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TRANSLATIONAL AND CLINICAL RESEARCH: MESENCHYMAL STEM CELLS SERIES

Bcl-2 Engineered MSCs Inhibited Apoptosis and Improved Heart Function

^aDepartment of Cardiac Surgery, University of Rostock, Rostock, Germany;
^bMiltenyi Biotec, Bergisch Gladbach, Germany;
^cInstitute of Polymer Research, GKSS Forschungszentrum, Teltow, Germany;
^dCardiac Surgery, German Heart Institute Berlin, Berlin, Germany;
^eDivisions of Cardiovascular Surgery and Cardiology, Toronto General Hospital and the University of Toronto, Toronto, Ontario, Canada

Key Words. Gene therapy • Stem cells • Transplantation • Angiogenesis • Antiapoptosis

Correspondence: Nan Ma, M.D., Ph.D., Department of Cardiac Surgery, University Rostock, Schillingallee 69, 18057 Rostock, Germany. Telephone: +49-381-494 6105; Fax: +49-381-494 6214; e-mail: nan.ma{at}med.uni-rostock.de

Received November 24, 2006; accepted for publication April 20, 2007.
First published online in STEM CELLS EXPRESS   May 3, 2007.



Engraftment of mesenchymal stem cells (MSCs) derived from adult bone marrow has been proposed as a potential therapeutic approach for postinfarction left ventricular dysfunction. However, limited cell viability after transplantation into the myocardium has restricted its regenerative capacity. In this study, we genetically modified MSCs with an antiapoptotic Bcl-2 gene and evaluated cell survival, engraftment, revascularization, and functional improvement in a rat left anterior descending ligation model via intracardiac injection. Rat MSCs were manipulated to overexpress the Bcl-2 gene. In vitro, the antiapoptotic and paracrine effects were assessed under hypoxic conditions. In vivo, the Bcl-2 gene-modified MSCs (Bcl-2-MSCs) were injected after myocardial infarction. The surviving cells were tracked after transplantation. Capillary density was quantified after 3 weeks. The left ventricular function was evaluated by pressure-volume loops. The Bcl-2 gene protected MSCs against apoptosis. In vitro, Bcl-2 overexpression reduced MSC apoptosis by 32% and enhanced vascular endothelial growth factor secretion by more than 60% under hypoxic conditions. Transplantation with Bcl-2-MSCs increased 2.2-fold, 1.9-fold, and 1.2-fold of the cellular survival at 4 days, 3 weeks, and 6 weeks, respectively, compared with the vector-MSC group. Capillary density in the infarct border zone was 15% higher in Bcl-2-MSC transplanted animals than in vector-MSC treated animals. Furthermore, Bcl-2-MSC transplanted animals had 17% smaller infarct size than vector-MSC treated animals and exhibited functional recovery remarkably. Our current findings support the premise that transplantation of antiapoptotic gene-modified MSCs may have values for mediating substantial functional recovery after acute myocardial infarction.

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