Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway

作者：Yu Ning, Peisen Huang, Guihao Chen, Yuyan Xiong, Zhaoting Gong, Chunxiao Wu, Junyan Xu, Wenyang Jiang, Xiaosong Li, Ruijie Tang, Lili Zhang, Mengjin Hu, Jing Xu, Jun Xu, Haiyan Qian, Jin Chen, Yuejin Yang · 发表于：BMC Medicine · 年份：2023 · DOI：10.1186/s12916-023-02778-x · 被引用次数：81 · 研究领域：Extracellular vesicles in disease、Cardiac Fibrosis and Remodeling、Tissue Engineering and Regenerative Medicine

Abstract Background Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSC ATV -EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSC ATV -EV. Methods MSC ATV -EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSC ATV -EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo. Results MSC ATV -EV significantly reduced the amount of CD68 + total macrophages and increased CD206 + M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group ( P < 0.01–0.0001). On day 28, MSC ATV -EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced ( P < 0.05–0.0001). In vitro, MSC ATV -EV also significantly reduced the protein and mRNA expressions of M1 markers ...