスのレスキューと条件付きEpo遺伝子破壊マウスの樹立

    山崎瞬, 鈴木教郎, 小原直, PAN Xiaoqing, 平野育生, 峯岸直子, 山本雅之

    生化学　82回　ROMBUNNO.4T4P-11-11　2009/09/25

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

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Presentations 13

  1. 低酸素非依存性のエリスロポエチン産生を異所的に誘導する化合物の探索

    平野育生, 長谷川敦史, 金子寛, 加藤剛英, 山本雅之, 清水律子

    第7回低酸素研究会学術集会　2019/07/27

  2. B cell development is influenced by expression of Gata1

    ConBio2017　2017/12/06

  3. 腎臓におけるエリスロポエチン遺伝子制御機構の解明

    鈴木教郎, 清水律子, 山本雅之

    腎とエリスロポエチン研究会　2016/11/05

  4. マウスモデルを用いた白血病発症に関わる遺伝的素因の探索

    鈴木美野里, 櫻井悠香子, 後藤あや, 山本雅之, 清水律子

    第89回 日本生化学会大会　2016/09/25

  5. 赤芽球系白血病の発症に寄与する遺伝的素因の探索

    櫻井悠香子, 南亮悟, 後藤あや, 山本雅之, 清水律子

    第２０回 造血器腫瘍研究会　2016/02/12

  6. エリスロポエチン遺伝子制御領域の同定および同領域を利用した腎性貧血モデルマウスの樹立

    鈴木教郎, 清水律子, 山本雅之

    酸素生物学・ダイイングコード若手合同会議　2016/01/26

  7. エリスロポエチン遺伝子の腎特異的転写制御領域の解析と腎性貧血モデルマウスの樹立

    平野育生, 鈴木教郎, 祢津昌広, 関根弘樹, 相馬友和, 峯岸直子, 清水律子, 山本雅之

    BMB2015（第８８回 日本生化学会大会）　2015/12/01

  8. エリスロポエチン産生制御機構の解析

    鈴木教郎, 潘小青, 小原直, 峯岸直子, 山本雅之, 清水律子

    第２回 低酸素研究会　2014/07/26

  9. 胎児期におけるエリスロポエチン産生機構の解析

    日本生化学会東北支部会 第８０回例会　2014/05/10

  10. 神経堤細胞におけるエリスロポエチン遺伝子発現

    鈴木教郎, 潘小青, 峯岸直子, 山本雅之

    第85回日本生化学会大会合同大会　2012/12/14

  11. Erythropoietin production in neural crest cells International-presentation

    Norio Suzuki, Xiaoqing Pan, Shun Yamazaki, Naoko Minegishi, Masayuki Yamamoto

    9th International Leubek Conference　2012/07/13

  12. 胎仔神経細胞、神経堤細胞によるエリスロポエチン産生

    鈴木教郎, 潘小青, 峯岸直子, 山本雅之

    第84回日本生化学会大会合同大会　2011/09/21

  13. Erythropoietin from neural and neural crest cells support primitive erythropoiesis International-presentation

    Norio Suzuki, Xiaoqing Pan, Naoko Minegishi, Masayuki Yamamoto

    5th Interntional Symposium on GATA factors　2010/11/17

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Research Projects 9

  1. ドライバー変異と協調して白血病発症を修飾する遺伝的素因の探索

    清水 律子, 平野 育生, 長谷川 敦史

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(B)

    Category: 基盤研究(B)

    Institution: 東北大学

    2019/04/01 - 2023/03/31

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    ヒト純赤白血病は比較的稀な白血病であり、その発症メカニズムの詳細は分かっていない。我々は、赤血球造血に必須な転写因子GATA1の機能異常が純赤白血病発症に関与している可能性を考えている。GATA1遺伝子はX染色体上に存在するため、GATA1遺伝子に変異をヘテロに持つマウスは変異アリルが活性化した細胞と野生型アリルが活性化した細胞が共存する。GATA1ノックダウンアリルを持つヘテロ雌は、GATA1ノックダウンアリルが活性化した細胞由来の細胞がドライバー遺伝子変異を獲得してcKit陽性CD71陽性の純赤白血病を発症すること、ノックアウトではアポトーシス死してしまう赤芽球前駆細胞が、ノックダウンでは僅かに存在するGATA1により分化できないまま残存するため、蓄積した赤芽球にドライバー変異が蓄積するためだと考えられる。本年度は、GATA1ノックダウンによる赤芽球系への影響を、マウス成獣を用いて解析した。ノックダウン雄マウスではGATA1機能不全による赤血球造血不全で胎生11.5日程度で死亡するため、また、ノックダウン雌マウスではX染色体のランダムな不活化により混在している正常赤芽球とGATA1ノックダウンにより分化異常を有する赤芽球を分離できないため、成獣でのGATA1の機能解析は困難であった。そこで、Hprt遺伝子座にGFPを挿入したレポーターマウスとのコンパウンドマウス（Gata1遺伝子発現が正常な細胞はGFP陽性となる）を樹立し、MEP（megakaryocyte erythroid progenitor）分画でのRNAseq解析と、ｃkit陽性のプロジェニター分画でのsingle cell RNAseq解析を行った。その結果、GATA1ノックダウンがあってもMEP分画までは分化しうるが、MEP分画の細胞は巨核球系の性質に偏っているというプレリミナリーな結果を得た。

