Exosomes extracted from mesenchymal stem cells (MSCs) was reported to reduce myocardial ischemia/reperfusion damage. Besides, stromal‐derived factor 1 (SDF1a) functions as cardiac repair after myocardial infarction (MI). Therefore, the present study aims to identify whether exosomes (Exo) released from SDF1‐overexpressing MSCs display a beneficial effect on ischemic myocardial infarction. Initially, a gain‐of‐function study was performed to investigate the function of SDF1 in ischemic myocardial cells and cardiac endothelial cells. Coculture experiments were performed to measure potential exosomic transfer of SDF1 from MSCs to ischemic myocardial cells and cardiac endothelial cells. During the coculture experiments, exosome secretion was disrupted by neutral sphingomyelinase inhibitor GW4869 and upregulated exosomal SDF1 using SDF1 plasmid. Effects of Exo‐SDF1 on cardiac function in MI mice were investigated in vivo. MSCs suppressed myocardial cell apoptosis and promoted microvascular regeneration of endothelial cells through secretion of exosomes. The addition of GW4869 led to increased apoptotic capacity of myocardial cells, decreased microvascular formation ability of endothelial cells, enhanced autophagy ability, and elevated Beclin‐1 level as well as ratio of LC3II/LC3I. Overexpression of SDF1 and Exo‐SDF1 inhibited apoptosis and autophagy of myocardial cells, but promoted tube formation of endothelial cells. The interference of PI3K signaling pathway promoted apoptosis and autophagy of myocardial cells, but inhibited tube formation of endothelial cells. SDF1 activated the PI3K signaling pathway. Exo‐SDF1 protected cardiac function of MI mice and inhibited myocardial tissue damage. This study provided evidence that SDF1 overexpression in MSCs‐derived exosomes inhibited autophagy of ischemic myocardial cells and promoted microvascular production of endothelial cells.

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Background/Objectives In recent years, as an alternative to stem cell therapy for cardiovascular diseases (CVD), exsomes have attracted wide attention among researchers. The present study aimed to investigate the role of human umbilical cord mesenchymal stem cells (UC‐MSCs) derived exosomes play on H9C2 cells apoptosis and possible mechanisms. Methods Exosomes were isolated from normal UC‐MSCs culture media and hypoxic preconditioning culture media. Transmission electron microscopy was used to observe the morphology of exosomes. Nanoparticle tracking analysis was used to detect the size distribution and concentration of exosomes. Western blot analysis was used to analyzed the surface marker CD63 of exosomes. H9C2 cells were induced apoptosis by hypoxia and serum deprivation (H/SD) and then were treated respectively by group. Cell Counting Kit‐8 assay was used to detect viability of H9C2 cells. Apoptosis was detected by Hochest staining and annexin V‐FITC/PI. The expression levels of related proteins of apoptosis, autophagy, and PI3K/Akt/mTOR pathway were analyzed by Western blot analysis. Immunofluorescence was used to analyze LC3B expression. Results Hypoxic preconditioning increased the exosomes secretion of UC‐MSCs. UC‐MSCs derived exosomes could inhibit H/SD‐induced H9C2 cells apoptosis. Hypoxic preconditioning strengthened this antiapoptosis effect of UC‐MSCs. Hypoxic preconditioning UC‐MSCs derived exosomes (H‐Exo) downregulated LC3B‐II/I and beclin‐1 and upregulated P62, p‐Akt/Akt and p‐mTOR/mTOR. The antiapoptotic effect of H‐Exo could be attenuated by treatment with LY294002 and rapamycin. Conclusion UC‐MSCs derived exosomes could inhibit H9C2 cells apoptosis induced by H/SD through regulating autophagy via PI3K/Akt/mTOR pathway. Hypoxia preconditioning could enhance above effects through increasing exosomes secretion of UC‐MSCs.