Abstract 21308: Mesenchymal Stem Cells Driven by Exosomal Mir-125b Protect Myocardial Infarction via P53-Mediated Autophagy Signalling

Abstract

Background and Objectives: Bone marrow derived mesenchymal stem cells (MSCs) transplantation confers protection against adverse cardiac remodeling mainly through paracrine effects, however, it remains largely unknow whether autophagy is involved in the protection offered by MSCs therapy. In the present study, we used the mice myocardial infarction(MI)model to investigate whether and how MSCs modulates autophagy activity to protect the injured myocardium. Methods and Results: Using a well established methodology of MSCs therapy for treating myocardial infarction, we reproduced the data that MSCs can reduce myocardial apoptosis to improve cardiac function post-MI, which was closely associated with attenuated autophagy flux in cardiac tissue. To further investigate how MSCs modulate autophagic activity, we co-cultured MSCs with neonatal mice cardiomyocytes (NMCMs) to test whether NMCMs co-cultured with MSCs exhibited enhanced tolerance to hypoxia. We showed that NMCMs exposed to hypoxia had increased autophagic flux, co-culture with MSCs resulted in a decrease in autophagic flux which was associated with improved apoptosis. Interestingly, NMCMs exposed to hypoxia exhibited up-regulated levels of p53 and its downward target Bnip3 at both mRNA and protein levels. Importantly, NMCMs co-cultured with MSCs had decreased p53 and bnip3 expression levels, suggesting that MSCs protected hypoxic cardiomyocytes via modulating autophagic flux through suppressing p53/bnip3 pathways. Exosome has been considered as the major paracrine components of MSCs, therefore, we extracted the exosomes from MSCs and it displayed the similar effects with MSCs on the autophagy modulation. We found miR-125b was an important component of exosome, inhibition of miR-125b in exosome abolished the effect of autophagy modulation via p53/Bnip3 signal pathway. Conclusion: MSCs, can exert the paracrine effects via miR-125b containing exosomes to block p53/Bnip3 pathway and decrease the autophagic related cell death, thus conferring protection for the cardiomyocytes.