造血幹細胞の冬眠を規定するニッチシグナルの同定

2007 Fiscal Year Annual Research Report

• Project/Area Number: 19209036
• Research Institution: The University of Tokyo
• Principal Investigator: 中内 啓光 The University of Tokyo, 医科学研究所, 教授 (40175485)
• Co-Investigator(Kenkyū-buntansha): 大津 真 東京大学, 医科学研究所, 助教 (30361330)
• Keywords: 造血幹細胞 / リピッドラフト / 冬眠 / ニッチ / FOXO

Research Abstract

造血幹細胞膜表面上に形成されるLipid Raft Clustering (LRC)の機能を明らかにすることを目指し、Lipid-raft分画の基本構造やコンポーネントを明らかにするとともに反応のKineticsの解析を試みた。しかし造血幹細胞は勿論のこと造血幹細胞より数が多い造血前駆細胞を使用しても薄層クロマトグラフィー等の生化学的解析において再現性のある結果が得られなかった。
視点を変えて骨髄ニッシェに存在する造血幹細胞にはLRCが無く、骨髄中の前駆細胞や骨髄から取り出してサイトカイン刺激した造血幹細胞にはLRCが存在するという事実から骨髄ニッシェにはLRCの形成を阻害する物質(シグナル)があるのではないかと考えた。この仮定のもと、Notch ligand,Tie2,Angiopoietin,c-Kitなど、ニッチシグナル分子とされている分子を対象として、サイトカイン刺激によるLRC形成を阻止する分子をスクリーニングした。その結果TGF-βがLRC形成を完璧に阻止することを明らかにした。
またLRC形成のkineticsならびにLRC形成が造血幹細胞の非対称性分裂の際の分子機構に関連があるかを明らかにするため、サイトカイン等で刺激後の造血幹細胞におけるLRCの集積を顕微鏡下で解析した。これまでの結果ではLRC形成と非対称性分裂を関連づける証拠は得られていない。

Research Products

• [Journal Article] The Plasminogen Fibrinolytic Pathway Is Required for Hematopoietic Regeneration (2007)
  • Author(s): Heissig B, Lund LR, Akiyama H, Ohki M, Morita Y, Romer J, Nakauchi H, Okumura K, Ogawa H, Werb Z, Dano K, Hattori K.
  • Journal Title: Cell Stem Cell 1 Pages: 658-70
  • Peer Reviewed
• [Journal Article] Foxo3a is essential for maintenance of the hematopoietic stem cell pool (2007)
  • Author(s): Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M, Chen C, Hosokawa K, Nakauchi H, Nakayama K
  • Journal Title: Cell Stem Cell 1 Pages: 101-12
  • Peer Reviewed
• [Journal Article] Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation (2007)
  • Author(s): Chiba T, Zheng YW, Kita K, Yokosuka O, Saisho H, Onodera M, Miyoshi H, Nakano M, Zen Y, Nakanuma Y, Nakauchi H, Iwama A, Taniguchi H.
  • Journal Title: Gastroenterology 133 Pages: 937-50
  • Peer Reviewed
• [Journal Article] Cytokine signaling, lipid raft clustering, and HSC hibernation (2007)
  • Author(s): Yamazaki S, Iwama A, Morita Y, Eto K, Ema H, Nakauchi H. Cytokine signaling, lipid raft clustering, HSC hibernation
  • Journal Title: Ann N Y Acad Sci 1106 Pages: 54-63
  • Peer Reviewed
• [Journal Article] The WAVE2/Abi1 complex differentially regulates megakaryocyte development and spreading : implications for platelet biogenesis and spreading machinery (2007)
  • Author(s): Eto K, Nishikii H, Ogaeri T, Suetsugu S, Kamiya A, Kobayashi T, Yamazaki D, Oda A, Takenawa T, Nakauchi H.
  • Journal Title: Blood 110 Pages: 3637-47
  • Peer Reviewed
• [Journal Article] De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells (2007)
  • Author(s): Tadokoro Y, Ema H, Okano M, Li E, Nakauchi H.
  • Journal Title: J Exp Med 204 Pages: 715-22
  • Peer Reviewed
• [Journal Article] Unique composition of polycomb repressive complex 1 in hematopoietic stem cells (2007)
  • Author(s): 26. Kato Y, Koseki H, Vidal M, Nakauchi H, Iwama A.
  • Journal Title: Int J Hematol 85 Pages: 179-81
  • Peer Reviewed
• [Journal Article] Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction (2007)
  • Author(s): Seita, J., Ema, H., Ooehara, J., Yamazaki, S., Tadokoro, Y., Yamazaki, A., Eto, K., Takaki, S., Takatsu, K., Nakauchi H.
  • Journal Title: Proc Natl Acad Sci USA 104 Pages: 2349-54
  • Peer Reviewed
• [Journal Article] Stable Transgene Expression in Mice Generated from Retrovirally Transduced Embryonic Stem Cells (2007)
  • Author(s): Hamanaka S, Nabekura T, Otsu M, Yoshida H, Nagata M, Usui J, Takahashi S, Nagasawa T, Nakauchi H, Onodera M.
  • Journal Title: Mol Ther. 15 Pages: 560-5
  • Peer Reviewed
• [Journal Article] Bmi1 cooperates with Dnmt1-assciated protein 1 in gene silencing (2007)
  • Author(s): Negishi M, Saraya A, Miyagi S, Nagao K, Inagaki Y, Nishikawa M, Tajima S, Koseki H, Tsuda H, Takasaki Y, Nakauchi H, Iawama A.
  • Journal Title: Biochem Biophys Res Commun 353 Pages: 992-8
  • Peer Reviewed
• [Presentation] Bone Marrow Niche and Hematopoietic Stem Cell Regulation (2008)
  • Author(s): Nakauchi H.
  • Organizer: 4th Annual CONSERT Meeting
  • Place of Presentation: Leukerbad, Switzerland
  • Year and Date: 20080123-20080126
• [Presentation] A Mechanism to Protect Hematopoietic Stem Cells in the Bone Marrow Niche : Implications for Cancer Stem Cells and Cancer Treatment (2007)
  • Author(s): Nakauchi H.
  • Organizer: Tissue Engineering International & Regenerative Medicine Society Asia-Pacific Chapter Meeting 2007
  • Place of Presentation: Akasaka, Tokyo Japan
  • Year and Date: 20071203-20071205
• [Presentation] Use of A Developmental Niche to Generative A Kidney From Donor Embrionic Stem Cells (2007)
  • Author(s): Nakauchi H.
  • Organizer: International Society for Stem Cell Research (ISSCR)5th Annual Meeting
  • Place of Presentation: Cairns, Australia
  • Year and Date: 20070617-20070620
• [Presentation] Hibernation of hematopoietic stem cells in the bone marrow niche (2007)
  • Author(s): Nakauchi H.
  • Organizer: JSPS Core to Core Program Symposium Lund University and Keio University "Collaboration of Research Centers for Stem Cell Biology and Regeneration Medicine"
  • Place of Presentation: Roppongi, Tokyo, Japan
  • Year and Date: 2007-11-30
• [Presentation] Molecular regulation of HSC self-renewal---Hibernation of Hematopoietic Stem Cells in the Bone Marrow Niche--- (2007)
  • Author(s): Nakauchi H.
  • Organizer: Hemato-Oncology Seminar Series 2007 at University Medical Center Groningen
  • Place of Presentation: The Netherlands
  • Year and Date: 2007-09-05