造血幹細胞の冬眠を規定するニッチシグナルの同定

2008 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: TGF-β / ニッチシグナル / 造血幹細胞 / 冬眠

Research Abstract

TGF-βがニッチシグナルとして造血幹細胞の冬眠に関与しているかを調べるため ex vivo において造血幹細胞の単細胞培養を行ない、TGF-βの影響を解析したところTGF-βの存在下では造血幹細胞は SCF+TPO に対して分裂せず、20%以上の細胞は10日経過しても一個のままで生存し続けた。さらに至適な条件を検討したところTGF-β3を用いることにより2週間以上にわたって造血幹細胞を一個のままで生存維持することが可能であることが示された。また、TGF-βがこういった作用をもたらすためには非活性型として細胞から分泌されるTGF-β(latent form TGF-β)が酵素処理をうけることにより活性化されることが必要と考えられた。非活性型のTGF-βは骨芽細胞や造血幹細胞を含む骨髄中の多種類の細胞が産生することから、骨髄ニッシェの役割りは非活性型のTGF-βを活性化することにあるのかもしれない。TGF-βが骨髄ニッシェシグナルであるのならば造血幹細胞にはTGF-β受容体の下流にあるSMADが活性化しているはずである。そこで骨髄から回収したばかりの造血幹細胞をSCIS法によっで解析したところSMAD3/4のリン酸化が確認され、骨髄ニッシェにある造血幹細胞がTGF-β受容体からの刺激を受けていることが強く示唆された。TGF-βの役割りをさらに照明するためにTGF-β2型受容体のコンディショナルノックアウトマウスを入手し移植実験を開始している。

