Enhanced Cardioprotection by Human Endometrium Mesenchymal StemCells Driven by Exosomal MicroRNA-21.
Wang K, Jiang Z, Webster KA, Chen J, Hu H, Zhou Y, Zhao J, Wang L, Wang Y, Zhong Z, Ni C, Li Q, Xiang C, Zhang L, Wu R, Zhu W, Yu H, Hu X, Wang J.
Our group recently reported positive therapeutic benefit ofhumanendometrium-derivedmesenchymalstemcells(EnMSCs) delivered to infarcted rat myocardium, an effect that correlated withenhancedsecretion of protective cytokines and growth factors compared with parallel cultures ofhumanbone 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 fromendometrium, 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 andhumanumbilical vein endothelialcells. A rat MI model was used to compare cell therapy by intramyocardial injection of BMMSCs, AdMSCs, and EnMSCs. We found that EnMSCs conferred superiorcardioprotectionrelative to BMMSCs or AdMSCs and supportedenhancedmicrovessel density. Inhibitor studies indicated that theenhancedparacrine actions of EnMSCs were mediated by secreted exosomes. Analyses ofexosomalmicroRNAs (miRs) by miR array and quantitative polymerase chain reaction revealed that miR-21 expression was selectivelyenhancedin 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 superiorcardioprotectionby 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. Theendometriummight be a preferential source of MSCs for cardiovascular cell therapy.StemCellsTranslational Medicine 2017;6:209-222.