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Establishment of Regenerative Therapy for Patients with Left Ventricular Assist Device 〜Aiming to 'Bridge to Recovery〜

Research Project

Project/Area Number 17390379
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Thoracic surgery
Research InstitutionOSAKA UNIVERSITY

Principal Investigator

MATSUMIYA Goro  Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (20314312)

Co-Investigator(Kenkyū-buntansha) MATSUDA Hikaru  Osaka University, Professor Emeritus, 名誉教授 (00028614)
SAWA Yoshiki  Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00243220)
FUKUSHIMA Norihide  Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (30263247)
NISHIMURA Motonobu  Tottori University, Faculty of Medicine, Professor, 医学部, 教授 (90291442)
ICHIKAWA Hajime  Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 特任教授(常勤) (60303939)
舩津 俊宏  大阪大学, 医学系研究科, 助手 (80379239)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2006: ¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 2005: ¥8,100,000 (Direct Cost: ¥8,100,000)
Keywordscell sheet / heart failure / stem cell / myoblast / tissue engineering / gene therapy / 骨髄単核球細胞 / 補助人工心臓
Research Abstract

1. Sheet-shaped myoblast implantation in dilated cardioyopathic 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 preoperati … More ve 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. Myobalst sheet implantation in pacing -induced canine model
Twelve dogs were given continuous ventricular pacing at 230 beats/min for 4weeks ; then the myoblast sheets (n=5) were grafted onto the left ventricular wall or a sham operation was performed (n=7). The number of cells was adjusted to 1.5〜2.5 x 10(6) cells per graft, and each dog received approximately 20 grafts. The cell sheets were easily grafted onto a large area of the left ventricular surface, and there were no serious sequelae. Four weeks after graft implantation, echocardiography demonstrated that the left ventricular ejection fraction and fractional shortening were significantly ameliorated with reduced left ventricular dilatation and increased wall thickness. Histologic evidence indicated the grafted myoblasts had survived, accompanied by a significant reduction in fibrosis and apoptosis, and a significant increase in proliferation.
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

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (13 results)

All 2006 2005

All Journal Article (13 results)

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

    • Author(s)
      Kondoh 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
      2006 Final Research Report Summary
  • [Journal Article] Grafted skeletal myoblast sheets attenuate myocardial remodeling in pacing-induced canine heart failure model.2006

    • Author(s)
      Hata H
    • Journal Title

      J Thorac Cardiovasc Surg 132(4)

      Pages: 918-924

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Angiogenic gene cell therapy using suicide gene system regulates the effect of angiogenesis in infracted rat heart2006

    • 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
      2006 Final Research Report Summary
  • [Journal Article] Tissue cardiomyoplasty using bioengineered contractile cardiomyocyte sheets to repair damaged myocardium : their integration with recipient myocardium.2006

    • 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
      2006 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
      2006 Final Research Report Summary
  • [Journal Article] Grafted skeletal myoblast sheets attenuate myocardial remodeling in pacing-induced canine heart failure model.2006

    • Author(s)
      Hata H., Matsumiya G., Miyagawa S., Kondoh H., Kawaguchi N., Matsuura N., Shimizu T., Okano T., Matsuda H., Sawa Y.
    • Journal Title

      J Thorac Cardiovasc Surg 132 (4)

      Pages: 918-924

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 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
      2006 Final Research Report Summary
  • [Journal Article] Grafted skeletal myoblast sheets attenuate myocardial remodeling in pacing-induced canine heart failure model2006

    • Author(s)
      Hata H., Matsumiya G., Sawa Y.
    • Journal Title

      The Journal of Thoracic and Cardiovascular Surgery 1324

      Pages: 918-924

    • Related Report
      2006 Annual Research Report
  • [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)
      Kondoh H
    • Journal Title

      J Thorac Cardiovasc Surg 130(2)

      Pages: 296-302

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 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
      2006 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
      2006 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
      2006 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
      2006 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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