Abstract 13178: Direct Transfer of miR-210 From Preconditioned Stem Cells to the Host Cardiomyocytes Via Gap Junctions Promote Functional Recovery of the Ischemic Myocardium
Background. Differential expression of miR-210 in preconditioned mesenchymal stem cells (PCMSCs) has critical influence on their survival via Caspase 8-associated protein 2 (Casp8ap2) activity. Here we report that transgenic induction of miR-210 in MSCs simulated the prosurvival effects of preconditioning. Moreover, engraftment of PCMSCs helped in functional recovery of the ischemic heart by miR-210 transfer to the host cardiomyocytes through gap junctions.
Methods and Results. MiR-210 expression in MSCs was achieved by ischemic preconditioning or nanoparticle based transfection of miR-210 plasmid (miRMSCs). Both PCMSCs and miRMSCs had higher survival under lethal anoxia in vitro as compared to the non-preconditioned MSCs and scramble-transfected MSCs (ScMSCs) controls, with concomitantly lower CASP8AP2 expression. Similarly, both PCMSCs and miRMSCs survived better post-transplantation and accelerated the functional recovery of ischemic heart by transferring miR-210 to host cardiomyocytes. Infarction size was significantly reduced in both PCMSCs (19.6±8.3) and miRMSCs (18.3±7.8) treated animal hearts as compared to their respective controls (p<0.05 vs controls). To validate our hypothesis that MSCs directly delivered miR-210 to the host cardiomyocytes post transplantation, in vitro co-culture between cardiomyocytes and PCMSCs or Non-PCMSCs showed co-localization of miR-210 with gap junctional protein connexin-43. MiR-210 transfer to cardiomyocytes was blocked by heptanol treatment. Moreover, increased survival of cardiomyocytes co-cultured with PCMSCs was observed with concomitant reduction in CASP8AP2 expression as compared to cardiomyocytes co-cultured with non-preconditioned MSCs thus suggesting that miR-210 translocated from MSCs protected the host cardiomyocytes.
Conclusions. Stem cell based miR-210 delivery to the infarcted heart is a novel strategy which effectively promotes donor stem cell survival and preserves left ventricle function through multiple mechanisms. Induction of prosurvival miR-210 not only addresses the issue of donor cell survival, the direct cell-to-cell transfer of the “repair” miRs from the donor cells to the host cardiomyocytes lead to protection of the ischemic heart.
- © 2011 by American Heart Association, Inc.