Regulation of Hematopoietic Stem Cell Division in a Niche

• Project/Area Number: 16002011
• Research Category: Grant-in-Aid for Specially Promoted Research
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Keio University
• Principal Investigator: SUDA Toshio Keio University, 医学部, 教授 (60118453)
• Co-Investigator(Kenkyū-buntansha): ARAI Fumio 慶應義塾大学, 医学部, 講師 (90365403) ; MIYAMOTO Takeshi 慶應義塾大学, 医学部, 講師 (70383768) ; MATSUOKA Sahoko 慶應義塾大学, 医学部, 助教 (20317340) ; TAKUBO Keiyo 慶應義塾大学, 医学部, 助教 (50502788) ; NAGAMATSU Go 慶應義塾大学, 医学部, 助教 (70453545) ; YOSHIHARA Hiroki 慶應義塾大学, 医学部, 助教 (90348706)
• Project Period (FY): 2004 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥457,600,000 (Direct Cost: ¥352,000,000、Indirect Cost: ¥105,600,000); Fiscal Year 2008: ¥91,520,000 (Direct Cost: ¥70,400,000、Indirect Cost: ¥21,120,000); Fiscal Year 2007: ¥91,520,000 (Direct Cost: ¥70,400,000、Indirect Cost: ¥21,120,000); Fiscal Year 2006: ¥91,520,000 (Direct Cost: ¥70,400,000、Indirect Cost: ¥21,120,000); Fiscal Year 2005: ¥91,520,000 (Direct Cost: ¥70,400,000、Indirect Cost: ¥21,120,000); Fiscal Year 2004: ¥91,520,000 (Direct Cost: ¥70,400,000、Indirect Cost: ¥21,120,000)
• Keywords: 造血幹細胞 / ニッチ / 骨芽細胞 / 自己複製能 / Tie2 / Angiopoietin-1 / 活性酸素 / Mpl / Thrombopoietin / ATM / Angiopoiedn-1 / TIE2 / mpl / thrombopoietin / TIE2受容体

Research Abstract

幹細胞の静止期性(G0)は、造血幹細胞を維持する上で重要である。我々は、骨髄の内骨膜領域にある造血幹細胞が、Tie2/Angiopoietin-1やmpl/thrombopoietinのシグナルを通じて骨芽細胞に接着し、静止期性を維持することを見出した。また、ストレス下では、活性酸素種(ROS)は上昇し、幹細胞がニッチから離れる。p38MAPKやINK4Aの増加は、幹細胞の消耗・老化を引き起こす。幹細胞は低酸素状態で、分裂・増殖が抑えられていて、解糖系優位という代謝学的特徴を有する。

