Induction of hematopoietic stemcells from iPS cells and the molecular basis in the induction

• Project/Area Number: 22390195
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Hiroshima University
• Principal Investigator: TAKIHARA Yoshihiro 広島大学, 原爆放射線医科学研究所, 教授 (60226967)
• Co-Investigator(Kenkyū-buntansha): YASUNAGA Shin'ichiro 広島大学, 原爆放射線医科学研究所, 准教授 (50336111) ; OHNO Yoshinori 広島大学, 原爆放射線医科学研究所, 助教 (10548986) ; TSUJI Kohichiro 東京大学, 医科学研究所, 准教授 (50179991) ; OHTSUBO Motoaki 別府大学, 食物栄養科学部, 教授 (10211799)
• Co-Investigator(Renkei-kenkyūsha): OHTSUBO Motoaki 別府大学, 食物栄養科学部, 教授 (10211799)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2012: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2011: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2010: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: 造血幹細胞移植学 / iPS 細胞 / 再生医学 / 造血幹細胞 / iPS細胞 / ES細胞 / 自己複製 / 分化 / Geminin / ポリコーム複合体1 / Hoxb4 / 造血幹細胞移植療法 / ポリコーム複合体

Research Abstract

Geminin is presumed to regulate cell fate decision whether the hematopoietic stem cells (HSCs) self-renew or differentiate to produce mature blood cells. We then generated Geminin-EYFP knockin mice to visualize Geminin and iPS cells from the murine knockin fibroblasts. And we also generated vector systems to overexpress or knock-down Geminin expression by using the shRNA. We here showed that Geminin induces quiescence and undifferentiated states in hematopoietic stem cells but that Geminin is down-regulated in the progeny subpopulations to induce differentiation and proliferation, resulting in production of large amount of mature blood cells. We further analyze expression profile and a role for Geminin in self-renewing hematopoietic stem cells, and aim to generate a new technology for inducing HSCs from iPS cells.

