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MSC‐Derived Exosomes Deliver Cardioprotective miR‐21

Mesenchymal stem cell (MSC) transplantation has been shown to improve outcomes after myocardial infarction (MI) in animal models and in man. Specifically, reduction of infarct size (cardioprotection), increased LV muscle, improved function, and preserved ejection fraction have variously been reported. However, the mechanism of beneficial effect is not well understood. While some data supports transdifferentiation of MSC into myocardial constituent cells, other results support direct cardioprotection against ischemia/reperfusion injury (IRI). Overall, there is a growing consensus that the MSC and their derivatives do not contribute in proportion to the extent of the reparative effects, supporting the concept of paracrine effects of MSC. If paracrine factors can be identified, they might be employed therapeutically and contribute to identification of new therapeutic targets. Several recent results, including ours, support that exosomes, and their microRNA (miR) cargo, underlie at least some of these paracrine effects. Our objective was to test the hypothesis that MSC‐derived exosomes from non‐treated MSC can mediate cardioprotection via specific miR cargo. To test this hypothesis, we identified by next generation RNA sequencing, the miRs present in exosomes isolated from murine MSC. We identified both protective and injurious miRs, and focused upon miR‐21, the most highly expressed miR in MSC derived exosomes. We also identified miRs associated with apoptotic signaling, cell proliferation, angiogenesis, and heat shock response. We report in vitro data that the exosomes and miR‐21 are protective in a dose‐dependent manner against sim I/R. We next showed in vivo that exosomes were cardioprotective, reducing infarct size (normalized for risk region) by 68%, (P≤0.01 vs. control) and that exosomes isolated from MSC having miR‐21 deleted reduced infarct size by only 28% (P=0.039 vs. control), demonstrating a major role for miR‐21. In vivo, the exosomes increased miR‐21 levels in myocardium, resulting in significant depression of four target protein levels, PDCD4, Peli1, FasL, and PTEN. These results support that suppression of cell death is by coordinated reduction of several parallel cell death pathways, and derepression of pro‐survival Akt. In conclusion, our data supports that the cardioprotective aspects of MSC are explained, at least in part, by secretion of exosomes and the action of the miR‐21 cargo. Whether other aspects of MSC action are regulated by other of the miR cargo is under study.