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発生工学を用いた心不全の病態解明と心血管再生細胞移植治療における骨髄幹細胞の役割

Research Project

Project/Area Number 12136207
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKyoto Prefectural University of Medicine (2003-2004)
Kansai Medical University (2000-2002)

Principal Investigator

松原 弘明  京都府立医科大学, 医学研究科, 教授 (10239072)

Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥72,200,000 (Direct Cost: ¥72,200,000)
Fiscal Year 2004: ¥19,100,000 (Direct Cost: ¥19,100,000)
Fiscal Year 2003: ¥19,100,000 (Direct Cost: ¥19,100,000)
Fiscal Year 2002: ¥17,000,000 (Direct Cost: ¥17,000,000)
Fiscal Year 2001: ¥17,000,000 (Direct Cost: ¥17,000,000)
Keywords血管再生 / 再生医学 / 幹細胞 / 骨髄移植 / 血管内皮 / 単球 / 血管新生 / 再生医療 / 心筋再生 / 骨髄細胞 / アンジオテンシンII / AT1受容体 / AT2受容体 / ブラジキニン / 遺伝子改変動物 / NO / プラジキニン / アンジオテンシン受容体 / 心不全
Research Abstract

【目的】骨髄単核球移植による血管新生効果が臨床的にも確立されている。内皮系幹細胞の関与が大きいが新生血管内皮に集積する細胞起源は明らかでない。骨髄由来単球系幹細胞の内皮細胞分化の可能性とバルーン傷害血管での内皮再生による内膜肥厚の抑制効果を検討する。
【方法】骨髄由来単球系幹細胞はCD14陽性細胞をソートして採取しVEGF存在下で培養し、造血系細胞マーカー、内皮系マーカー、間葉系マーカー抗体にて免疫染色行い分化誘導を検討した。ヌードラット頸動脈をバルーン傷害して内膜肥厚モデルを作製し、直後にPKH2-GL蛍光染色したヒト骨髄由来CD14陽性細胞を動脈内に投与した。
【結果および考察】VEGF存在下で培養された骨髄由来CD14陽性細胞はVEGF存在下で造血系細胞マーカー(CD14,CD45,CD11b)を失い、内皮系マーカー(Tie2,CD34,Flk)出現が観察された。間葉系マーカーは陰性であった。バルーン傷害後に移植された骨髄CD14陽性細胞は傷害部位にMCP-1依存性に接着し、内膜肥厚を完全に抑制した。末梢血由来CD14陽性細胞では接着は観察されなかった。接着した骨髄CD14陽性細胞は造血系細胞マーカー(CD14,CD45,CD11b)を失い、内皮系マーカー(vWF, eNOS)を発現していた。再生内皮はエバンスブルーの侵出が抑制され、アセチルコリン依存性の拡張を示した。HUVECを用いたflow assayではMCP-1で刺激された骨髄CD14陽性細胞が明らかに高い接着能を示した。骨髄由来CD14陽性単球系幹細胞はbeta-integrin定常発現量が末梢血由来CDl4陽性単球系細胞より著明に元進していた。MCP-1により活性化beta-integrinが増加していた。CCR2発現は差がなかった。
【結論】骨髄由来単球系幹細胞は内皮前駆細胞への分化能を持ち、MCP-1依存性にバルーン傷害内膜に強固に接着した。内皮再生により内膜肥厚は抑制され再狭窄も阻止された。PTCA後の内皮再生を目的とした細胞治療に応用可能と考えられた。

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

(25 results)

All 2005 2004 Other

All Journal Article (6 results) Book (1 results) Publications (18 results)

  • [Journal Article] Carbon Dioxide-Rich Water Bathing Enhances Collateral Blood Flow In Ischemic Hindlimb via Mobilization of Endothelial Progenitor Cells and Activation of NO-cGMP System2005

    • Author(s)
      Irie, Hidekazu
    • Journal Title

      Circulation 111・12

      Pages: 1523-1529

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts2004

    • Author(s)
      Tatsumi, Tetsuya
    • Journal Title

      Journal of Molecular and Cellular Cardiology 37・3

      Pages: 775-778

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Aldosterone directly induces myocyte apoptosis through calcineurin-dependent pathways2004

    • Author(s)
      Mano, Akiko
    • Journal Title

      Circulation 110・3

      Pages: 317-323

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Ampulla('Takotsuo')CardiomyoPathy of Both Ventricles 口 Evaluation of Microcirculation Disturbance Using 99mTc-Tetrofosmin Myocardial Single Photon Emission Computed Tomography and Doppler Guide Wire-2004

    • Author(s)
      Nishikawa, Susumu
    • Journal Title

      Circulation Journal 68・11

      Pages: 1076-1080

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mechanism for IL-1β-mediated neovascularization unmasked by IL-1βknock-out mice2004

