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造血微小環境による造血幹細胞の分化制御機構

Research Project

Project/Area Number 12215004
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTohoku University

Principal Investigator

帯刀 益夫  東北大学, 加齢医学研究所, 教授 (10099971)

Co-Investigator(Kenkyū-buntansha) 東海林 亙  東北大学, 加齢医学研究所, 助手 (40250831)
山本 融  東北大学, 加齢医学研究所, 助手 (10251480)
矢内 信昭  宮城学院女子大学, 教授 (80200525)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥57,400,000 (Direct Cost: ¥57,400,000)
Fiscal Year 2004: ¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 2003: ¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 2002: ¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2001: ¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2000: ¥10,000,000 (Direct Cost: ¥10,000,000)
Keywords造血微小環境 / 骨髄 / 間質細胞 / MysPDZ / Myo18A / ephrinB2 / tenascin-c / sphingoshine-1 phosphate / 幹細胞 / 可塑性 / 微小環境 / サイトカイン / 遺伝子発現プロファイル / マイクロアレイ / 造血幹細胞 / 共培養 / 細胞間相互作用 / 多能性造血幹細胞 / STAT5 / STAT1 / 骨髄間質細胞 / 不死化細胞株 / 新規ミオシン遺伝子
Research Abstract

造血幹細胞の増殖と分化は骨髄などの造血組織の微小環境(Niche)によって制御を受けており、この微小環境による幹細胞の制御機構は、がん細胞が悪性化してゆく際の間質との相互作用の役割を考える上からも重要である。本研究では、間質細胞依存に増殖する未分化血液細胞株を用いて、間質細胞の制御因子の機能解析を行い、以下のような結果を得た。
(1)未分化血液細胞の増殖には、sphingosine-1 phosphateやLysophosphatidic acidなどの脂質が必要であり、血液細胞の間質細胞への潜り込みなど運動性を制御していることを明らかにした。
(2)赤血球造血支持機能を示す骨髄間質細胞において、tenascin-cが支持細胞株で有意に発現が高いことを確認し、siRNAによりその発現を低下させると赤血球支持機能の低下が認められ、間質細胞の赤血球前駆細胞増殖制御の重要な因子であることを実証した。
(3)造血幹細胞維持機能の高い間質細胞株に強い発現が認められる遺伝子(MysPDZ=Myo18A)を単離し、そのドメイン構造に依存して細胞内顆粒および細胞膜直下の局在、細胞内の移動や細胞内輸送が制御される事を示した。
(4)ephrinB2の発現が血液細胞の運動性を規定し、その受容体としてのEph受容体とともに細胞間の双方向のシグナル伝達に関係し、未分化血液細胞の分化の可塑性の制御を担う分子として機能していることを示した。
(5)造血微小環境を構成する骨髄間質細胞が間葉系幹細胞の性状をもつことを示した。とくに、数株の細胞の培養系で拍動する心筋への分化誘導が起きることを確認した。また、いくつかの間質細胞株が骨格筋、平滑筋、骨、脂肪、内皮細胞などに分化する能力を持つ間葉系の幹細胞の性状を持つことを明らかにした。

Report

(5 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (27 results)

All 2005 2004 Other

All Journal Article (6 results) Publications (21 results)

  • [Journal Article] Subcellular localization and dynamics of MysPDZ (Myo18A) in live mammalian cells.2005

    • Author(s)
      Mori K, Matsuda K, Furusawa T, Kawata M, Inoue T, Obinata M.
    • Journal Title

      Biochem Biophys Res Commun 326

      Pages: 491-498

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Immortalized dendritic cell line with efficient cross-priming ability established from transgenic mice harboring the temperature-sensitive SV40 large T-antigen gene.2004

    • Author(s)
      Ebihara S, Endo S, Ito K, Ito Y, Akiyama K, Obinata M, Takai T.
    • Journal Title

      J Biochem (Tokyo). 136

      Pages: 321-328

    • NAID

      10016202020

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Reporter gene stimulation by MIDA1 through its DnaJ homology region.2004

    • Author(s)
      Yoshida, M, Inoue, T, Shoji W, Ikawa S, Obinata. M.
    • Journal Title

      Biochem Biophys Res Commun 324

      Pages: 326-332

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Transporter mRNA Expression in a Conditionally Immortalized Rat Small Intestine Epithelial Cell Line (TR-SIE).2004

    • Author(s)
      Hosoya, K, Tomi, M, Takayama, M, Komokata, Y, Nakai, D, Tokui, T, Nishimura, K, Ueda, M, Obinata, M, Hori, S, Ohtsuki, S, Amidon, L.M, Terasakl, T
    • Journal Title

      Drug Metabol.Pharmacokin. 19

      Pages: 264-269

    • NAID

      10014514079

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Repulsion and attraction of axons by Semaphorin3D are mediated by different neuropilins in vivo.2004

    • Author(s)
      Wolman MA, Liu Y, Tawarayama H, Shoji W, Halloran MC.
    • Journal Title

      J Neurosci. 24

      Pages: 8428-8435

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Vegfc is required for vascular development and endoderm morphogenesis in zebrafish.2004

    • Author(s)
      Ober EA, Olofsson B, Makinen T, Jin SW, Shoji W, Koh GY, Alitalo K, Stainier DY.
    • Journal Title

