Basic research on regulatory system for self-renewal and differentiation of hematopoietic stem cells for the purpose of future application to regenerative medicine

• Project/Area Number: 26501004
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Regenerative medicine
• Research Institution: Fukuoka University (2015-2016); Hiroshima University (2014)
• Principal Investigator: YASUNAGA Shin'ichiro 福岡大学, 医学部, 教授 (50336111)
• Co-Investigator(Kenkyū-buntansha): 大野 芳典 広島大学, 原爆放射線医科学研究所, 助教 (10548986) ; 瀧原 義宏 広島大学, 原爆放射線医科学研究所, 教授 (60226967)
• Research Collaborator: TAKEDACHI Kyoko (SUZUKI Kyoko) 広島大学, 原爆放射線医科学研究所, 技術職員 ; Sato MIMOKO 広島大学, 原爆放射線医科学研究所, 技術職員 ; KUROGI Toshiaki 広島大学, 原爆放射線医科学研究所, 技術職員 ; YAMADA Hiromi 福岡大学, 医学部, 技術職員
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 再生医学 / 造血幹細胞 / 自己複製 / 細胞周期 / 細胞増殖 / 細胞分化 / Geminin / ユビキチン化

Outline of Final Research Achievements

Geminin regulates both of self-renewal and quiescence maintenance of hematopoietic stem cells (HSCs), and is a candidate key molecule for HSC regulation. Therefore, sophisticated manipulation of Geminin expression and function may be able to control HSC activity. In this study, we sorted out quiescent HSCs and self-renewing HSCs from bone marrow cells derived from Geminin-EYFP knock-in mice and examined difference in their gene expression at single cell level. In addition, we generated recombinant Geminin protein with membrane-translocating motif for easy induction and withdraw of Geminin expression in hematopoietic cells.

Research Products

• [Journal Article] Is a bare-metal stent still useful for improving the outcome of percutaneous coronary intervention? From the FU-Registry (2017)
  • Author(s): GONDO, K., IKE, A., OGAWA, M., SHIRAI, K., SUGIHARA, M., NISHIKAWA, H., IWATA, A., KAWAMURA, A., MORI, K., ZHANG, B., MIURA, S., YASUNAGA, S. & SAKU, K.
  • Journal Title: J Cardiol Volume: 69 Issue: 4 Pages: 652-659
  • DOI: 10.1016/j.jjcc.2016.06.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Manipulation of cell cycle and chromatin configuration by means of cell-penetrating Geminin. (2016)
  • Author(s): Ohno Y., Suzuki-Takedachi K., Yasunaga S., Kurogi T., Santo M., Masuhiro Y., Hanazawa S., Ohtsubo M., Naka K. & Takihara Y.
  • Journal Title: PLoS ONE Volume: 11(5) Issue: 5 Pages: 1-14
  • DOI: 10.1371/journal.pone.0155558
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of Geminin in cell fate determination of hematopoietic stem cells (HSCs) (2016)
  • Author(s): YASUNAGA, S., OHNO, Y., SHIRASU, N., ZHANG, B., SUZUKI-TAKEDACHI, K., OHTSUBO, M. & TAKIHARA, Y.
  • Journal Title: Int J Hematol Volume: 104 Issue: 3 Pages: 324-9
  • DOI: 10.1007/s12185-016-2060-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Duplex PCR-RFLP for the simultaneous genotypeing of single nucleotide polymerisms in ADH1B abd ALDH2 genes. (2016)
  • Author(s): Shirasu N. & Yasunaga S.
  • Journal Title: Anal. Sci. Volume: 32(12) Pages: 1363-1366
  • Peer Reviewed / Open Access
• [Journal Article] Anti-tumor Effect of Intravenous Administration of CRM197 for Triple-negative Breast Cancer Therapy. (2016)
  • Author(s): Nam S.O., Yotsumoto F., Miyata K., Fukagawa S., Odawara T., Manabe S., Ishikawa T,. Kuroki M., Yasunaga S. & Miyamoto S.