Research Products

• [Journal Article] Heterozygosity for the Y701C STAT1 mutation in a multiplex kindred with multifocal osteomyelitis. (2013)
  • Author(s): Hirata, O., Okada, S., Tsumura, M., Kagawa, R., Miki, M., Kawaguchi, H., Nakamura, K., Boisson-Dupuis, S., Casanova, J.-L., Takihara, Y., Kobayashi, M.
  • Journal Title: Haematologica
  • Peer Reviewed
• [Journal Article] Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin in mitosis. (2013)
  • Author(s): Tsunematsu, T., Takihara, Y., Ishimura, N., Pagano, M., Takata, T., Kudo, Y.
  • Journal Title: Nature Commun. Volume: 4 Pages: 1885-1885
  • Peer Reviewed
• [Journal Article] Hoxa9 transduction induces mouse hematopoietic stem and progenitor cell activity through direct down-regulation of Geminin. (2013)
  • Author(s): Ohno, Y., Yasunaga, S., Janmohamed, S., Ohtubo, M., Mihara, K., Iscove, N., Takihara, Y.
  • Journal Title: PLoS ONE Volume: 8(1) Issue: 1 Pages: e53161-e53161
  • DOI: 10.1371/journal.pone.0053161
  • Peer Reviewed
• [Journal Article] Scmh1 has E3 ubiquitin ligase activity for Geminin and histone H2A and regulates Geminin stability directly or indirectly via transcriptional repression of Hoxa9 and Hoxb4. (2013)
  • Author(s): Yasunaga, S., Ohtsubo, M., Ohno, Y., Tanaka-Okamoto, M., Ishizaki, H., Shirai, M., Mihara, K., Brock, W. H., Miyoshi, J., Takihara, Y.
  • Journal Title: Mol. Cell. Biol. Volume: 33 Pages: 644-660
  • Peer Reviewed
• [Journal Article] MK3 controls Polycomb-target gene expression via negative feedback on ERK. (2013)
  • Author(s): Prickaerts, P.
  • Journal Title: Epigenetics Chromatin Volume: 5 Issue: 1 Pages: 12-12
  • DOI: 10.1186/1756-8935-5-12
  • Peer Reviewed
• [Journal Article] Aurora-A controls pre-replicative complex formation and DNA replication by promoting the stabilization of geminin in mitosis. (2013)
  • Author(s): Tsunematsu, T.
  • Journal Title: Nature Commun. Volume: -
  • Peer Reviewed
• [Journal Article] MK3 controls Polycomb-target gene expression via negative feedback on ERK. (2012)
  • Author(s): Prickaerts, P., Niessen, H., Mou-chel-Vielh, E., Dahlmans, V., Geijselaers, C., Adriaens, M., Spaapen, F., Takihara, Y., Rapp, U., Peronnet, F., Voncken, J.W.
  • Journal Title: Epigenetics Chromatin Volume: 5 Pages: 12-12
  • Peer Reviewed
• [Journal Article] T-cell immunotherapy with a chimeric receptor against CD38 is effective in eradicating refractory B-lymphoma cells overexpressing survivin induced by BMI-1. (2012)
  • Author(s): Bhattacharyya, J., Mihara, K., Kitanaka, A., Yanagihara, K., Kubo, T. , Takei, Y., Kuroda, T., Kimura, A., Takihara, Y.
  • Journal Title: T-cell immunotherapy with a chimeric receptor against CD38 is effective in eradicating refractory B-lymphoma cells overexpressing survivin induced by BMI-1. Volume: 2
  • Peer Reviewed
• [Journal Article] T-cell immunotherapy with a chimeric receptor against CD38 is effective in eliminating myeloma cells (2012)
  • Author(s): Mihara, K., Bhattacharyya, J., Kitanaka, A., Yanagihara, K., Kubo, T., Takei, Y., Sakai, A., Asaoku, H., Takihara, Y., Kimura, A.
  • Journal Title: Leukemia Volume: 26 Pages: 365-367
  • Peer Reviewed
• [Journal Article] Dominant-negative STAT1 mutations in the SH2 domain predispose to mycobacterial diseases. (2012)
  • Author(s): Tsumura, M., Okada, S., Sakai, H., Yasunaga, S., Ohtsubo, M., Murata, T., Obata, H., Yasumi, T., Kong, X., Abhyankar, A., Heike, T., Nakahata, T., Nishikomori, R., Al-Muhsen, S., Boisson-Dupuis, S., Casanova, J.-L., AlSherhri, M., ElGhazali, G., Takihara, Y., Kobayashi, M.
  • Journal Title: Hum. Mutat. Volume: 33 Pages: 1377-1387
  • Peer Reviewed
• [Journal Article] Poly-ADP ribosylation of Miki by tankyrase-1 promotes centrosome maturation. (2012)
  • Author(s): Ozaki, Y., Matsui, H., Asou, H., Nagamachi, A., Aki, D., Honda, H., Yasunaga, S., Takihara, Y., Yamamoto, T., Izumi, S., Ohsugi, M., Inaba, T.
  • Journal Title: Mol. Cell Volume: 47 Pages: 694-706
  • Peer Reviewed
• [Journal Article] 幹細胞における細胞周期制御 特集:がん幹細胞研究の新たな展開 (2012)
  • Author(s): 瀧原義宏、安永晋一郎、大野芳典、大坪素秋
  • Journal Title: 血液フロンティア(医薬ジャーナル社) Volume: 22 Pages: 33-43
• [Journal Article] Overexpression of BMI-1 correlates with drug resistance in B-cell lymphoma through the stabilization of survivin expression (2012)
  • Author(s): Bhattacharyya, J.
  • Journal Title: Cancer Sci. Volume: 103 Pages: 34-41
  • Peer Reviewed
• [Journal Article] Role for Geminin in sustaining the activity of hematopoietic stem cells. (2011)