      EMBO Rep. 5

      Pages: 78-84

    • Related Report
      2004 Annual Research Report
  • [Publications] Mori K, Furusawa T, Okubo T, Inoue T, Ikawa S, Yanai N, Mori KJ, Obinata M: "Genome Structure and Differential Expression of Two Isoforms of a Novel PDZ-Containing Myosin (MysPDZ) (Myo18A)."J Biochem (Tokyo).. 133. 405-413 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tabuchi Y, Arai Y, Shioya H, Kuribayashi R, Ishibashi K, Sugiyama N, Obinata M, Takeguchi N, Asano S: "New gastric epithelial cell lines from mice transgenic for temperature-sensitive simian virus 40 large T antigen show distinct types of cell differentiation."Digestion.. 67. 71-81 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shoji W., Isogai S., Sato-Maeda M., Obinata M., Kuwada, J.Y.: "Semaphorin 3A1 regulates angioblast migration and vascular development in zebrafish."Development.. 130. 3227-3236 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Salingcarnboriboon R, Yoshitake H, Tsuji K, Obinata M, Amagasa T, Nifuji A, Noda M: "Establishment of tendon-derived cell lines exhibiting pluripotent mesenchymal stem cell-like property."Exp Cell Res.. 287. 289-300 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tomi, M, Funaki, T, Abukawa H, Katayama, K, Kondo T, Ohtsuki S, Ueda M, Obinata M, Terasaki T, Hosaya K-I: "Expression and Regulation of L-Cystine Transporter, System Xc-, in the Newly Developed Rat Retinal Muller Cell Line (TR-MUL)."GLIA.. 43. 208-217 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Asashima T., Iizuka H., Terasaki T., K-I Hosoya, Tetsuka, K., Ueda, M., Obinata, M., Nakashima, E.: "Newly developed rat brain pericyte cell lines, TR-PCT1, responds to transforming growth factor-beta1 and beta-glycerophosphate"Eur. J. Cell Biol.. 81. 145-152 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takeuchi K, Sakurada K, Endou H, Obinata M, Quinlan MP.: "Differential effects of DNA tumor virus genes on the expression profiles, differentiation, and morphogenetic reprogramming potential of epithelial cells"Virology. 300. 8-19 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Okubo T, Yanai N, Ikawa S, Obinata M.: "Reversible switching of expression of c-kit and Pax-5 in immature hemato poietic progenitor cells by stromal cells"Exp Hematol.. 30. 1193-1201 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Araki Y, Suzuki K, Matusik RJ, Obinata M, Orgebin-Crist MC.: "Immortalized Epididymal Cell Lines From Transgenic Mice Overexpressing Temperature-Sensitive Simian Virus 40 Large T-Antigen Gene"J Androl. 23. 854-869 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sugiyama N, Obinata M, Matsui Y.: "Bcl-2 inhibits apoptosis of spermatogonia and growth of spermatogonial stem cells in a cell-intrinsic manner"Mol Reprod Dev.. 58. 30-38 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Toaka E, Satomura K, Hayashi E, Yamanouchi K, Tobiume S, Kume K, Obinata M, Nagayama M: "Establishment and characterization of chondrocyte ceil lines from the costal cartilage of SV4O large T antigen transgenic mice"J Cell Biochem.. 81. 571-582 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoshimizu, T., Obinata, M., Matsui, Y.: "Stage specific tissue and cell interaction play key roles for mouse germ cell specification"Development. 1287. 481-490 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sato, K.A., Yanai, N., Okubo, T., Mori, K.J.Obinata, M.: "Stromal cells provide signals different from cytokines for STAT5 activation in hematopoietic cells"Cell Struct. Funct.. 26. 95-101 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yanai, N., Obinata, M.: "Oncostatin M regulates mesenchymal cell differentiation and enhances hematopoletic supportive activity of bone marrow stromal cell lines"In Vitro Cellular & Developmental Biology. 37. 698-704 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Obinata, M.: "Possible applications of conditionally mmortalized tissue cell lines with differentiation functions, (Mini review for the Breakthroughs and Views)"Biochem Biopys Res Commun. 286. 667-672 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okubo,T.,Yanai,N.,Watanabe,S.,Arai K-I,and Obinata,M.: "Effect of Human Granulocyte-macrophage Colony Stimulating Factor (hGM-CSF) on Lyrhphoid and Myeloid Differentiation of Sorted Hematopoietic Stem Cells from hGM-CSF Receptor Gene Transgenic Mice."J.Biochem. 127. 591-596 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okubo,T.,Yanai,N.and Obinata,M.: "Self-renewal and differentiation of a novel bipotent myeloid progenitor cells in the stroma-dependent culture."Exp.Hematol. 28. 651-659 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yanai,N.,Matsui,N.,furusawa,T.,Okubo,T.,and Obinata,M.: "Sphingosine-1-phosphate and lysophosphatidic acid trigger invasion of primitive hematopoietic cells into stromal cell layers."Blood. 96. 139-144 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Furusawa,T.,Ikawa,S.,Yanai,N.and Obinata,M.: "Isolation of a novel PDZ-containing myosin from hematopoietic supportive bone marrow stromal cell lines."Biophys Biochem Res.Commn. 270. 67-75 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Inoue T,Shoji W.and Obinata,M.: "An Id-associating protein, MIDA1, is a sequence specific DNA binding protein with novel DNA binding properties."Genes to Cells. (in press). (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yoshimizu,T.,Obinata,M.,and Matsui,Y.: "Stage-specific tissue and cell interaction play key roles for mouse germ cell specification."Development. (in press). (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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