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TECHNOLOGY DEVELOPMENT |
1 Department of Cardiac Surgery, University Rostock, Germany
2 Miltenyi Biotec, Bergisch Gladbach, Germany
3 Institute of Polymer Research, GKSS Forschungszentrum, Germany
4 Cardiac Surgery, German Heart Institute Berlin, Germany
5 Division of Cardiovasculary Surgery, Toronto General Hospital and the University of Toronto, Canada
* To whom correspondence should be addressed. E-mail: nan.ma{at}med.uni-rostock.de.
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Abstract |
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Engraftment of mesenchymal stem cells (MSCs) derived from adult bone marrow has been proposed as a potential therapeutic approach for postinfarction left ventricular (LV) dysfunction. However, limited cell viability after transplantation into the myocardium has restricted its regenerative capacity. In this study, we genetically modified MSCs with an anti-apoptotic Bcl-2 gene and evaluated cell survival, engraftment, revascularization and functional improvement in a rat left anterior descending (LAD) ligation model via intracardiac injection.
Rat MSCs were manipulated to overexpress the Bcl-2 gene. In vitro, the anti-apoptotic 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 (PV) loops.
The Bcl-2 gene protected MSCs against apoptosis. In vitro, Bcl-2 overexpression reduced MSCs apoptosis by 32% and enhanced VEGF 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-MSCs group. Capillary density in the infarct border zone was 15% higher in Bcl-2-MSCs transplanted animals than in vector-MSCs treated animals. Furthermore, Bcl-2-MSCs transplanted animals had 17% smaller infarct size than vector-MSCs treated animals and exhibited functional recovery remarkably.
Our current findings support the premise that transplantation of anti-apoptotic gene modified MSCs may have values for mediating substantial functional recovery after acute myocardial infarction.
Key Words. gene therapy, stem cells, transplantation, angiogenesis, anti-apoptosis
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