Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA-21.
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.
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Kan
K
Wang
Department of Cardiology, Guizhou Provincial People's Hospital, Guiyang, People's Republic of China.
Zhi
Z
Jiang
Vascular Biology Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA.
Keith A
KA
Webster
Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.|The Institute of Translational Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Jinghai
J
Chen
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Hengxun
H
Hu
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Yu
Y
Zhou
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Jing
J
Zhao
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Lihan
L
Wang
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Yingchao
Y
Wang
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Zhiwei
Z
Zhong
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Cheng
C
Ni
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Qingju
Q
Li
Zhejiang-California International Nanosystems Institute, Zhejiang University, Hangzhou, People's Republic of China.
Charlie
C
Xiang
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Ling
L
Zhang
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Rongrong
R
Wu
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Wei
W
Zhu
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Hong
H
Yu
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Xinyang
X
Hu
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.|Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China.
Jian'an
J
Wang
D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D000273:Adipose Tissue / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology; D002316:Cardiotonic Agents / Q000378:metabolism; D004705:Endocytosis; D004717:Endometrium / Q000166:cytology; D055354:Exosomes / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy; D032383:Myocytes, Cardiac / Q000378:metabolism; D019899:Paracrine Communication; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D051381:Rats
D002316:Cardiotonic Agents; D035683:MicroRNAs; C524940:MIRN21 microRNA, human
Adipose; Bone marrow; Cell therapy; Endometrium; Mesenchymal stem cells; Myocardial infarction