  • Journal Title: Anticanceer Res. Volume: 36(7) Pages: 3651-3657
  • Peer Reviewed
• [Journal Article] Significance of ACADM mutations identified from newborn screening of MCAD deficiency in Japan (2016)
  • Author(s): Keiichi Hara, Go Tajima, Satoshi Okada, Miyuki Tsumura, Reiko Kagawa, Kenichiro Shirao, Yoshinori Ohno, Shin'ichiro Yasunaga, Motoaki Ohtsubo, Ikue Hata, Nobuo Sakura, Yosuke Shigematsu, Yoshihiro Takihara, Masao Kobayashi
  • Journal Title: Molecular Genetics and Metabolism Volume: 118 Issue: 1 Pages: 9-14
  • DOI: 10.1016/j.ymgme.2015.12.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Gemininによる白血病幹細胞の制御 (2015)
  • Author(s): 安永晋一郎、大野芳典、瀧原義宏
  • Journal Title: 日本臨床 Volume: 73(5) Pages: 800-805
• [Journal Article] Mosaicism of an ELANE mutation in an asymptomatic mother in a familial case of cyclic neutropenia. (2015)
  • Author(s): Hirata O, Okada S, Ttsumura M, Karakawa S, Matsumura I, Kimura Y, Mihara T, Yasunaga S, Takihara Y, Ohara O, Kobayashi M
  • Journal Title: Journal of Clinical Immunology Volume: 2015 Issue: 5 Pages: 1-5
  • DOI: 10.1007/s10875-015-0165-1
  • Peer Reviewed / Open Access
• [Journal Article] Transcription of the Geminin gene is regulated by a negative-feedback loop. (2014)
  • Author(s): Ohno, Y., Saeki, K., Yasunaga, S., Kurogi. T., Suzuki-Takedachi, K., Shirai, M., Mihara K., Yoshida, K., Voncken J. W, Ohtsubo, M. & Takihara Y.
  • Journal Title: Mol. Biol. Cel Volume: 25(8) Issue: 8 Pages: 1374-1383
  • DOI: 10.1091/mbc.e13-09-0534
  • Peer Reviewed / Open Access
• [Journal Article] Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. (2014)
  • Author(s): Mizoguchi Y, Tsumura M, Okada S, Hirata O, Minegishi S, Imai K, Hyakuna N, Muramatsu H, Kojima S, Ozaki Y, Imai T, Takeda S, Okazaki T, Ito T, Yasunaga S, Takihara Y, Bryant VL, Kong XF, Cypowyj S, Boisson-Dupuis S, Puel A, Casanova JL, Morio T, Kobayashi M.
  • Journal Title: J. Leukoc. Biol. Volume: 95 Issue: 4 Pages: 667-76
  • DOI: 10.1189/jlb.0513250
  • Peer Reviewed / Open Access
• [Presentation] Effect of low dose-rate irradiation on the hematopoietic system. (2017)
  • Author(s): Ohno Y. , Shirasu N., Suzuki-Takedachi K., Santo M.,Guo Y., Kanno M., Yasunaga S., Ohtsubo M. , Takihara Y.
  • Organizer: The 1st International Symposium of the network-type Joint Usage/Research Center for Radiation Disaster Medical Science
  • Place of Presentation: Hiroshima, Japan
  • Year and Date: 2017-02-21
  • Int'l Joint Research
• [Presentation] 造血幹細胞の低線量率放射線被ばくに対する分子応答の解析 (2016)
  • Author(s): 大野芳典、鈴木－竹立恭子、山藤幹茂子、郭芸、菅野雅元、白須直人、大坪素秋、仲一仁、安永晋一郎、瀧原義宏
  • Organizer: 第３９回日本分子生物学年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] Mechanism of anticancer effect on sonodynamic therapy in combination with DEG and microtubules. (2016)
  • Author(s): Shibaguchi H., Shirasu N., Kuroki M., Yasunaga S.
  • Organizer: The 75th Annual Meering of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2016-10-06
• [Presentation] Screening of microRNA as a prognosis factor for ovarian cancer. (2016)
  • Author(s): Fukagawa S., Miyata K., Kiyoshima C., Yotsumoto F., Yasunaga S. , Miyamoto S.
  • Organizer: The 75th Annual Meering of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2016-10-06
• [Presentation] Screening of microRNA associated with HB-EGF as a biomarker of ovaryan prognosis. (2016)
  • Author(s): Kiyoshima C., Fukagawa S., Miyata K., Yotsumoto F., Yasunaga S. , Miyamoto S.
