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

Background and objective:Myocardial infarction (MI) leads to irreversible injury and loss of cardiomyocytes, becoming a major death cause of congestive heart failure worldwide. Mesenchymal stem cells (MSCs) therapy have great promise for myocardium regeneration and cardiac function recovery. A large number of clinical trials have proved efficacy and safety of MSCs therapy for MI. Human endometrium-derived mesenchymal stem cells (EnMSCs) were isolated from menstrual blood with MSCs characteristics and low immunogenicity. In recent years, our group reported therapeutic benefit of EnMSCs, and found more cardioprotective cytokines and growth factors were secreted from EnMSCs. To explore underlying molecular mechanism of EnMSCs therapy, we compared paracrine potentials of EnMSCs with that of bone marrow-derived mesenchymal stem cell (BMMSCs) and adipose-derived mesenchymal stem cell (AdMSCs) for further study.Method and results:In vivo part, EnMSCs, BMMSCs and AdMSCs were delivered intramyocardially into border zone of rat infarcted hearts, while the control group received same volume of Phosphate Buffered Saline (PBS). Compared with other groups, EnMSCs obviously ameliorated heart function, promoted angiogenesis, reduce myocardium loss and infarction zone. In vitro part, mesenchymal markers of EnMSCs, BMMSCs and AdMSCs were determined by FACS. Then neonatal rat cardiomyocytes (NRCMs) and human umbilical vein endothelial cells (HUVECs) were co-cultured with conditioned mediums (CMs) of 3 types of MSCs for cardiomyocytes apoptosis and HUVECs angiogenesis test. Our results indicated that EnMSC’s CM could prevent more cardiomyocytes from hypoxia injury and provoke higher capiliary density of HUVECs than others. Furrhermore, we isolated exosomes from CMs of MSCs, microRNA array were underwent and microRNA-21 were upregulated most significantly in all types of exosomes. We confirmed expression of PTEN, a predict target gene of microRNA-21, in NRCMs and HUVECs after EnMSC’s exosomes incubation. PTEN was down-regulated dramatically and stimulated downstream signaling pathway which modulated antiapoptosis and angiogenesis.Conculsion:Our study demonstrated EnMSCs possessed superior cardioprotection relative to BMMSCs or AdMSCs by releasing highest level of exosomal microRNA-21 into target cells and functioned on PTEN/Akt signaling pathway.