Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA-21

Abstract

Our group recently reported positive therapeutic benefit of human endometrium‐derived mesenchymal stem cells (EnMSCs) delivered to infarcted rat myocardium, an effect that correlated with enhanced secretion of protective cytokines and growth factors compared with parallel cultures of human bone marrow MSCs (BMMSCs). To define more precisely the molecular mechanisms of EnMSC therapy, in the present study, we assessed in parallel the paracrine and therapeutic properties of MSCs derived from endometrium, bone marrow, and adipose tissues in a rat model of myocardial infarction (MI). EnMSCs, BMMSCs, and adipose‐derived MSCs (AdMSCs) were characterized by fluorescence‐activated cell sorting (FACS). Paracrine and cytoprotective actions were assessed in vitro by coculture with neonatal cardiomyocytes and human umbilical vein endothelial cells. A rat MI model was used to compare cell therapy by intramyocardial injection of BMMSCs, AdMSCs, and EnMSCs. We found that EnMSCs conferred superior cardioprotection relative to BMMSCs or AdMSCs and supported enhanced microvessel density. Inhibitor studies indicated that the enhanced paracrine actions of EnMSCs were mediated by secreted exosomes. Analyses of exosomal microRNAs (miRs) by miR array and quantitative polymerase chain reaction revealed that miR‐21 expression was selectively enhanced in exosomes derived from EnMSCs. Selective antagonism of miR‐21 by anti‐miR treatment abolished the antiapoptotic and angiogenic effects of EnMSCs with parallel effects on phosphatase and tensin homolog (PTEN), a miR‐21 target and downstream Akt. The results of the present study confirm the superior cardioprotection by EnMSCs relative to BMMSCs or AdMSCs and implicates miR‐21 as a potential mediator of EnMSC therapy by enhancing cell survival through the PTEN/Akt pathway. The endometrium might be a preferential source of MSCs for cardiovascular cell therapy. Stem Cells Translational Medicine 2017;6:209–222

Self‐assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction

“…The latest data showed that miR-21 played a vital role in MSC-Exo-mediated effects on cardiac contractility and calcium handling, probably via PI3K signaling (38). In addition, miR-21 mediated the proangiogenic effects of exosomes on endothelial cells (37,39), and consistently we found the exosomes derived from DSAP-MSCs enhanced angiogenesis after MI via miR-21. Thus, the elevated level of miR-21 in DSAP-MSC-Exos partly accounted for the molecular mechanisms underlying It has been reported that the degree of cell attachment of SAP was relatively low due to the lack of adhesion motif.…”

“…We also found that miR-21 contributed to the improvement of cardiac function after DSAP-MSC-Exo injection in rat model of MI. miR-21 is a well-known cardioprotective microRNA, and it has been confirmed that exosomal miR-21 was a major cardioprotective paracrine factor produced by MSCs through the phosphatase and tensin homolog deleted on chromosome 10/Akt pathway (36,37). The latest data showed that miR-21 played a vital role in MSC-Exo-mediated effects on cardiac contractility and calcium handling, probably via PI3K signaling (38).…”

Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way

“…Left ventricular ejection fraction (LVEF) and fractional shortening (FS) were calculated as previously described [20] and shown in Supplemental Table S1.…”

The immunomodulatory activity of extracellular vesicles derived from endometrial mesenchymal stem cells on CD4+ T cells is partially mediated by TGFbeta

“…In vitro and in vivo studies from our laboratory have demonstrated that exosomes derived from MSCs have an immunomodulatory potential against in vitro activated T cells (Blazquez et al, ) as well as an anti‐inflammatory effect in an antigen‐induced synovitis animal model (Casado et al, ). In two recent papers from Chen, Xiang, Wang, and Xiang () and Wang et al (), it was found that the potent paracrine effect of endMSCs was mediated by secreted exosomes. In the first report, a cardioprotective effect (antiapoptotic and proangiogenic) was demonstrated through the release of miR‐21 (Wang et al, ).…”

“…In two recent papers from Chen, Xiang, Wang, and Xiang () and Wang et al (), it was found that the potent paracrine effect of endMSCs was mediated by secreted exosomes. In the first report, a cardioprotective effect (antiapoptotic and proangiogenic) was demonstrated through the release of miR‐21 (Wang et al, ). In the second report, the exosomes from endMSCs showed an antiapoptotic capacity in the setting of fulminant hepatic failure.…”