© 2005 European Society of Cardiology
Reversal of myocardial injury using genetically modulated human skeletal myoblasts in a rodent cryoinjured heart model
a Department of Cardiothoracic and Vascular Surgery National University of Singapore-117597, Singapore
b National University Medical Institutes, Clinical Research Centre 10-Medical Drive, National University of Singapore-117597, Singapore
c National Heart Centre Singapore
d Division of Cardiology, Department of Medicine National University of Singapore-119074, Singapore
e Departement of Biological Sciences, National University of Singapore Singapore
f Cell Therapy Research Foundation Memphis TN 38117-7126, USA
* Corresponding author. Department of Cardiothoracic and Vascular Surgery, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore. Tel.: +65 772 5214; fax: +65 776 6475. E-mail address: sursimkw{at}nus.edu.sg
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Abstract |
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Background: We hypothesized that combination therapy using human myoblasts and VEGF165 will lead to better prognosis in a failing heart.
Methods: Forty-eight female Wistar rats with cryoinjured hearts were randomized into non-treated normal (group-1, n=12), DMEM injected (group-2, n=10), myoblast-transplanted (group-3, n=12) and myoblast–hVEGF165 (group-4, n=14). Ten days after cryoinjury, 200 µl DMEM containing 3 x 106 cells or without cells was injected into the injured myocardium. Animals were maintained on cyclosporine for 6 weeks post cell transplantation. Heart function was assessed by echocardiography. Animals were sacrificed and hearts were processed for histochemical and immunohistochemical studies.
Results: Histological examination showed survival of the donor myoblasts expressing lac-z and hVEGF165 in rat cardiac tissue. Fluorescent immunostaining for vWillebrand Factor-VIII and smooth muscle actin expression at low power microscope (x 100) showed significantly higher blood vessel density in group-4 (31.25±1.82; 24.63±0.92) as compared to group-2 (13.29±1.0; p<0.001; 9.71±0.81, p<0.001) and group-3 (16.50±1.43, p<0.001; 14.5±1.34, p<0.001). Echocardiography showed that ejection fraction and fractional shortening of group-3 (93.36±1.52%, p=0.005; 75±3.75%, p=0.024) and group-4 (94.8±1.62%, p=0.003; 76.13±2.15%, p=0.011) significantly improved as compared to group-2 (81.8±3.3%, 55.1±7.18%).
Conclusion: Myoblasts carrying of hVEGF165 are potential therapeutic transgene carriers for cardiac repair.
Key Words: Angiogenesis • Myogenesis • Myoblast • Gene therapy • Cryoinjury
Received July 1, 2004; Revised December 29, 2004; Accepted March 2, 2005
Source of funding: Partially funded by NMRC (Singapore) Grant # R-176-000-042-213 and NUMI Cardiovascular Research Program Grant # R-364-000-021-213.
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