  • Organizer: The 75th Annual Meering of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2016-10-06
• [Presentation] 飲酒関連遺伝子の一塩基多型を同時に検出する安価で迅速な duplex PCR-RFLP法の開発 (2016)
  • Author(s): 白須直人、安永晋一郎
  • Organizer: 第８９回日本生化学会大会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
• [Presentation] A new strategy for manipulating expression and activity of Geminin could make it possible to regulate cell fates of HSCs. (2016)
  • Author(s): Takihara Y., Ohno Y., Suzuki-Takedachi K., Santo M., Yasunaga S., Ohtsubo M., Naka K.
  • Organizer: ISEH (International Society for Experimental Hematology) 45th Annual Scientific Meeting
  • Place of Presentation: San Diego, U.S.A.
  • Year and Date: 2016-08-25
  • Int'l Joint Research
• [Presentation] Effect of low dose-rate irradiation on the hematopoietic system. (2016)
  • Author(s): Ohno Y., Suzuki-Takedachi K., , Santo M., Guo Y., Kanno, Yasunaga S., Ohtsubo M., Naka K., Takihara Y.
  • Organizer: The 14th Stem Cell Research Symposium
  • Place of Presentation: Awaji, Japan
  • Year and Date: 2016-05-20
• [Presentation] DNA複製とクロマチンリモデリングを制御するCell-penetrating (CP-)Gemininの開発 (2015)
  • Author(s): 竹立（鈴木）恭子、大野芳典、黒木利知、安永晋一郎、山藤幹茂子、舛廣善和、花澤重正、大坪素秋、仲一仁、瀧原義宏
  • Organizer: 第３８回日本分子生物学会・第８８回日本生化学会合同年会（BMB２０１５）
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] A new strategy for manipulating expression and activety of Geminin, a cell-fate determinant for HSCs. (2015)
  • Author(s): Ohno Y., Suzuki-Takedachi K., Kurogi T., Santo M., Yasunaga S., Ohtsubo M., Naka K., Takihara Y.
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Kanazawa, Japan.
  • Year and Date: 2015-10-16
• [Presentation] Analysis of molecular role for Geminin in self-renewal and differentiation of HSCs. (2015)
  • Author(s): Suzuki-Takedachi K.,Ohno Y., Kurogi T., Santo M., Yasunaga S., Ohtsubo M., Naka K., Takihara Y.
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Kanazawa, Japan.
  • Year and Date: 2015-10-16
• [Presentation] Manipulation of the Geminin activety by using cell-penetrating Geminin and its domein-specific mutants. (2015)
  • Author(s): Ohno Y., Yasunaga S., Suzuki-Takedachi K., Kurogi T., Santo M., Ohtsubo M., Naka K., Takihara Y.
  • Organizer: The 13th Stem Cell Research Symposium
  • Place of Presentation: Tokyo, Japan.
  • Year and Date: 2015-05-15
• [Presentation] Cell-penetrating Geminin is exerted to provide a new strategy for manipulating the activity and number of HSCs. (2015)
  • Author(s): Kurogi T., Ohno Y., Yasunaga S., Suzuki-Takedachi K., Santo M., Ohtsubo M., Takihara Y.
  • Organizer: The 5th International Symposium of RIRBM, Hiroshima University
  • Place of Presentation: Hiroshima, Japan
  • Year and Date: 2015-03-02 – 2015-03-03
• [Presentation] Analysis of molecular rele for Geminin in self-renewal and differentiation of HSCs. (2015)
  • Author(s): Suzuki-Takedachi K., Yasunaga S., Ohno Y., Kurogi T., Santo M., Ohtsubo M., Takihara Y.
  • Organizer: The 5th International Symposium of RIRBM, Hiroshima University
  • Place of Presentation: Hiroshima, Japan
  • Year and Date: 2015-03-02 – 2015-03-03
• [Presentation] Simple diagnosis of STAT1 gain-of-function alleles in patient with chronic mucocutaneous candidiasis presenting various clinical signs. (2015)
  • Author(s): Mizoguchi Y., Okada S., Tsumura M., Yasunaga S., Takihara Y., Casanova J.-L., Morio T., Kobayashi M.
  • Organizer: The 5th International Symposium of RIRBM, Hiroshima University
  • Place of Presentation: Hiroshima, Japan
  • Year and Date: 2015-03-02 – 2015-03-03
• [Presentation] Effects of low-dose irradiation on the hematopoietic system. (2015)
  • Author(s): Yasunaga S., Ohno Y., Suzuki-Takedachi K., Kurogi T., Santo M., Ohtsubo M., Takihara Y.
