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2010 Fiscal Year Final Research Report

Molecular mechanisms for hematopoietic stem cells by HIF-1/VHL regulatory system

Research Project

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Project/Area Number 21790925
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionKeio University

Principal Investigator

TAKUBO Keiyo  Keio University, 医学部, 助教 (50502788)

Project Period (FY) 2009 – 2010
Keywords造血幹細胞 / 低酸素 / 静止期 / 老化
Research Abstract

Hematopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Mammalian HSCs are kept quiescent in the endosteal niche, a hypoxic zone of the bone marrow (BM). We found that normal HSCs maintain intracellular hypoxia and stabilize hypoxia-inducible factor-1alpha (HIF-1alpha) protein. In HIF-1alpha-deficient mice, the HSCs lost their cell cycle quiescence and HSC numbers decreased during various stress settings including bone marrow transplantation, myelosuppression, or aging, in a p16Ink4a/p19Arf-dependent manner. Overstabilization of HIF-1alpha by biallelic loss of an E3 ubiquitin ligase for HIF-1alpha (VHL) induced cell cycle quiescence in HSCs and their progenitors but resulted in an impairment in transplantation capacity. In contrast, monoallelic loss of VHL induced cell cycle quiescence and improved BM engraftment during bone marrow transplantation. These data indicate that HSCs maintain cell cycle quiescence through the precise regulation of HIF-1alpha levels.

  • Research Products

    (21 results)

All 2011 2010 2009 Other

All Journal Article (11 results) (of which Peer Reviewed: 11 results) Presentation (9 results) Remarks (1 results)

  • [Journal Article] Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells.2011

    • Author(s)
      Kinoshita T, Nagamatsu G, Kosaka T, Takubo K, Hotta A, Ellis J, Suda T.
    • Journal Title

      Biochem Biophys Res Commun. [Epub ahead ofprint]

    • Peer Reviewed
  • [Journal Article] Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere independent mechanism.2011

    • Author(s)
      Nitta E, Yamashita M, Hosokawa K, Xian M, Takubo K, Arai F, Nakada S, Suda T.
    • Journal Title

      Blood [Epub ahead of print]

    • Peer Reviewed
  • [Journal Article] A germ cell specific gene, Prmt5 works as somatic cell reprogramming.2011

    • Author(s)
      Nagamatsu G, Kosaka T, Kawasumi M, Kinoshita T, Takubo K, Akiyama H, Sudo T, Kobayashi T, Oya M, Suda T.
    • Journal Title

      J Biol Chem. [Epub ahead ofprint]

    • Peer Reviewed
  • [Journal Article] Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation.2011

    • Author(s)
      Honda H, Takubo K, Oda H, Kosaki K, Tazaki T, Yamasaki N, Miyazaki K, Moore KA, Honda Z, Suda T, Lemischka IR.
    • Journal Title

      Proc Natl Acad Sci USA. 108(6)Epub

      Pages: 2468-2473

    • Peer Reviewed
  • [Journal Article] Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7&alpha ; overexpression.2011

    • Author(s)
      Iriuchishima H, Takubo K, Matsuoka S, Onoyama I, Nakayama KI, Nojima Y, Suda T.
    • Journal Title

      Blood. 117(8)Epub

      Pages: 2373-2377

    • Peer Reviewed
  • [Journal Article] Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.2010

    • Author(s)
      Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M, Suda T.
    • Journal Title

      Cell Stem Cell. 7(3)

      Pages: 391-402

    • Peer Reviewed
  • [Journal Article] Acquisition of Go state by CD34-positive cord blood cells after bone marrow transplantation.2010

    • Author(s)
      Shima H, Takubo K, Tago N, Iwasaki H, Arai F, Takahashi T, Suda T.
    • Journal Title

      Exp Hematol. 38(12)Epub

      Pages: 1231-1240

    • Peer Reviewed
  • [Journal Article] von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina.2010

    • Author(s)
      Kurihara T, Kubota Y, Ozawa Y, Takubo K, Noda K, Simon MC, Johnson RS, Suematsu M, Tsubota K, Ishida S, Goda N, Suda T, Okano H.
    • Journal Title

      Development 137(9)

      Pages: 1563-1571

    • Peer Reviewed
  • [Journal Article] Cadherin-based adhesion is a potential target for niche manipulation to protect hematopoietic stem cells in adult bone marrow.2010

