Exosomal miR-25-3p from mesenchymal stem cells alleviates myocardial infarction by targeting pro-apoptotic proteins and EZH2

Abstract

Mesenchymal stem cell (MSC) therapy is a promising approach against myocardial infarction (MI). Studies have demonstrated that MSCs can communicate with other cells by secreting exosomes. In the present study, we aimed to identify exosomal microRNAs that might contribute to MSC-mediated cardioprotective effects. Primary cardiomyocytes were deprived of oxygen and glucose to mimic MI in vitro. For the animal model of MI, the left anterior descending artery was ligated for 1 h, followed by reperfusion for 12 h. MSC-derived exosomes were used to treat primary cardiomyocytes or mice. Cardioprotection-related microRNAs were determined, followed by target gene identification and functional studies with quantitative PCR, western blotting, MTT assay, flow cytometry assay, chromatin immunoprecipitation and dual-luciferase assay. We found that MSC co-culture reduced OGD-induced cardiomyocyte apoptosis and inflammatory responses. Cardioprotection was also observed upon treatment with MSC-derived exosomes in vitro and in vivo. In line with this, exosome uptake led to a significant increase in miR-25-3p in cardiomyocytes. Depletion of miR-25-3p in MSCs abolished the protective effects of exosomes. Mechanistically, miR-25-3p directly targeted the pro-apoptotic genes FASL and PTEN and reduced their protein levels. Moreover, miR-25-3p decreased the levels of EZH2 and H3K27me3, leading to derepression of the cardioprotective gene eNOS as well as the anti-inflammatory gene SOCS3. Inhibition of EZH2 or overexpression of miR-25-3p in cardiomyocytes was sufficient to confer cardioprotective effects in vitro and in vivo. We concluded that exosomal miR-25-3p from MSCs alleviated MI by targeting pro-apoptotic proteins and EZH2.

The Role of Exosomes and Exosomal MicroRNA in Cardiovascular Disease

“…Similarly, Li Y. et al (2019) demonstrated that exosomal miR-301 derived from bone marrow MSCs (BMSCs) reduces the area of myocardial infarction and improves autophagy of myocardial cells. Further, Peng et al (2020) showed that miR-25-3p secreted by MSCs reduces myocardial infarction area by targeting EZH2; Wen et al (2020) showed that exosomal miR-144 derived from MSCs targets the regulation of the PTEN/AKT pathway, thus improving the apoptosis of cardiomyocytes under hypoxia. Geng et al (2020) showed that miR-143, which is derived from serum exosomes, promotes myocardial angiogenesis through the IGF-IR/NO pathway.…”

Therapeutic Features and Updated Clinical Trials of Mesenchymal Stem Cell (MSC)-Derived Exosomes

“…In rat myocardial infarction model, Wang et al showed that the cardioprotective effect of MSC exosomes was mediated by miR-21 enhanced cell survival via the PTEN/Akt pathway [93]. A recent study reported that MSC exosomes containing miR-25-3p had cardioprotective effects by decreasing EZH2, H2K27me3, and SOCS3 expression, alleviating myocardial infarction by targeting pro-apoptotic proteins and inflammatory genes [94]. According to the finding that MSCderived exosomes promote angiogenesis remodeling and functional recovery after stroke, a recent clinical study form Isfahan University of Medical Sciences is exploring the use of miR-124-loaded MSC-derived exosomes to improve angiogenesis in patients with acute stroke (NCT03384433).…”

The pivotal roles of exosomes derived from endogenous immune cells and exogenous stem cells in myocardial repair after acute myocardial infarction

“…Many studies have found that BMMSC-derived exosomes (BMMSC-Exos) can regulate the local inflammatory cytokines in infarcted myocardium. The injection of BMMSC-Exos could greatly repress inflammatory cytokines including IL1B, IL6 and TNFA which were induced by AMI, as well as targeting pro-apoptotic proteins like FASL and PTEN to alleviate MI mainly through miR-25 71 . Further studies confirmed that BMMSC-Exos could promote the polarization of M1 macrophages to the M2 macrophages both in vivo and in vitro , thereby alleviating inflammation response.…”