Regulation of Hematopoietic Stem Cell Division in a Niche

2008 Fiscal Year Final Research Report

• 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
• 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

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] 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] 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] 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] 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
• [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
  • Year and Date: 20080611-14
• [Presentation] Quiescent stem cells in the niche. (2006)
  • Author(s): Toshio Suda
  • Organizer: The 4th ISSCR Annual Meeting
  • Place of Presentation: Toronto
  • Year and Date: 20060629-0701
• [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
  • Year and Date: 20060311-16
• [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
  • Year and Date: 20050201-04
• [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
  • Year and Date: 20041204-07