    • Author(s)
      Hosokawa K, Arai F, Yoshihara H, Iwasaki H, Hembree M, Yin T, Nakamura Y, Gomei Y, Takubo K, Shiama H, Matsuoka S, Li L, Suda T.
    • Journal Title

      Cell Stem Cell. 6(3)

      Pages: 194-198

    • Peer Reviewed
  • [Journal Article] M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis.2009

    • Author(s)
      Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M, Saya H, Suda T.
    • Journal Title

      J Exp Med. 206(5)Epub

      Pages: 1089-1102

    • Peer Reviewed
  • [Journal Article] Craniofacial malformation in R-spondin2 knockout mice.2009

    • Author(s)
      Yamada W, Nagao K, Horikoshi K, Fujikura A, Ikeda E, Inagaki Y, Kakitani M, Tomizuka K, Miyazaki H, Suda T, Takubo K.
    • Journal Title

      Biochem Biophys Res Commun. 381(3)Epub

      Pages: 453-458

    • Peer Reviewed
  • [Presentation] Anaerobic Metabolism Maintains Quiescence of Hematopoietic Stem Cell USA-Japan Cooperative Cancer Research Workshop2011

    • Author(s)
      Takubo K.
    • Place of Presentation
      Hayama, Japan
    • Year and Date
      2011-02-25
  • [Presentation] Pdk-mediated Modulation of Cell Cycle of Long-Term Hematopoietic Stem Cells2011

    • Author(s)
      田久保圭誉, 入内島裕乃, 須田年生
    • Organizer
      第8回がんとハイポキシア研究会
    • Place of Presentation
      札幌
    • Year and Date
      2011-01-29
  • [Presentation] Purification analysis of testicular germ line and somatic subpopulations.2010

    • Author(s)
      Takubo K, Nagamatsu G, Iriuchishima H, Ishikawa C, Suda T.
    • Organizer
      International Symposium on Epigenome Network, Development and Reprogramming of Germ Cells
    • Place of Presentation
      福岡
    • Year and Date
      2010-11-22
  • [Presentation] VHL/HIF-1・制御系による造血幹細胞の恒常性維持機構「代謝調節機構解析に基づく細胞機能制御基盤技術」2010

    • Author(s)
      田久保圭誉, 須田年生
    • Organizer
      第3回公開シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2010-10-21
  • [Presentation] Suppressor Effect of Novel Antitumor Drug, Bendamustine on Multiple Myeloma in Humanized Mouse Model2010

    • Author(s)
      Takubo K, Iriuchishima H, Yamada W, Miyakawa Y, Miyamoto T, Suda T.
    • Organizer
      第72回日本血液学会学術集会
    • Place of Presentation
      横浜
    • Year and Date
      2010-09-25
  • [Presentation] Regulation of "stemness" by Hypoxic Bone Marrow Microenvironment2010

    • Author(s)
      Takubo K.
    • Organizer
      第69回日本癌学会学術総会
    • Place of Presentation
      大阪
    • Year and Date
      2010-09-22
  • [Presentation] 低酸素応答シグナルによる造血幹細胞の維持2010

    • Author(s)
      田久保圭誉
    • Organizer
      第31回日本炎症・再生医学会 ミニシンポジウム5「幹細胞と老化、ストレス」
    • Place of Presentation
      東京・新宿
    • Year and Date
      2010-08-06
  • [Presentation] マウス未分化型精原細胞特異的遺伝子群のプロモーター解析「生殖系列の世代サイクルとエピゲノムネットワーク」2009

    • Author(s)
      田久保圭誉, 須田年生
    • Organizer
      第2回公開シンポジウム
    • Place of Presentation
      品川・コクヨホール
    • Year and Date
      20091126-20091127
  • [Presentation] A Protective Program for Hematopoietic Stem Cells by Anaerobic Metabolism2009

    • Author(s)
      Takubo K.
    • Organizer
      第71回日本血液学会学術集会 シンポジウム5"Hematopoietic Stem Cell Niche"
    • Place of Presentation
      京都
    • Year and Date
      2009-10-24
  • [Remarks] ホームページ等

    • URL

      http://web.sc.itc.keio.ac.jp/celldiff/taisya.html

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Published: 2012-02-13   Modified: 2016-04-21  

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