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Myocardial regeneration therapy using nanotechnology enhances self-regeneration in damaged myocardium

Research Project

Project/Area Number 15209046
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Thoracic surgery
Research InstitutionOsaka University

Principal Investigator

MATSUDA Hikaru  Osaka University, Professor Emeritus, 名誉教授 (00028614)

Co-Investigator(Kenkyū-buntansha) SAWA Yoshiki  Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00243220)
MIYAMOTO Yuji  Hyogo College of Medicine, Faculty of Medicine, Professor, 医学部, 教授 (80229898)
FUKUSHIMA Norihide  Osaka University, Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (30263247)
MATSUMIYA Goro  Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (20314312)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥45,890,000 (Direct Cost: ¥35,300,000、Indirect Cost: ¥10,590,000)
Fiscal Year 2005: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
Fiscal Year 2004: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
Fiscal Year 2003: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000)
Keywordscell sheet / gene therapy / heart failure / HGF / stem cell / myoblast / ティシュエンジニアリング / 拡張型心筋症 / 肝細胞増殖因子 / 構造蛋白 / 筋芽細胞シート
Research Abstract

1.Sheet-shaped myoblast implantation in dilated cardiomyopathic hamsters
Male 27-week-old BIO TO-2 (DCM) hamsters that showed moderate cardiac remodeling were used as recipients. Myoblasts isolated from BIO F1B hamsters were cultured on dishes coated with poly(N-isopropylacrylamide). Three different therapies were conducted : (1)sheet-shaped myoblast graft implantation (S group, n=29) ; (2)myoblast injection (M group, n=28) ; and (3)sham operation (C group, n=28). In the S group, two sheet-shaped myoblast grafts were implanted on the left ventricle (LV) wall, and in the M group, myoblasts were injected into the right ventricle (RV) and LV walls. After the sheet-shaped myoblast grafts were implanted, echocardiography demonstrated that the dilated LV dimension was significantly reduced, whereas the hearts in other groups showed a progression of LV dilation. The fractional shortening in the M and C groups decreased significantly while that in the S group was maintained at the preoperative … More level for 3 months after the operation. Histological examination demonstrated that in the S group, the LV wall thickness was increased, with viable myoblasts, and myocardial fibrosis was decreased compared with the other groups. Immunohistochemical staining demonstrated alpha-sarcoglycan and beta-sarcoglycan expression on the basement membrane of the cardiomyocytes in the S group but not in the other groups. The life expectancy was significantly prolonged in the S group. Sheet-shaped myoblast graft implantation improved cardiac performance and prolonged life expectancy, associated with a reduction in myocardial fibrosis and re-organization of the cytoskeletal proteins in DCM hamsters.
2.Myoblast sheet implantation in rat myocardial infarction model
Left anterior descending coronary artery-ligated Lewis rat hearts (2 weeks) received 1 x 10(7) autologous skeletal myoblasts by means of cell transplantation either through myoblast injection or implantation of 2 monolayer-constructed myoblast sheets (5 x 10(6) cells per sheet) or through medium injection. Echocardiographic results indicated higher improvement of cardiac performance in the myoblast sheet group than among the other groups until 8 weeks after cell transplantation. Histologic comparison revealed greater cellularity and abundant widespread neocapillaries within the noticeable uniform thickened wall in myoblast sheet group hearts only. Fibrosis was substantially reduced with skeletal myoblast sheet implantation compared with skeletal myoblast cell injection. Obviously higher numbers of hematopoietic stem cells (c-kit, stem cell antigen 1, and CD34) were observed in the myoblast sheet group infarct heart region. Reverse transcription-polymerase chain reaction results showed expression of stromal-derived factor 1, hepatocyte growth factor, and vascular endothelial growth factor as follows : myoblast sheets > myoblast injection > control. Myoblast sheets repaired the impaired myocardium, reduced fibrosis, and prevented remodeling in association with recruitment of hematopoietic stem cells through the release of stromal-derived factor 1 and other growth factors.
3.Suicide gene system regulates the effect of angiogenesis in infarcted rat heart
We developed human HGF (hHGF)-producing cells that regulated hHGF production using the thymidine kinase gene of Herpes Simplex Virus (TK) and the Ganciclovir (GCV) system. We tested whether these cells induced and regulated angiogenic effects in infarcted myocardium. NIH3T3 cells were stably transfected with an hHGF cDNA expression plasmid (NIH/HGF). Next, the NIH/HGF cells were stably transfected with TK (NIH/HGF/TK). The left anterior descending artery was ligated in the heart of severe combined immunodeficiency rats, and four materials were transplanted : 1)NIH/HGF (n=10), 2)NIH/HGF/TK, with orally administered GCV (n=10), 3)NIH3T3 (n=10), and 4)culture medium (n=10). In vitro, the proliferation of NIH/HGF/TK cells was suppressed by GCV. In vivo, significant increases in cardiac performance and angiogenesis were observed in the NIH/HGF and NIH/HGF/TK groups 4 weeks after transplantation. Although tumorous lesions were detected in the NIH/HGF group, their growth was completely controlled in the NIH/HGF/TK group. Angiogenic gene cell therapy using the TK-GCV suicide gene system induces and regulates angiogenesis under the control of cell growth. Less

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (21 results)

All 2006 2005 2004 Other

All Journal Article (15 results) Publications (6 results)