  • Organizer: The 5th International Symposium of RIRBM, Hiroshima University
  • Place of Presentation: Hiroshima, Japan
  • Year and Date: 2015-03-02
• [Presentation] Geminin-EYFP knock-in mice provide a powerful tool for dissecting a molecular mechanism regulating self-renewal or differentiation of hematopoietic stem cells. (2014)
  • Author(s): Suzuki-Takedachi K., Yasunaga S., Ohno Y., Kurogi T., Ohtsubo M., Takihara Y.
  • Organizer: The 37th Annual Meeting of the Molecular Biology of Japan
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Cell-penetrating recombinant Geminin protein may provide a new strategy for regulating self-renewal or cellular differentiation in hematopoietic stem cells. (2014)
  • Author(s): Kurogi T., Ohno Y., Yasunaga S., Suzuki-Takedachi K., Santo M., Masuhiro Y., Hanazawa S., Ohtsubo M., Takihara Y.
  • Organizer: The 37th Annual Meeting of the Molecular Biology of Japan
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Geminin visualization aids detailed molecular analysis of self-renewing hematopoietic stem cells. (2014)
  • Author(s): Yasunaga S., Ohno Y., Suzuki-Takedachi K., Kurogi T., Santo M., Ohtsubo M., Takihara Y.
  • Organizer: The 76th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Direct transmission of a cell-penetrating form of Geminin, a regulator for hematopoietic stem cells. (2014)
  • Author(s): Ohno Y., Yasunaga S., Kurogi T., Suzuki-Takedachi K., Santo M., Ohtsubo M., Takihara Y.
  • Organizer: The 76th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Direct transduction of a cell-penetrating form of Geminin, a molecule regulating DNA replication and chromatin remodeling. (2014)
  • Author(s): Takihara Y., Yasunaga S., Ohno Y., Kurogi T., Suzuki-Takedachi K., , Santo M., Ohtsubo M.
  • Organizer: ISEH (International Society for Experimental Hematology) 43rd Annual Scientific Meeting
  • Place of Presentation: Montreal , Canada
  • Year and Date: 2014-08-21 – 2014-08-24
• [Presentation] Identification and functional analysis of self-renewing hematopoietic stem cells by using Geminin-EYFP knock-in mice. (2014)
  • Author(s): Yasunaga S., Ohno Y., Suzuki-Takedachi K., Kurogi T., , Santo M., Ohtsubo M., Takihara Y.
  • Organizer: The 12th Stem Cell Research Symposium
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2014-05-30 – 2014-05-31
• [Presentation] Geminin regulates transcription via chromatin remodeling to govern cellular proliferation and differentiation. (2014)
  • Author(s): Ohno Y., Yasunaga S., Kurogi T., Suzuki-Takedachi K., Santo M., Ohtsubo M., Takihara Y.
  • Organizer: The 12th Stem Cell Research Symposium
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2014-05-30 – 2014-05-31
• [Book] モデル・コア・カリキュラム対応 医用生化学－生体物質の代謝と異常－２０１７年版 ISBN978-4-9909426-0-1 (2017)
  • Author(s): 安永晋一郎（編著）、黒木政秀、黒木求、瀬川波子、衣笠哲史、芝口浩智、白須直人、四元房典
  • Total Pages: 464
  • Publisher: 福岡大学医学部生化学講座
• [Book] モデル・コア・カリキュラム対応 医用生化学－生体物質の代謝と異常－２０１６年版 (2016)
  • Author(s): 安永晋一郎
  • Total Pages: 402
  • Publisher: 福岡大学医学部生化学講座 ISBN978-4-9903146-8-2
• [Remarks] 福岡大学医学部生化学
  • URL: http://www.med.fukuoka-u.ac.jp/biochem1/index-j.htm
• [Remarks] 福岡大学医学部生化学講座
  • URL: http://www.med.fukuoka-u.ac.jp/biochem1/index-j.htm
• [Remarks] 広島大学原爆放射線医科学研究所 幹細胞機能学研究分野
  • URL: http://home.hiroshima-u.ac.jp/dscb/index.html
• [Remarks] 広島大学 原爆放射線医科学研究所 幹細胞機能学研究分野
  • URL: http://home.hiroshima-u.ac.jp/dscb/index.html
• [Remarks] 福岡大学 医学部 生化学講座
  • URL: http://www.med.fukuoka-u.ac.jp/biochem1/index-j.htm