Research Products

• [Journal Article] Stepwise development of hematopoietic stem cells from embryonic stem cells. (2009)
  • Author(s): Matsumoto K, Isagawa T, Nishimura T, Ogaeri T, Eto K, Miyazaki S, Miyazaki JI, Aburatani H, Nakauchi H, Ema H.
  • Journal Title: PLoS ONE 4(3) Pages: e4820
  • Peer Reviewed
• [Journal Article] TGF-b induces hibernation of hematopoietic stem cells in the bone marrow niche. (2009)
  • Author(s): Yamazaki S, Iwama A, Takayanagi S, Eto K, Ema H, Nakauchi H.
  • Journal Title: Blood 113 Pages: 1250-1256
  • Peer Reviewed
• [Journal Article] A rapid and efficient strategy to generate allele-specific anti-HLA monoclonal antibodies. (2009)
  • Author(s): Yamazaki S, Suzuki N, Saito T, Ishii Y, Takiguchi M, Nakauchi H, Watanabe N.
  • Journal Title: J Immunol Methods 343 Pages: 56-60
  • Peer Reviewed
• [Journal Article] Sall4 regulates cell fate decision in fetal hepatic stem/progenitor cells. (2009)
  • Author(s): Oikawa T, Kamiya A, Kakinuma S, Zeniya M, Nishinakamura R, Tajiri H, Nakauchi H.
  • Journal Title: Gastroenterology. 136 Pages: 1000-11
  • Peer Reviewed
• [Journal Article] Transcriptional profiling of hematopoietic stem cells by high-throughput sequencing. (2009)
  • Author(s): Yashiro Y, Bannai H, Minowa T, Yabiku T, Miyano S, Osawa M, Iwama A, Nakauchi H.
  • Journal Title: Int J Hematol 89 Pages: 24-33
  • Peer Reviewed
• [Journal Article] The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. (2008)
  • Author(s): Chiba T, Miyagi S, Saraya A, Aoki R, Seki A, Morita Y, Yonemitsu Y, Yokosuka 0, Taniguchi H, Nakauchi H, Iwama A.
  • Journal Title: Cancer Re 68 Pages: 7742-9
  • Peer Reviewed
• [Journal Article] Generation of functional erythrocytes from human embryonic stem cell-derived definitive hematopolesis. (2008)
  • Author(s): Ma F, Ebihara Y, Umeda K, Sakai H, Hanada S, Zhang H, Zaike Y, Tsuchida E, Nakahata T, Nakauchi H, Tsuji K.
  • Journal Title: Proc Natl Acad Sci U S A 105 Pages: 13087-92
  • Peer Reviewed
• [Journal Article] Prospero-related homeobox 1 and liver receptor homolog 1 coordinately regulate long-term proliferation of murine fetal hepatoblasts. (2008)
  • Author(s): Kamiya A, Kakinuma S, Onodera M, Miyajima A, Nakauchi H.
  • Journal Title: Hepatology 48 Pages: 252-64
  • Peer Reviewed
• [Journal Article] Metalloprotrinase regulation improves in vitro generation of efficacious platelets from mouse embryonic stem cells. (2008)
  • Author(s): Nishikii H, Eto K, Tamura N, Hattoril K, Heissig B, Kanaji T, Sawaguchi A, Goto S, Ware J, Nakauchi H.
  • Journal Title: J Exp Med 205 Pages: 1917-27
  • Peer Reviewed
• [Journal Article] Recipient-derived cells after cord blood transplantation: dynamics elucidated by multicolor FACS, reflecting graft failure and relapse. (2008)
  • Author(s): Watanabe N, Takahashi S, Ishige M, Ishii Y, Ooi J, Tomonari A, Tsukada N, Konuma T, Kato S, Sato A, Tojo A, Nakauchi H.
  • Journal Title: Biol Blood Marrow Transplant 14 Pages: 693-701
  • Peer Reviewed
• [Journal Article] Generation of functional platelets from human embryonic stem cells in vitro via ES-sacs, VEGF-promoted structures that concentrate hematopoietic progenitors. (2008)
  • Author(s): Takayama N, Nishikii H, Usui J, Tsukui H, Sawaguchi A, Hiroyama T, Eto K, Nakauchi H.
  • Journal Title: Blood 1 Pages: 5298-306
  • Peer Reviewed
• [Journal Article] Growth and maturation of megakaryocytes is regulated by Lnk/Sh2b3 adaptor protein through crosstalk between cytokine-and integrin-mediated signals. (2008)
  • Author(s): Takizawa H, Eto K, Yoshikawa A, Nakauchi H, Takatsu K, Takaki S.
  • Journal Title: Exp Hematol 36 Pages: 897-906
  • Peer Reviewed
• [Journal Article] Interleukin-27 directly induces differentiation in hematopoietic stem cells. (2008)
  • Author(s): Seita J, Asakawa M, Ooehara J, Takayanagi SI, Morita Y, Watanabe N, Fujita K, Kudo M, Mizuguchi J, Ema H, Nakauchi H, Yoshimoto Y.
  • Journal Title: Blood 111 Pages: 1903-12
  • Peer Reviewed
• [Journal Article] T cell growth control using hapten-specific antibody/interleukin-2 receptor chimera.
  • Author(s): Sogo T, Kawahara M, Ueda H, Otsu M, Onodera M, Nakauchi H, Nagamune T.
  • Journal Title: Cytokine. in press
  • Peer Reviewed
• [Journal Article] The actin polymerization regulator WAVE2 is required for early bone marrow repopulation by hematopoietic stem cells.
  • Author(s): Ogaeri T, Eto K, Otsu M, Ema H, Nakauchi H.
  • Journal Title: Stem Cells. in press
  • Peer Reviewed
• [Presentation] Analysis of Signaling Events in hematopetic Stem Cells, a Vary rare Population in the Bone Marrow. (2009)
  • Author(s): Nakauchi H.
  • Organizer: 34th Lorne Conference on Protein Structure and Function.
  • Place of Presentation: Eskine Mantra Resort, Lorne Australia
  • Year and Date: 20090208-12
• [Presentation] Generation of functional platelets from human Pluripotent stem cells in vitro (2008)
  • Author(s): Nakauchi H.
  • Organizer: 2008 TREMIS-AP Chapter Meeting
  • Place of Presentation: Taipei
  • Year and Date: 20081106-08
• [Presentation] Hibemation of hematopoietic stem sells in the bone marrow niche (2008)
  • Author(s): Nakauchi H.
  • Organizer: The 9th International Congress on Cell Biology (ICCB 2008) & The 20th Annual Conference of the Korean Society for Molecular and Cellular Biology.
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20081007-10
• [Presentation] TGF-βas a Candidate Bone Marrow Niche Signal to induce Hematopoietic Stem Cell Hibemation. (2008)
  • Author(s): Nakauchi H.
  • Organizer: ISEH 2008 Meeting
  • Place of Presentation: Boston, U.S.A.
  • Year and Date: 20080710-12
• [Presentation] "Hibemation of Hematopoietic Stem Cells in the Bone Marrow Nich" 13th Congress of the European Hematology Association. (2008)
  • Author(s): Nakauchi H.
  • Organizer: 13th Congress of the European Hematology Association.
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 20080612-15
• [Presentation] Cytokine Signals Modulated Via Lipid Rafts Induce Hibernation in Hematopoietic Stem Cells (2008)
  • Author(s): Nakauchi H.
  • Organizer: International Society for Stem Cell Research 6th Annual Meeting(ISSCR)
  • Place of Presentation: Philadelphia, U.S.A.
  • Year and Date: 20080611-14
• [Presentation] Next generation regenerative medicine: From cell therapy to organ replacement therapy (2008)
  • Author(s): Nakauchi H.
  • Organizer: The 10^<th> Anniversary celebration of Korean Tissue Engineering and Regenerative Medicine Society (TERMIS)
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20080522-23
• [Presentation] TGF-β as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation (2008)
  • Author(s): Nakauchi H.
  • Organizer: The 5th Nikko International Symposium 2008
  • Place of Presentation: shimotsuke, Tochigi Japan
  • Year and Date: 2008-10-25
• [Presentation] Hibernation of Hematopoietic Stem Cells in the bone marrow niche (2008)
  • Author(s): Nakauchi H.
  • Organizer: Harvard Stem Cell Institute scminar series.
  • Place of Presentation: Massachusetts general Hospital, Boston
  • Year and Date: 2008-05-06