    • Author(s)
      Amano, Katsuya
    • Journal Title

      Journal of Molecular and Cellular Cardiology 36・4

      Pages: 469-480

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Very low frequency power of heart rate variability is a powerful predictor ofclinical prognosis in patients with congestive heart failure2004

    • Author(s)
      Hadase, Mitsuyoshi
    • Journal Title

      Circulation Journal 68・4

      Pages: 343-347

    • Related Report
      2004 Annual Research Report
  • [Book] 血管再生医療の実施と展望-骨髄系体細胞移植を用いた末梢性血管疾患・狭心症への血管新生医療-2004

    • Author(s)
      松原 弘明
    • Publisher
      メジカルビュー社(日本老年医学会雑誌編集委員会編)
    • Related Report
      2004 Annual Research Report
  • [Publications] Fujiyama S, Amano K, Matsubara H.他6人: "Bone Marrow Monocyte-Lineage Cells Adhere on Injured Endothelium by MCP-1-Dependent Manner and Accelerate Reendothelialization as Endothelial Progogenitor Cells"Circ Res. 93. 980-989 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Amano K, Matsubara H, 他5人: "Enhancement of Ischemia-Induced Angiogenesis by eNOS overexpression."Hypertension. 41. 156-162 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tateishi-Yuyama E, Matsubara H, 他7名: "Therapeutic angiogenesis for patients with limb ischemia by autologous transplantation of bone marrow cells : a pilot study and a randomised controlled trial"Lancet. 360. 427-435 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iba O, Matsubara H, 他5名: "Angiogenesis by implantation of peripheral blood mononuclear cells and platelets into ischemic limbs."Circulation. 106. 2019-2025 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kamihata H, Matsubara H, 他6名: "Improvement of Collateral Perfusion and Regional function by Catheter-Based Implantation of Peripheral blood Mononuclear Cells into Ischemic Hibernating Myocardium"Arterioscler Thromb Vasc Biol. 22. 1804-1810 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yang Z, Matsubara H, 他7名: "Angiotensin II type 2 receptor overexpression preserves left ventricular function after myocardial infarction."Circulation. 106. 106-111 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Amano K, Matsubara H, 他7人: "Enhance ment of ishemia-induced angiogenesis by eNOS expression"Hypertension. 41:2. 156-162 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kurisu S, Matsubara H, 他8人: "Carciac angiotensin II type 2 receptor activates the kinin/NO system"Hypertension. 41:2. 99-107 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tateishi-yuyama E, Matsubara H, 他6人: "Therapeutic angiogenesis for patients with limb ischemia by antologous transplatation of bone marrow cells"Lancet. 360:18. 427-435 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iba O, Matsubara H, 他7人: "Angiogeneis by implantation of peripheral blood mononuclear cells and platelets into ischenic limbs"Circulation. 106:81. 2019-2025 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kamihata H, Matsubara H, 他6人: "Improvement of collateral perfusion and regional function by catheter-based implantation of peripheral blood cells"Arterioscler Thromb Vasc Biol. 22. 1804-1810 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kamihata H, Matsubara H 他7人: "Implantation of autologous bone marrow cells into ischemic myocardium enhances collateral perfusion and regional function"Circulation. 104・3. 1046-1052 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shibasaki Y, Matsubara H: "Angiotensin type2 receptor inhibits EGF receptor transactivation by increasing association of SHP1 tyrosine phosphatare"Hypertension. 38・3. 367-372 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fujiyama S, Matsubara H: "Angiotensin AT1 and AT2 receptors differentially regulate angiopoietin 2 expression and VEGF expression"Circ Res. 88:2. 22-29 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fujiyama S,Matsubara H. 他8名: "Angiotensin AT1 and AT2 Receptors Differentially Regulate Angiopoietin 2 Expression an VEGD Expression and Angiogenesis by Modulating Heparin Binding EGF-Mediated EGF Receptor Transactivation."Circ Res. 88(1). 22-29 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Fujiyama S,Matsubara H 他11名: "Angiotensin II initiates tyrosine kinase Pyk2-dependent signalings leading to activation of Racl-mediated c-Jun NH2-terminal kinase."J Biol Chem. 275(35). 26856-26863 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 松原弘明,長谷川隆正 他2名: "治療学 特集:高血圧レニン・アンジオテンシン系研究の現況"ライフサイエンス出版. 385-389 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 松原弘明,立石恵里子 他2名: "分子心血管病連載講座-アンジオテンシンの新たな展開-第5回心不全におけるARBとACE阻害薬,また,その併用療法の可能性〜臨床編〜"先端医学社. 553-558 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2001-03-31   Modified: 2018-03-28  

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