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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.

SUBMITTER: Peng Y

PROVIDER: S-EPMC7200668 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Peng Yi Y Zhao Ji-Ling JL Peng Zhi-Yong ZY Xu Wei-Fang WF Yu Guo-Long GL

Cell death & disease 20200505 5

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 reperfus ...[more]

PMID: 32371945

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Project description:Infiltration by dendritic cells (DCs) is markedly increased in the infarcted area following myocardial infarction (MI), and DC ablation has been shown to impair angiogenesis in mice post?MI. Exosomes (EXs) have long been known to act as messengers between cells; however, whether EXs derived from DCs can enhance myocardial angiogenesis post?MI remains unknown. The aim of the present study was to elucidate whether EXs derived from DCs induce myocardial angiogenesis via paracrine signaling post?MI. In vitro, suspensions of mouse bone marrow?derived DCs (BMDCs) were incubated with the supernatant of necrotic or normal cultured HL?1 myocardial cells (as the MI or control group, respectively) for 24 h. EXs isolated from the supernatant of BMDCs were termed DEXs, which were added to primary cultures of rat cardiac microvascular endothelial cells (CMECs), and angiogenesis was evaluated by measuring tube formation and vascular endothelial growth factor (VEGF) expression. In vivo, different groups of DEXs were injected into the infarcted myocardium of MI model mice. Then, angiogenesis was evaluated by measuring the number of vessels and the expression of VEGF and CD31 in the infarcted myocardium using immunohistochemistry. Moreover, the expression profile of microRNAs (miRNAs or miRs) in splenic DCs of MI model mice was analyzed by Affymetrix miRNA 4.0 chip assays, then certified in DEXs by reverse transcription?quantitative PCR analysis. Finally, miRNA?loaded DEXs were used to induce tube formation by CMECs and angiogenesis in MI model mice. It was observed that, compared with the control group, DEXs from the MI group significantly upregulated the expression of VEGF in CMECs, enhanced tube formation by CMECs, and upregulated the expression of VEGF and CD31 in the infarcted myocardium of MI model mice. miR?494?3p and miR?16a?5p, which are associated with angiogenesis, were significantly upregulated in splenic DCs of MI model mice by Affymetrix miRNA 4.0 chip assays, miR?494?3p was significantly upregulated and highly enriched in DEXs from the MI group compared with the control, and DEX?miR?494?3p enhanced tube formation by CMECs and angiogenesis in mice post?MI. These results suggest that miR?494?3p may be secreted from DCs via EXs and promotes angiogenesis post?MI. These findings indicate a novel DEX?based approach to the treatment of MI.

Dataset Information

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

Publications

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

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