Mesenchymal stem cells (MSCs) have potential application for the treatment of ischemic heart diseases. Besides differentiation properties, MSCs protect ischemic cardiomyocytes by secretion of paracrine factors. In this study, we found exosomes enriched with miR-22 were secreted by MSCs following ischemic preconditioning (ExoIPC) and mobilized to cardiomyocytes where they reduced their apoptosis due to ischemia. Interestingly, by time-lapse imaging, we for the first time captured the dynamic shedding of miR-22 loaded exosomes from cytosol to extracellular space. Furthermore, the anti-apoptotic effect of miR-22 was mediated by direct targeting of methyl CpG binding protein 2 (Mecp2). In vivo data showed that delivery of ExoIPC significantly reduced cardiac fibrosis. Our data identified a significant benefit of ExoIPC for the treatment of cardiac diseases by targeting Mecp2 via miR-22.

Cardiac progenitor cells derived from adult heart have emerged as one of the most promising stem cell types for cardiac protection and repair. Exosomes are known to mediate cell–cell communication by transporting cell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we investigated the cardiac progenitor cell (CPC)-derived exosomal miRNAs on protecting myocardium under oxidative stress. Sca1+CPCs-derived exosomes were purified from conditional medium, and identified by nanoparticle trafficking analysis (NTA), transmission electron microscopy and western blotting using CD63, CD9 and Alix as markers. Exosomes production was measured by NTA, the result showed that oxidative stress-induced CPCs secrete more exosomes compared with normal condition. Although six apoptosis-related miRNAs could be detected in two different treatment-derived exosomes, only miR-21 was significantly upregulated in oxidative stress-induced exosomes compared with normal exosomes. The same oxidative stress could cause low miR-21 and high cleaved caspase-3 expression in H9C2 cardiac cells. But the cleaved caspase-3 was significantly decreased when miR-21 was overexpressed by transfecting miR-21 mimic. Furthermore, miR-21 mimic or inhibitor transfection and luciferase activity assay confirmed that programmed cell death 4 (PDCD4) was a target gene of miR-21, and miR-21/PDCD4 axis has an important role in anti-apoptotic effect of H9C2 cell. Western blotting and Annexin V/PI results demonstrated that exosomes pre-treated H9C2 exhibited increased miR-21 whereas decreased PDCD4, and had more resistant potential to the apoptosis induced by the oxidative stress, compared with non-treated cells. These findings revealed that CPC-derived exosomal miR-21 had an inhibiting role in the apoptosis pathway through downregulating PDCD4. Restored miR-21/PDCD4 pathway using CPC-derived exosomes could protect myocardial cells against oxidative stress-related apoptosis. Therefore, exosomes could be used as a new therapeutic vehicle for ischemic cardiac disease.