The Reverse Remodeling Effect of Mesenchymal Stem Cells is Independent from the Site of Epimyocardial Cell Transplantation

Abstract

The transplantation of mesenchymal stem cells (MSCs) represents a promising approach for treating the ischemic and the nonischemic diseased heart. The positive effects of transplanting these cells could be shown, but the exact mechanisms remain unknown. We evaluated whether the injection site affects the improvement in left ventricular (LV) ejection fraction (EF) and angiogenesis in doxorubicin (Dox)-induced failing hearts. Heart failure was induced in New Zealand white rabbits by doxorubicin treatment, followed by right ventricular MSC transplantation (RV-MSC, n = 6), LV MSC transplantation (LV-MSC, n = 6), sham treatment (sham group, n = 6), or no therapy (Dox group, n = 5). Healthy rabbits were used as control group (n = 8). Cells were isolated after bone marrow aspiration and transplanted locally into the ventricular myocardium. After 4 weeks, cardiac function and capillary density (CD31 staining) were measured. The transplantation of MSCs increased the EF significantly (LV-MSC, 39.0% ± 1.4%, and RV-MSC, 39.2% ± 2.6%, vs sham group, 29.8% ± 3.7%; P < 0.001), without significance between the MSC groups (P = 0.858). Neither the evidence of a transdifferentiation nor any signs of cell engraftment of transplanted cells could be found. The capillary density (capillaries/high-power field) increased in both MSC groups compared with the sham group (LV-MSC by 8.3% ± 3.4%; and RV-MSC, 8.1% ± 2.2%; P < 0.05), without significance between the two MSC groups (P = 0.927). Injection of autologous MSCs in doxorubicin-induced cardiomyopathic rabbit hearts improves EF and enhances angiogenesis. Despite local application, we observed global effects on heart function and capillary density without significant difference between right and LV injection. The paracrine mechanism might be one possible explanation for these findings.