Research Products

• [Journal Article] FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging. (2008)
  • Author(s): Miyamoto K, Miyamoto T, Kato R, Yoshimura A, Motoyama N, Suda T
  • Journal Title: Blood 112 Pages: 4485-4493
  • Peer Reviewed
• [Journal Article] Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL (2008)
  • Author(s): Matsuoka S, Oike Y, Onoyama I, Iwama A, Arai F, Takubo K, Mashimo Y, Oguro H, Nitta E, Ito K, Miyamoto K, Yoshiwara H, Hosokawa K, Nakamura Y, Gomei Y, Iwasaki H, Hayashi Y, Matsuzaki Y, Nakayama K, Ikeda Y, Hata A, Chiba S, Nakayama KI, Suda T
  • Journal Title: Genes Dev 22 Pages: 986-991
  • Peer Reviewed
• [Journal Article] Stem cell defects in ATM-deficient undifferentiated spermatogonia through DNA damage-induced cell cycle arrest (2008)
  • Author(s): Takubo K, Ohmura M, Azuma M, Nagamatsu G, Yamada Y, Arai F, Hirao A, Suda T
  • Journal Title: Cell Stem Cell 2 Pages: 170-182
  • Peer Reviewed
• [Journal Article] Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL (2008)
  • Author(s): Matsuoka S, et.al.
  • Journal Title: Genes Dev 22 Pages: 986-991
  • Peer Reviewed
• [Journal Article] Identification of stem cells during prepubertal spermatogenesis via monitoring of nucleostemin promoter activity (2008)
  • Author(s): Omura M, et.al.
  • Journal Title: Stem Cells 26 Pages: 3237-3246
  • Peer Reviewed
• [Journal Article] FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging (2008)
  • Author(s): Miyamoto K, et.al.
  • Journal Title: Blood 112 Pages: 4485-4493
  • Peer Reviewed
• [Journal Article] Reconstitution activity of hypoxic cultured human cord blood CD34-positive cells in NOG mice (2008)
  • Author(s): Shima H, et.al.
  • Journal Title: Biochem Biophys Res Commun 378 Pages: 467-472
  • Peer Reviewed
• [Journal Article] Stem cell defects in ATM-deficient undifferentiated spermatogonia through DNA damage-induced cell cycle arrest. (2008)
  • Author(s): Takubo K., et. al.
  • Journal Title: Cell Stem Cell 2 Pages: 170-182
  • Peer Reviewed
• [Journal Article] Thrombopoietin/Mpl signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche (2007)
  • Author(s): Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y, Gomei Y, Iwasaki H, Matsuoka S, Miyazaki H, Takahashi T, Suda T
  • Journal Title: Cell Stem Cell 1 Pages: 685-697
  • Peer Reviewed
• [Journal Article] Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification. (2007)
  • Author(s): Morita K, Miyamoto T, Fujita N, Kubota Y, Ito K, Takubo K, Miyamoto K, Ninomiya K, Suzuki T, Iwasaki R, Yagi M, Takaishi H, Toyama Y, Suda T
  • Journal Title: J Exp Med 204 Pages: 1613-1623
  • Peer Reviewed
• [Journal Article] Foxo3a is essential for maintenance of the hematopoietic stem cell pool (2007)
  • Author(s): Miyamoto K, Y. Araki K, Naka K, Arai F, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M, Chen C, Hosokawa K, Nakauchi H, Nakayama K, Nakayama K, Harada M, Motoyama N, Suda T, Hirao A
  • Journal Title: Cell Stem Cell 1 Pages: 101-112
  • Peer Reviewed
• [Journal Article] Foxo3a is essential for maintenance of liie hematopoietic stem cell pool. (2007)
  • Author(s): Miyamoto K, et. al.
  • Journal Title: Cell Stem Cell 1 Pages: 101-112
  • Peer Reviewed
• [Journal Article] Thrombopoietin/Mpl signaling regulates hematopoietic stem ceU quiescence and interaction with Ihe osteoblastic niche. (2007)
  • Author(s): Yoshihara H, et. al.
  • Journal Title: Cell Stem Cell 1 Pages: 685-697
  • Peer Reviewed
• [Journal Article] Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice. (2007)
  • Author(s): Ninomiya M, et al.
  • Journal Title: Leukemia 21 Pages: 136-142
• [Journal Article] Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes. (2007)
  • Author(s): Ito K, et al.
  • Journal Title: J Immunol 178 Pages: 103-110
• [Journal Article] Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool. (2007)
  • Author(s): Miyamoto K, et al.
  • Journal Title: Cell Stem Cell (in press)
• [Journal Article] Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. (2006)
  • Author(s): Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y, Suda T
  • Journal Title: Nature Med 12 Pages: 446-451
  • Peer Reviewed
• [Journal Article] Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. (2006)
  • Author(s): Ito K, et al.
  • Journal Title: Nat Med 12 Pages: 446-451
• [Journal Article] Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. (2006)
  • Author(s): Zhao C, et al.
  • Journal Title: Cell Metabolism 4 Pages: 111-121
• [Journal Article] CTX family cell adhesion molecule, JAM4, is expressed in stem cell and progenitor cell populations of both male germ cell and hematopoietic cell lineages. (2006)
  • Author(s): Nagamatsu G, et al.
  • Journal Title: Mol Cell Biol 26 Pages: 8498-8506
• [Journal Article] Loss of Tie2 receptor compromises embryonic stem cell-derived endothelial but not hematopoietic cell survival. (2006)
  • Author(s): Hamaguchi I, et al.
  • Journal Title: Blood 107 Pages: 1207-1213
• [Journal Article] Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. (2006)
  • Author(s): Ito K, et al.
  • Journal Title: Nat Med (in press)
• [Journal Article] DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. (2005)
