巨噬细胞极化
间充质干细胞
医学
微泡
M2巨噬细胞
基因敲除
心功能曲线
阿托伐他汀
心肌梗塞
炎症
细胞生物学
川地68
祖细胞
巨噬细胞
小RNA
免疫学
癌症研究
干细胞
微泡
体外
内科学
病理
细胞凋亡
生物
心力衰竭
生物化学
免疫组织化学
基因
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,Hai-Yan Qian,Chen Jin,Yue-Jin Yang
出处
期刊:BMC Medicine
[Springer Nature]
日期:2023-03-16
卷期号:21 (1)
被引量:12
标识
DOI:10.1186/s12916-023-02778-x
摘要
Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-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 MSCATV-EV.MSCATV-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 MSCATV-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.MSCATV-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, MSCATV-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05-0.0001). In vitro, MSCATV-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05-0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSCATV-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSCATV-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy.We uncovered a novel mechanism that MSCATV-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.
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