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

The beneficial effects offered by MSC transplantation after myocardial infarction are at least partially because of improved autophagic flux through excreted exosome containing mainly miR-125b-5p.

Bone marrow mesenchymal stem cells (MSCs) have improved cardiac performance when administered after acute myocardial infarction (MI) in both large-animal models and in patients.1,2 However, the results from randomized controlled clinical trials have been less impressive; the authors of one meta-analysis concluded that left ventricular ejection fractions (LVEFs) increased by just 2.92% in response to cell therapy.

Bone marrow mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been widely used for treating myocardial infarction (MI). However, low retention and short-lived therapeutic effects are still significant challenges. This study aimed to determine whether incorporation of MSC-derived sEVs in alginate hydrogel increases their retention in the heart thereby improving therapeutic effects.Methods: The optimal sodium alginate hydrogel incorporating sEVs system was determined by its release ability of sEVs and rheology of hydrogel. Ex vivo fluorescence imaging was utilized to evaluate the retention of sEVs in the heart. Immunoregulation and effects of sEVs on angiogenesis were analyzed by immunofluorescence staining. Echocardiography and Masson's trichrome staining were used to estimate cardiac function and infarct size.Results: The delivery of sEVs incorporated in alginate hydrogel (sEVs-Gel) enhanced their retention in the heart. Compared with sEVs only treatment (sEVs), sEVs-Gel treatment significantly decreased cardiac cell apoptosis and promoted the polarization of macrophages at day 3 after MI. sEVs-Gel treatment also increased scar thickness and angiogenesis at four weeks post-infarction. Measurement of cardiac function and infarct size were significantly better in the sEVs-Gel group than in the group treated with sEVs only.Conclusion: Delivery of sEVs incorporated in alginate hydrogel provides a novel approach of cell-free therapy and optimizes the therapeutic effect of sEVs for MI.

This is the largest study of hPSCs in nonhuman primates in cardiovascular field to date (n=32). Compared with cyclosporine alone, MDR attenuates immune rejection and improves survival of hPSC-CVPCs in primates; this is associated with less apoptosis of native cardiac cells and better recovery of left ventricular function at 28 days. However, even with MDR, transplanted hPSC-CVPCs do not engraft and do not survive at 140 days after transplantation, thereby excluding remuscularization as a mechanism for the functional effect.