The harsh microenvironment in infarcted heart accelerates transplanted bone marrow mesenchymal stem cells injury: the role of injured cardiomyocytes-derived exosomes

Stem cell therapy can be used to repair and regenerate damaged hearts tissue; nevertheless, the low survival rate of transplanted cells limits their therapeutic efficacy. Recently, it has been proposed that exosomes regulate multiple cellular processes by mediating cell survival and communication among cells. The following study investigates whether injured cardiomyocytes-derived exosomes (cardiac exosomes) affect the survival of transplanted bone marrow mesenchymal stem cells (BMSCs) in infarcted heart. To mimic the harsh microenvironment in infarcted heart that the cardiomyocytes or transplanted BMSCs encounter in vivo, cardiomyocytes conditioned medium and cardiac exosomes collected from H(2)O(2)-treated cardiomyocytes culture medium were cultured with BMSCs under oxidative stress in vitro. Cardiomyocytes conditioned medium and cardiac exosomes significantly accelerated the injury of BMSCs induced by H(2)O(2); increased cleaved caspase-3/caspase-3 and apoptotic percentage, and decreased the ratio of Bcl-2/Bax and cell viability in those cells. Next, we explored the role of cardiac exosomes in the survival of transplanted BMSCs in vivo by constructing a Rab27a knockout (KO) mice model by a transcription activator-like effector nuclease (TALEN) genome-editing technique; Rab27a is a family of GTPases, which has critical role in secretion of exosomes. Male mouse GFP-modified BMSCs were implanted into the viable myocardium bordering the infarction in Rab27a KO and wild-type female mice. The obtained results showed that the transplanted BMSCs survival in infarcted heart was increased in Rab27a KO mice by the higher level of Y-chromosome Sry DNA, GFP mRNA, and the GFP fluorescence signal intensity. To sum up, these findings revealed that the injured cardiomyocytes-derived exosomes accelerate transplanted BMSCs injury in infarcted heart, thus highlighting a new mechanism underlying the survival of transplanted cells after myocardial infarction.