Novel critical insights into the mechanism of cell-based therapy after myocardial infarction

Cell transplantation therapy is considered a novel and promising strategy in regenerative medicine. Recent studies point out that paracrine effects and inflammation induced by transplanted cells are key factors for the improvement of myocardial function. The present study aims at differentiating paracrine effects from inflammatory reactions after cell transplantation. Therefore, in vitro induced apoptotic bodies were transplanted after myocardial infarction in a rat model. Eight weeks after transplantation, the functional results showed no improvement in left ventricular function. Histological analysis revealed no significant differences in the amount of infiltrated cells and collagen content did not differ among the four groups, which sustains the functional data. Surprisingly, angiogenesis increased in groups with apoptotic bodies derived from HUVEC and endothelial progenitor cells, but not from fibroblasts. A complex genetic analysis of apoptotic bodies indicated that miRNAs could be responsible for these changes. In conclusion, our study demonstrates both that neoangiogenesis alone is not sufficient to improve function and that inflammation is critical for scar remodeling and improvement of the heart function after cell therapy. Given what we have learned about microRNAs, we hypthesized that the molecular mechanisms of angiogenesis induction could involve apoptotic bodies exerting paracrine angiogenic effects. Using GeneChip miRNA 3.0 Array, microRNAs were analysed in apoptotic bodies from endothelial progenitor cells (EPCs), human umbilical veno-endothelial cells (HUVECs), and fibroblasts. From human EPCs, human dermal fibroblasts, and HUVECs, apoptotic bodies were isolated after treatment with cycloheximide in hypoxia for 24 hours.