Enhanced therapeutic effects of mesenchymal stem cells on myocardial infarction by ischemic postconditioning through paracrine mechanisms in rats

Ischemic postconditioning (IPC) is cardioprotective against ischemia–reperfusion injury which impairs the myocardial micro-environment and reduces the survival of transplanted cells. We tested the hypothesis that IPC may improve the survival of transplanted cells and enhance their therapeutic effects. In this study, bone marrow-derived mesenchymal stem cells (BMSCs) from Sprague–Dawley rats were infected with lentivirus carrying green fluorescent protein (GFP) gene. The left main coronary arteries of rats were occluded for a 30-min ischemia, followed by a 72 h or 28 d reperfusion. IPC was induced by 3 cycles of 10 s reperfusion and 10 s ischemia before sustained reperfusion. GFP–BMSCs were intramyocardially injected at 2 h reperfusion. At 70 h after transplantation, IPC treatment increased the level of interleukin-10, B-cell leukemia-lymphoma-2 (BCL-2), and vascular endothelial and basic fibroblast growth factor (VEGF and bFGF), and decreased the level of tumor necrosis factor-α, interleukin-1β and BCL-2-associated X protein by ELISA or PCR or western blotting. The BMSCs therapy with IPC produced more surviving GFP-positive cells than the BMSCs therapy alone by fluorescent staining [at 70 h, (90 ± 14)/mm2 vs. (61 ± 12)/mm2, and at 28 days, (55 ± 14)/mm2 vs. (26 ± 8)/mm2, P < 0.01, respectively]. At 28 days, it, when compared with the Control, IPC treatment, and BMSCs therapy, demonstrated higher left ventricular ejection fraction by echocardiography (62% ± 8%, 69% ± 6%, and 75% ± 4% vs. 82% ± 4%, P < 0.05, respectively), higher expression of VEGF and bFGF by western blotting and PCR, less myocardial fibrosis by Masson's trichrome staining, and higher capillary density by immunohistochemistry. These results suggest that ischemic postconditioning promotes the survival of transplanted cells and enhances their repair of infarcted myocardium through paracrine mechanisms.

► Ischemic postconditioning modifies impaired cardiac micro-environment. ► The survival of transplanted cells is enhanced by modified cardiac environment. ► Stem cell therapy with ischemic postconditioning improves cardiac outcome. ► The paracrine effects might contribute to improved cardiac outcome.