VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart

Aims The objective of this study was to investigate whether vascular endothelial growth factor (VEGF) secreted by mesenchymal stem cells (MSC) improves myocardial survival and the engraftment of implanted MSC in infarcted hearts and promotes recruitment of stem cells through paracrine release of myocardial stromal cell-derived factor-1 alpha (SDF-1 alpha). Methods and results VEGF-expressing MSC ((MSC)-M-VEGF)-conditioned medium enhanced SDF-1 alpha expression in heart slices and H9C2 cardio-myoblast cells via VEGF and the vascular endothelial growth factor receptor (VEGFR). The (MSC)-M-VEGF-conditioned medium markedly promoted cardiac stem cell (CSC) migration at least in part via the SDF-1 alpha/CXCR4 pathway and involved binding to VEGFR-1 and VEGFR-3. In vivo, (MSC)-M-VEGF-stimulated SDF-1 alpha expression in infarcted hearts resulted in massive mobilization and homing of bone marrow stem cells and CSC. Moreover, VEGF-induced SDF-1 alpha guided the exogenously introduced CSC in the atrioventricular groove to migrate to the infarcted area, leading to a reduction in infarct size. Functional studies showed that (MSC)-M-VEGF transplantation stimulated extensive angiomyogenesis in infarcted hearts as indicated by the expression of cardiac troponin T, CD31, and von Willebrand factor and improved the left ventricular performance, whereas blockade of SDF-1 alpha or its receptor by RNAi or antagonist significantly diminished the beneficial effects of (MSC)-M-VEGF. Conclusion Exogenously expressed VEGF promotes myocardial repair at least in part through SDF-1 alpha/CXCR4-mediated recruitment of CSC.