  2. Analysis of the regulation of early erythropoiesis by transcription factor GATA1 and erythropoietin signal

    Hirano Ikuo

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Early-Career Scientists

    Institution: Tohoku University

    2020/04/01 - 2022/03/31

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    The purpose of this study was to elucidate the details of the regulatory mechanism of erythropoiesis by EPO, a cytokine that promotes erythropoiesis, and GATA1, a transcription factor that regulates erythroid differentiation. I performed a comparative analysis using mice in which GATA1 KD or GATA1 KO cells could be compared to normal cells within the same individual. The results showed that GATA1 is essential for differentiation at the MEP stage and that GATA1 KD cells produce an abnormal cell cluster that exhibits a specific gene expression pattern. We also suggested that GATA1 regulates EPO signaling by regulating Epor gene expression during the MEP stage, while there is no regulation of Gata1 gene expression by EPO signaling.

  3. Development of novel erythropoiesis-stimulating agents that enhance erythropoietin gene expression

    Hirano Ikuo

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2017/04/01 - 2020/03/31

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    Anemia of renal disease is mainly due to deficient erythropoietin (EPO) that produced from the kidney. Recombinant human EPO treatment is the first choice of treatment of the renal anemia, but rhEPOs are very expensive and need intravenous administration. Our purpose of this study was finding the seeds of new erythropoiesis-stimulating agents that was inexpensive and oral administrative. We established reporter cell lines using mouse kidney collecting duct derived cell line (mIMCD). We done high throughput screening with the drug libraries, and identified several compounds as seeds of new ESA. One of them, Compound-A showed inducing activity of EPO gene expression in vitro (mIMCD, A549 and TFK-1) and in vivo (mouse lung). It is reported that Epo gene expression is negatively regulated in some epithelial cells by transcription factor GATA. The Compound-A maybe affects GATA factor binding to GATA motif located on Epo promoter region and induce ectopic expression of Epo gene.

  4. Multistep leukemogenesis caused by imbalanced GATA1 function

    Shimizu Ritsuko

    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

    2015/04/01 - 2019/03/31

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    Somatic GATA1 gene mutations leading to the production of GATA1s that lacks the amino-terminal transactivation domain is both requisite and sufficient for the development of the preleukemic condition referred to as transient myeloproliferative disorder (TMD) for acute megakaryoblastic leukemia (AMKL) in Down-syndrome newborns. We have established mice exclusively expressing GATA1s which phenocopy the human TMD. In this research, we found that reduced apoptosis and increased proliferation capacities in GATA1s megakaryocyte progenitors are involved in the pathogenesis of TMD. We also found that megakaryocyte progenitors with relatively lower level of GATA1s reduced in differentiation potency, consequently the progenitors persistently stay in mice and the mice are prone to develop leukemia. Higher amount of GATA1s expression partially compensates the defect in megakaryocyte maturation mediated through the Ras signaling cascade and enable progenitors to pass quickly without transformation.

  5. Systemic mechanisms of response to hypoxic stresses

    Yamamoto Masayuki, SEKINE Hiroki, HIRANO Ikuo, NEZU Masahiro

    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: Tohoku University

    2014/07/10 - 2019/03/31

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    A lack of oxygen causes harmful hypoxic stress in cells and organs, while oxygen is also a source of harmful oxidative stressors, including reactive oxygen species. Because oxygen is delivered into every organ by erythrocytes, cellular oxygen levels largely depend on the circulation of erythrocytes. Erythrocyte production is mainly controlled by the erythroid growth factor erythropoietin (Epo) which is secreted by REP (renal Epo producing) cells in a hypoxia-inducible manner. This study elucidated the regulatory mechanism of Epo production in REP cells, and demonstrated that defects in the mechanism are closely associated with the pathogenesis and progression of many types of diseases through the synergistic effects of hypoxic and oxidative stresses. These results confirm that therapeutic strategies targeting the cellular mechanisms of adaptation to hypoxic or oxidative stress, which are currently going on clinical trials, are plausible for treating a variety of diseases.

