Stem cell-based delivery of Hypoxamir-210 to the infarcted heart: Implications on stem cell survival and preservation of infarcted heart function

This study seeks to test our hypothesis that transgenic induction of miR-210 in mesenchymal stem cells (MSC) simulates the pro-survival effects of ischemic preconditioning (IPC) and that engraftment of ^PCMSC helps in the functional recovery of ischemic heart by miR-210 transfer to host cardiomyocytes through gap junctions. miR-210 expression in MSC was achieved by IPC or nanoparticlebased transfection of miR-210 plasmid (^miRMSC) and functional recovery of the infarcted heart of rat transplanted with ^PCMSC or ^miRMSC was evaluated. Both ^PCMSC and ^miRMSC showed higher survival under lethal anoxia as compared to ^non-PCMSC and scramble-transfected MSC (^ScMSC) controls with concomitantly lower CASP8AP2 expression. Similarly, both ^PCMSC and ^miRMSC survived better and accelerated functional recovery of ischemic heart post-transplantation. To validate our hypothesis that MSC deliver miR-210 to host cardiomyocytes, in vitro co-culture between cardiomyocytes and ^PCMSC or ^miRMSC (using ^non-PCMSC or ^ScMSC as controls) showed co-localization of miR-210 with gap-junctional connexin-43. miR-210 transfer to cardiomyocytes was blocked by heptanol pretreatment. Moreover, higher survival of cardiomyocytes co-cultured with ^PCMSC was observed with concomitant expression of CASP8AP2 as compared to cardiomyocytes co-cultured with ^non-PCMSC thus suggesting that miR-210 was translocated from MSC to protect host cardiomyocytes. Induction of miR-210 in MSC promoted their survival postengraftment in the infarcted heart. Moreover, direct transfer of pro-survival miR-210 from ^miRMSC to host cardiomyocytes led to functional recovery of the ischemic heart.