Journal
STEM CELLS TRANSLATIONAL MEDICINE
Volume 6, Issue 1, Pages 209-222Publisher
WILEY
DOI: 10.5966/sctm.2015-0386
Keywords
Mesenchymal stem cells; Endometrium; Bone marrow; Adipose; Myocardial infarction; Cell therapy
Categories
Funding
- National Basic Research Program of China (973 Program) [2014CB965100, 2014CB965103]
- National High-Tech Research & Development 863 Program [2013AA020101, 2015AA020922]
- National Natural Science Foundation of China [31171418, 81320108003, 31371498, 81170308, 81370247, 81470382, 81573641]
- Science and Technology Department of Zhejiang Province [2013C37054, 2014C33190]
- Natural Science Foundation of Zhejiang Province [LY16H280003]
- Fundamental Research Funds for the Central Universities [2016XZZX00203, 2016FZA7005]
- NIH [HL072924]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL072924] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R03AA020101] Funding Source: NIH RePORTER
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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 andhumanumbilical vein endothelial cells. AratMImodel 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.
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