  • [Journal Article] Longer preservation of cardiac performance by sheet-shaped myoblast implantation in dilated cardiomyopathic hamsters.2006

    • Author(s)
      Kondo H
    • Journal Title

      Cardiovasc Res. 69(2)

      Pages: 466-475

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Angiogenic gene cell therapy using suiclde gene system regulates the effect of angiogenesis in infaroted rat heart.2006

    • Author(s)
      Miyagawa S
    • Journal Title

      Transplantation. 81(6)

      Pages: 902-907

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Longer preservation of cardiac performance by sheet-shaped myoblast implantation in dilated cardiomyopathic hamsters.2006

    • Author(s)
      Kondoh H., Sawa Y., Miyagawa S., Sakakida-Kitagawa S., Memon IA., Kawaguchi N., Matsuura N., Shimizu T., Okano T., Matsuda H.
    • Journal Title

      Cardiovasc Res. 69(2)

      Pages: 466-475

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Angiogenic gene cell therapy using suicide gene system regulates the effect of angiogenesis in infarcted rat heart.2006

    • Author(s)
      Miyagawa S, Sawa Y, Fukuda K, Hisaka Y, Taketani S, Imran Ahmed Memon, Matsuda H.
    • Journal Title

      Transplantation. 81(6)

      Pages: 902-907

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Reorganization of cytoskeletal proteins and prolonged life expectancy caused by hepatocyte growth factor in a hamster model of late-phase dilated cardiomyopathy.2005

    • Author(s)
      Kondo H
    • Journal Title

      J Thorac Cardiovasc Surg 130(2)

      Pages: 295-302

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Combined autologous cellular cardiomyoplasty with skeletal myoblasts and bone marrow cells in canine hearts for ischemic cardiomyopathy.2005

    • Author(s)
      Memon IA
    • Journal Title

      J Thorac Cardiovasc Surg 130(3)

      Pages: 646-653

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Repair of impaired myocardium by means of implantation of engineered autologous myoblast sheets.2005

    • Author(s)
      Memon IA
    • Journal Title

      J Thorac Cardiovasc Surg 130(5)

      Pages: 1333-1341

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Tissue cardiomyoplasty using bioengineered contractile cardiomyocyte sheets to repair damaged myocardium: their integration with recipient myocardium.2005

    • Author(s)
      Miyagawa S
    • Journal Title

      Transplantation. 80(11)

      Pages: 1586-1595

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Reorganization of cytoskeletal proteins and prolonged life_expectancy caused by hepatocyte growth factor in a hamster model of late-phase dilated cardiomyopathy.2005

    • Author(s)
      Kondo H., Sawa Y., Fukushima N., Matsumiya G., Miyagawa S., Kitagawa-Sakakida S., Memon IA., Kawaguchi N., Matsuura N., Matsuda H.
    • Journal Title

      J Thorac Cardiovasc Surg 130(2)

      Pages: 295-302

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Combined autologous cellular cardiomyoplasty with skeletal myoblasts and bone marrow cells in canine hearts for ischemic cardiomyopathy.2005

    • Author(s)
      Memon IA., Sawa Y., Miyagawa S., Taketani S., Matsuda H.
    • Journal Title

      J Thorac Cardiovasc Surg 130(3)

      Pages: 646-653

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Repair of impaired myocardium by means of implantation of engineered autologous myoblast sheets.2005

    • Author(s)
      Memon IA., Sawa Y., Fukushim N., Matsumiya G., Miyagawa S., Taketani S., Kitagawa-Sakakida S., Kondoh H., Aleshin AN., Shimizu T., Okano T., Matsuda H.
    • Journal Title

      J Thorac Cardiovasc Surg 130(5)

      Pages: 1333-1341

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Tissue cardiomyoplasty using bioengineered contractile cardiomyocyte sheets to repair damaged myocardium : their integration with recipient myocardium.2005

    • Author(s)
      Miyagawa S., Sawa Y., Sakakida S., Taketani S., Kondoh H., Memon IA., Imanishi Y., Shimizu T., Okano T., Matsuda H.
    • Journal Title

      Transplantation. 80(11)

      Pages: 1586-1595

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 重症虚血性心疾患に対するHGF遺伝子や細胞移植による血管新生治療法2004

    • Author(s)
      宮川 繁
    • Journal Title

      日本医工学治療 Vol.16 no.2

      Pages: 103-107

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Combined strategy using myoblasts and hepatocyte growth factor in dilated cardiomyopathic hamsters.

    • Author(s)
      Kondo H
    • Journal Title

      Ann Thorac Surg (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Combined strategy using myoblasts and hepatocyte growth factor in dilated cardiomyopathic hamsters.

    • Author(s)
      Kondo H., Sawa Y., Fukushima N., Matsumiya G., Miyagawa S., Kitagawa-Sakakida S., Imanishi Y., Kawaguchi N., Matsuura N., Matsuda H.
    • Journal Title

      Ann Thorac Surg (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Publications] Miyagawa S: "Myocardial regeneration therapy for heart failure : hepatopcyte growth factor enhances the effect of cellular cardiomyoplasty"J Cardiol. 41. 36-8 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 澤 芳樹: "麻酔科診療プラクティス"1 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 澤 芳樹: "実験医学"6 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 澤 芳樹: "医学のあゆみ"6 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 澤 芳樹: "再生医療のパイオニア"11 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 澤 芳樹: "Heart Failure Today"6 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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