Journal Article

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

Li, Xiaosong, Huang, Peisen, Yang, Yuejin, Tang, Ruijie, Chen, Guihao, Zhang, Lili, Qian, Haiyan, Xu, Jing, Jiang, Wenyang, Xu, Jun, Jin, Chen, Wu, Chunxiao, Ning, Yu, Gong, Zhaoting, Xiong, Yuyan, Hu, Mengjin, Xu, Junyan

2023

Overview

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 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 MSC ATV -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, MSC ATV -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. Conclusions We uncovered a novel mechanism that MSC ATV -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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Atorvastatin / Atorvastatin - metabolism / Atorvastatin - pharmacology / Atorvastatin - therapeutic use / Bioinformatics / Biomarkers / Biomedicine / Bone marrow / Cardiac function / Drug therapy / Effectiveness / Extracellular vesicle / Extracellular vesicles / Extracellular Vesicles - metabolism / Gene sequencing / Health aspects / Heart / Heart attack / Heart attacks / Inhibitors / Lipopolysaccharides / Macrophage polarization / Macrophages / Macrophages - metabolism / Medicine / Medicine & Public Health / Mesenchymal stem cell / Mesenchymal stem cells / Mesenchymal Stem Cells - metabolism / Methods / MicroRNA / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / miRNA / Myocardial infarction / Myocardial Infarction - genetics / Myocardial Infarction - metabolism / Myocardial Infarction - therapy / Ostomy / Polarization / Rats / Research Article / Ribonucleic acid / RNA / RNA sequencing / Stat1 protein / STAT1 Transcription Factor - metabolism / Stem cells / Vesicles