  6. 異所性EPO遺伝子発現を誘導する新規貧血改善薬の候補化合物の作用機序の解明

    平野 育生

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 国際共同研究加速基金(国際共同研究強化(A))

    Category: 国際共同研究加速基金(国際共同研究強化(A))

    Institution: 東北大学

    2019 - 2019

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    赤血球産生は、エリスロポエチン（EPO）シグナルや、転写因子GATA1により制御されている。EPO遺伝子は、低酸素応答性転写因子HIFによる低酸素刺激特異的な正の制御と、GATA転写因子による負の制御を受けている。GATA因子による制御機構は、EPO遺伝子プロモーター領域に存在するGATA結合配列を介したものであることが報告されており、また同抑制性制御機構が個体内では異所性EPO産生の抑制に重要であることが示されている。申請者は基課題においてEPO遺伝子発現誘導が可能なGATA阻害薬の探索を行い、化合物を複数同定した。本国際共同研究は、GATA因子による赤血球分化制御機構の解析、およびそれに対するGATA阻害薬の影響を解析し、造血促進薬としてGATA阻害薬が利用可能か否か検証することが目的となっている。昨年度と同様に今年度もCOVID-19のパンデミックの影響により、海外共同研究者であるJames Douglas Engel教授のもとで研究を進めることは叶わなかった。その一方で、Engel教授とオンライン形式で話し合いを重ねることで、今後の研究計画を練ることができた。新たな解析として、内在性Epo遺伝子プロモーター領域のGATAモチーフを破壊したマウス（TTTA-Epo）を複数樹立した。TTTA-Epoマウスは、GATA因子による抑制性制御が破綻することで、過剰に発現したEPOにより多血になることが予想されたが、むしろ同腹仔コントロールと比較して赤血球数が低下しており、腎臓Epo遺伝子発現も低下していた。この結果は、Epo遺伝子プロモーター領域のGATAモチーフがEpo遺伝子発現を正に制御していることを示唆するとともに、同定したEPO遺伝子発現誘導可能なGATA阻害薬が、同モチーフを介さない未知の機構を介してEpo遺伝子発現に影響していることを示している。

  7. Analysis of kidney-specific transcriptional regulation of Epo gene and establishment of mouse model of renal anemia

    Hirano Ikuo

    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: Tohoku University

    2014/04/01 - 2017/03/31

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    We performed transgenic reporter mouse analyses to analyze a mechanism of renal Epo gene regulation. We have found that a 13.8-kbp region (CURE region), spanning the region from 17.4 kb to 3.6 kb upstream of the Epo gene, is necessary for renal Epo gene regulation. we have also found that mice lacking the CURE region suffer from severe anemia caused by the EPO-deficiency. We named the anemic mice “AnRED (anemic model with renal EPO deficiency) mice”. CURE region harbors several phylogenetically conserved elements between humans and mice (among mammals). Our results obtained by transgenic reporter mouse analyses show that these elements redundantly and cooperatively work for the regulation of Epo gene in renal EPO-producing cells.

  8. 若手研究(B) 「腎機能保護作用を狙った腎特異的エリスロポエチン遺伝子発現誘導薬の探索」 Competitive

    平野育生

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    2014/04 - 2017/03

  9. Regulation of Erythropoietin production and its roles on adult hematopoiesis

    MINEGISHI Naoko, SUZUKI Mikiko, HIRANO Ikuo, SUZUKI Norio, SOUMA Tomokazu, YAMAZAKI Shun

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2012/04/01 - 2016/03/31

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    Erythropoietin, secreted from adult kidney, is essential for erythropoiesis. We made ISAM (Inherited Super Anemic Mice), which exhibited Epo-deficient-anemia in their adulthood. We found the significantly decreased number of proerythroblasts and basophilic erythroblasts in their bone marrow, and several downstream-genes of Epo signals in bone marrow cells. Epo producing cells of ISAM were demonstrated as the cells expressing green fluorescence, among cortical fibroblasts in adult kidneys, and also in the portion of embryonic neural cells and neural crest cells. In the experimental fibrotic kidneys, Epo-producing cells transformed into myofibroblasts and halted Epo production. These changes were reversible. We have an impression that the inhibition of inflammatory signals might be a novel therapeutic strategy for renal fibrosis and renal anemia.

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Teaching Experience 4

  1. Analytical Chemistry of biological components　Tohoku University

  2. 輸血免疫学 「ABO血液型と血液型の遺伝子診断」　東北大学 医学系研究科医学部保健学科

  3. 血液学 II 「染色体検査」　東北大学 医学系研究科医学部保健学科

  4. 臨床血液学実習　東北大学 医学系研究科医学部保健学科