  • Author(s): Takihara, Y.
  • Journal Title: Cell Cycle Volume: 10 Pages: 561-562
  • Peer Reviewed
• [Journal Article] 造血幹細胞の守護神Geminin (2011)
  • Author(s): 瀧原義宏
  • Journal Title: 原医研ニュース Volume: 2 Pages: 6-7
• [Journal Article] Decreased expression in nuclear factor kappaB essential modulator due to a novel splice-site mutation caused X-linked ectodermal dysplasia (2011)
  • Author(s): Karakawa, S.
  • Journal Title: J.Clin.Immunol. Volume: 31 Pages: 762-772
  • Peer Reviewed
• [Journal Article] HOXB4 transduction down-regulates Geminin protein, providing hematopoietic stem and progenitor cells with growth potential. (2010)
  • Author(s): Ohno, Y., Yasunaga, S., Ohtsubo, M., Mori, S., Tsumura, M., Okada, S., Ohta, T., Ohtani, K., Kobayashi, M., Takihara, Y.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 107 Pages: 21529-21534
  • Peer Reviewed
• [Journal Article] Synergistic and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin's lymphoma. (2010)
  • Author(s): Mihara, K., Yanagihara, K., Takigahira, M., Kitanaka, A., Imai, C., Bhattachayya, J., Kubo, T., Takei, Y., Yasunaga, S., Takihara, Y., Kimura, A.
  • Journal Title: Br. J. Haematol. Volume: 151 Pages: 37-46
  • Peer Reviewed
• [Journal Article] 細胞周期のフロンティア (2010)
  • Author(s): 瀧原義宏
  • Journal Title: 細胞分化と増殖制御-造血幹細胞の活性支持におけるポリコーム複合体の機能 蛋白質 核酸 酵素(共立出版) Pages: 230-235
• [Journal Article] HOXB4 transduction down-regulates Geminin protein, providing hematopoietic stem and progenitor cells with growth potential. (2010)
  • Author(s): Ohno, Y.
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: 107 Pages: 21529-21534
  • Peer Reviewed
• [Journal Article] Synergistic and Persistent effect of T-cell immunotherapy with anti-CD190 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin's lymphoma. (2010)
  • Author(s): Mihara, K.
  • Journal Title: Br.J.Haematol. Volume: 151 Pages: 37-46
  • Peer Reviewed
• [Presentation] Current hematopoietic stem cell transplantation therapy and the perspective (2012)
  • Author(s): Takihara, Y.
  • Organizer: The 1^<st> international symposium on phoenix leader education program for renaissance from radiation disaster
  • Place of Presentation: Hiroshima(招待講演)
  • Year and Date: 2012-02-21
• [Presentation] Novel molecular regulatory network governing Geminin maintains hematopoietic homeostasis. (2012)
  • Author(s): Takihara, Y., Yasunaga, S., Ohno, Y., Saeki, K., Nakashima, Y., Ohtsubo, M.
  • Organizer: 41st annual scientific meeting of the international society for hematology and stem cells
  • Place of Presentation: Amsterdam, Netherlands
• [Presentation] ポリコーム複合体1と Hoxb4による Geminin 制御と造血幹細胞活性 (2012)
  • Author(s): 瀧原義宏
  • Organizer: 特定領域研究「細胞増殖制御」終了シンポジウム
  • Place of Presentation: 東京
• [Presentation] Scmh1 regulates Geminin through the ubiquitin-proteasome systems to govern hematopoietic homeostasis. (2012)
  • Author(s): Yasunaga, S.
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Repression of Geminin plays an important role in Hoxa9-induced hematopoiesis and leukemogenesis. (2012)
  • Author(s): Ohno, Y.
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Scmh1 is required for maintaining hematopoietic homeostasis through the molecular network governing Geminin expression. (2012)
  • Author(s): Ohno, Y.
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Molecular role for Geminin in E2F-mediated transcriptional regulation. (2012)
  • Author(s): Saeki, K.
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] 造血幹細胞制御における DNA複製ライセンス化制御因子の役割 (2010)
  • Author(s): 瀧原義宏
  • Organizer: 第9回日本再生医療学会総会 シンポジウム 13「造血幹細胞」
  • Place of Presentation: 広島
  • Year and Date: 2010-03-19
• [Presentation] Role for Geminin in sustaining hematopoietic stem cell activity. (2010)
  • Author(s): Takihara, Y.
  • Organizer: The 13thUS-Japan Cellular and Gene Therapy Conference: Systems Biology in Cell Cycle Regulation, National Institute of Health
  • Place of Presentation: Bethesda, Maryland, USA
  • Year and Date: 2010-02-25
• [Presentation] Role for Geminin in hematopoietic stem cell regulation. (2010)
  • Author(s): Yasunaga, S.
  • Organizer: The 8^<th> Stem Cell Research Symposium
  • Place of Presentation: 淡路夢舞台
• [Book] 細胞周期フロンティア (2010)
  • Author(s): 瀧原義宏
  • Total Pages: 252
  • Publisher: 共立出版
• [Remarks]
  • URL: http://home.hiroshima-u.ac.jp/dscb/
• [Remarks]
  • URL: http://home.hiroshima-u.ac.jp/dscb/
• [Remarks]
  • URL: http://home.hiroshima-u.ac.jp/dscb/