Extracellular vesicles derived from myocardial infarction plasma inhibit BMSCs apoptosis and enhance cardiac function via AKT signaling pathway

This study aimed to investigate whether extracellular vesicles (EVs) secreted in myocardial infarction (MI) plasma could protect against apoptosis of bone marrow mesenchymal stem cells (BMSCs) following hypoxia or serum deprivation in vitro and improve cardiac function following MI in vivo. The plasma samples were taken from female rats 24 h after MI. EVs were obtained and co-cultured with BMSCs. We found that EVs could be taken up by BMSCs. Co-culturing with EVs attenuated hypoxia-induced apoptosis of BMSCs in EVs in a dose- dependent manner, which was reversed by the pharmacological inhibition of AKT signaling. Co-culturing with EVs improved transplantation efficiency and blunted MI-induced apoptosis of BMSCs in vivo. Furthermore, transplantation of BMSCs together with EVs can effectively promote the increase in capillary density both at the border and central zone of myocardium and ameliorate myocardial remodeling in MI rats. BMSCs and EVs transplantation treatment exhibited significant improvements in ejection fraction, fraction shortening, left ventricular end-diastolic dimensions, and left ventricular end-systolic dimensions, as evaluated by echocardi- ography four weeks after MI in rats. Finally, levels of differentiation- and apoptosis-related microRNAs expression in EVs that may mediate these effects were also identified by microarray and quantitative real-time PCR. In conclusion, the present results suggest a potential role of plasma-derived EVs in decreasing apoptosis of BMSCs by activating AKT signaling, promoting angiogenesis, ameliorating myocardial remodeling, and improving cardiac function in MI rats. EV application may be a novel option to ameliorate the therapeutic ef- ficiency of BMSCs to improve cardiac function following MI.