Bcl-2 Engineered MSCs Inhibited Apoptosis and Improved Heart Function.

Wenzhong Li; Nan Ma; Lee-Lee Ong; Nesselmann, Catharina; Klopsch, Christian; Ladilov, Yury; Furlani, Dario; Piechaczek, Christoph; Moebius, Jeannette M.; Lützow, Karola; Lendlein, Andreas; Stamm, Christof; Ren-Ke Li; Steinhoff, Gustav

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.

HEMATOPOIETIC stem cells; BONE marrow cells; STEM cell transplantation; GENE therapy; NEOVASCULARIZATION; APOPTOSIS; VASCULAR endothelial growth factors

Stem Cells, 2007, Vol 25, Issue 8, p2118

1066-5099

Academic Journal

10.1634/stemcells.2006-0771