Abstract 16827: miR-34a Expression in Cardiac Neonatal Mesenchymal Stem Cells is Essential for Heart Regeneration

Abstract

Advancing chronological age negatively impacts the functional activity of stem cell-based therapies. Despite the early promise stem cell mediated differentiation into selected cellular lineages when injected in the chosen organ, stem cell’s functional unit is the secretome that is directly modulated by chronological aging. However, the precise mechanism driving the secretome potency is unknown. Here we show a single miRNA, influenced by aging, drives the potency of the stem cell secretome at multiple cellular levels by increasing exosome production and directly increasing the levels of independent stem cell paracrine factors. We show differential miRNA microarray analysis of cardiac neonatal mesenchymal stem cells (nMSCs) and adult MSCs (aMSCs) identified miR34a among the top ten differentially expressed miRNAs present in aMSCs but not nMSCs. We demonstrated that miR34a singly inhibits the aMSC’s regenerative abilities in the acute myocardial infarct model by decreasing the secretome potency when compared to nMSCs in knockdown studies of miR-34a. Moreover, overexpression of miR-34a in nMSCs reversed the strong regenerative properties of nMSCs by decreasing their secretome potency. Mechanistically, miR-34a regulates the secretome potency firstly by decreasing Heat Shock Factor 1 (HSF1) levels that directly decreases exosome production and alters the exosome cargo to a less-regenerative phenotype, and secondly by directly inhibiting transcriptional levels of critical stem cell paracrine factors. These results implicate the miR34a-HIF1 pathway as a critical pathway controlling the secretome of MSCs impacted by advancing chronological age. Our findings further advance miRNA-based therapeutic approaches to cardiac repair and heart regeneration by indicating how to improve the quality of secretome of transplanted stem cells.