The stem cell adjuvant with Exendin-4 repairs the heart after myocardial infarction via STAT3 activation.
The poor survival of cells in ischaemic myocardium is a major obstacle for stem cell therapy. Exendin-4 holds the potential of cardioprotective effect based on its pleiotropic activity. This study investigated whether Exendin-4 in conjunction with adipose-derived stem cells (ADSCs) could improve the stem cell survival and contribute to myocardial repairs after infarction. Myocardial infarction (MI) was induced by the left anterior descending artery ligation in adult male Sprague-Dawley rats. ADSCs carrying double-fusion reporter gene [firefly luciferase and monomeric red fluorescent protein (fluc-mRFP)] were quickly injected into border zone of MI in rats treated with or without Exendin-4. Exendin-4 enhanced the survival of transplanted ADSCs, as demonstrated by the longitudinal in vivo bioluminescence imaging. Moreover, ADSCs adjuvant with Exendin-4 decreased oxidative stress, apoptosis and fibrosis. They also improved myocardial viability and cardiac function and increased the differentiation rates of ADSCs into cardiomyocytes and vascular smooth muscle cells in vivo. Then, ADSCs were exposed to hydrogen peroxide/serum deprivation (H(2)O(2)/SD) to mimic the ischaemic environment in vitro. Results showed that Exendin-4 decreased the apoptosis and enhanced the paracrine effect of ADSCs. In addition, Exendin-4 activated signal transducers and activators of transcription 3 (STAT3) through the phosphorylation of Akt and ERK1/2. Furthermore, Exendin-4 increased the anti-apoptotic protein Bcl-2, but decreased the pro-apoptotic protein Bax of ADSCs. In conclusion, Exendin-4 could improve the survival and therapeutic efficacy of transplanted ADSCs through STAT3 activation via the phosphorylation of Akt and ERK1/2. This study suggests the potential application of Exendin-4 for stem cell-based heart regeneration.
Department of Cardiology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China; Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences, Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, China.
Jianfeng
J
Liu
Haibin
H
Wang
Yan
Y
Wang
Yujing
Y
Yin
Zhiyan
Z
Du
Zhiqiang
Z
Liu
Junjie
J
Yang
Shunying
S
Hu
Changyong
C
Wang
Yundai
Y
Chen
D000273:Adipose Tissue / Q000166:cytology / Q000637:transplantation*; D000276:Adjuvants, Immunologic; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017024:Chemotherapy, Adjuvant; D000077270:Exenatide; D005455:Fluorescent Antibody Technique; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000276:Adjuvants, Immunologic; D007004:Hypoglycemic Agents; D010455:Peptides; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014688:Venoms; D000077270:Exenatide
Exendin-4; STAT3; adipose-derived stem cell; myocardial infarction; paracrine