  • Author(s): Yagi M, Miyamoto T, Sawatani Y, Iwamoto K, Hosogane N, Fujita N, Morita K, Ninomiya K, Suzuki T, Miyamoto K, Oike Y, Takeya M, Toyama Y, Suda T
  • Journal Title: J Exp Med 203 Pages: 345-351
  • Peer Reviewed
• [Journal Article] Oncogenic transcription factor Evi-1 regulates hematopoietic stem cell proliferation through GATA-2 expression. (2005)
  • Author(s): Yuasa H, et al.
  • Journal Title: EMBO J 24 Pages: 1976-1987
• [Journal Article] Hematopoietic stem cells and their niche. (2005)
  • Author(s): Suda T, et al.
  • Journal Title: Trends Immunol 26 Pages: 426-433
• [Journal Article] DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. (2005)
  • Author(s): Yagi M, et al.
  • Journal Title: J Exp Med 203 Pages: 345-351
• [Journal Article] Cooperative interaction of Angiopoietin-like proteins, Angptl1 and Angptl2, in zebrafish vascular development. (2005)
  • Author(s): Kubota Y, et al.
  • Journal Title: Proc Natl Acad Sci U S A 102 Pages: 13502-13507
• [Journal Article] Angiopoietin-related growth factor (AGF) antagonizes obesity and related insulin resistance. (2005)
  • Author(s): Oike Y, et al.
  • Journal Title: Nature Medicine 11 Pages: 400-408
• [Journal Article] Angiopoietin-1 promotes lymphatic hyperplasia. (2005)
  • Author(s): Tammela T, et al.
  • Journal Title: Blood (印刷中)
• [Journal Article] Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. (2005)
  • Author(s): Morisada T, et al.
  • Journal Title: Blood (印刷中)
• [Journal Article] Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. (2004)
  • Author(s): Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Nakagata N, Ikeda Y, Tak W. Mak, Suda T
  • Journal Title: Nature 431 Pages: 997-1002
  • Peer Reviewed
• [Journal Article] Tie2/Angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. (2004)
  • Author(s): Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, Ito K, Koh GY, Suda T
  • Journal Title: Cell 118 Pages: 149-161
  • Peer Reviewed
• [Journal Article] Angiopoietin-related/Angiopoietin-like proteins regulate angiogenesis. (2004)
  • Author(s): Oike Y, et al.
  • Journal Title: Int J Hematol 80 Pages: 21-28
• [Journal Article] Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. (2004)
  • Author(s): Ito K, et al.
  • Journal Title: Nature 431 Pages: 997-1002
• [Journal Article] Tie2/Angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. (2004)
  • Author(s): Arai F, et al.
  • Journal Title: Cell 118 Pages: 149-161
• [Journal Article] Angiopoietin-related growth factor (AGF) promotes angiogenesis. (2004)
  • Author(s): Oike Y, et al.
  • Journal Title: Blood 103 Pages: 3760-3766
• [Journal Article] Regulation of cell cycle in hematopoietic stem cells by the niche. (2004)
  • Author(s): Hirao A, et al.
  • Journal Title: Cell Cycle 3 Pages: 1481-1483
• [Presentation] Quiescent stem cells in the niche (2008)
  • Author(s): Toshio Suda
  • Organizer: The 6th International Society for Stem Cell Research (ISSCR) Annual Meeting
  • Place of Presentation: Philadelphia
• [Presentation] Quiescent stein cells in the niche (2008)
  • Author(s): Suda T
  • Organizer: 6^<th> International Society for Stem Cell Research (ISSCR) Annual Meeting 2008
  • Place of Presentation: Philadelphia
• [Presentation] Quiescent hematopoietic stem cells in hypoxic niche (2008)
  • Author(s): Suda T
  • Organizer: Summer School 2008- Stem Cell Research, Mechanisms of early differentiation
  • Place of Presentation: Barsinghausen, Germany
• [Presentation] Hematopoietic stem cell in the hypoxic niche (2008)
  • Author(s): Suda T
  • Organizer: Taiwan Society for Stem Cell Research (TSSCR), International Symposia on Stem Cells, Epigenetics and Develonment
  • Place of Presentation: Taipei
• [Presentation] Quiescent hematopoietic stem cell in the niche (2008)
  • Author(s): Suda T
  • Organizer: The 32^<nd> World Congress of the International Society of Hematology
  • Place of Presentation: Bangkok
• [Presentation] Quiescence of hematopoietic stem cells regulation by ROS. (2007)
  • Author(s): Suda T
  • Organizer: 36th Annual Scientific Meeting of International Society for Experimental Hematology
  • Place of Presentation: Hamburg
  • Year and Date: 2007-09-28
• [Presentation] Niche regulation of hematopoietic stem cells by ROS. (2006)
  • Author(s): Toshio Suda
  • Organizer: Gordon Research Conferences on Oxidative Stress and Disease
  • Place of Presentation: Ventura, California
• [Presentation] Quiescent stem cells in the niche. (2006)
  • Author(s): Toshio Suda
  • Organizer: The 4th ISSCR Annual Meeting
  • Place of Presentation: Toronto
• [Presentation] Tools for identifying stem cell/niche cell interactions in the mouse. (2005)
  • Author(s): Toshio Suda
  • Organizer: AACR Workshop on Cancer Stem Cells
  • Place of Presentation: Lansdowne, Maryland
• [Presentation] Hematopoietic stem cell quiescence in the bone marrow niche. (2004)
  • Author(s): Toshio Suda
  • Organizer: ASH 46th Annual Meeting
  • Place of Presentation: San Diego
• [Book] Endothelial and Hematopoietic Cells in the Intra-Embryonic Compartment in Hematopoietic Stem Cells. (2004)
  • Author(s): Arai F, et al.
  • Publisher: Eurekah.com and Kluwer Academic/Plenum Publisher