title: Exendin-4 pretreated adipose derived stem cells are resistant to oxidative stress and improve cardiac performance via enhanced adhesion in the infarcted heart.
abstract: Reactive oxygen species (ROS), which were largely generated after myocardial ischemia, severely impaired the adhesion and survival of transplanted stem cells. In this study, we aimed to determine whether Exendin-4 pretreatment could improve the adhesion and therapeutic efficacy of transplanted adipose derived stem cells (ADSCs) in ischemic myocardium. In vitro, H2O2 was used to provide ROS environments, in which ADSCs pretreated with Exendin-4 were incubated. ADSCs without pretreatment were used as control. Then, cell adhesion and viability were analyzed with time. Compared with control ADSCs, Exendin-4 treatment significantly increased the adhesion of ADSCs in ROS environment, while reduced intracellular ROS and cell injury as determined by dihydroethidium (DHE) staining live/Dead staining, lactate dehydrogenase-release assay and MTT assay. Western Blotting demonstrated that ROS significantly decreased the expression of adhesion-related integrins and integrin-related focal adhesion proteins, which were significantly reversed by Exendin-4 pretreatment and followed by decreases in caspase-3, indicating that Exendin-4 may facilitate cell survival through enhanced adhesion. In vivo, myocardial infarction (MI) was induced by the left anterior descending artery ligation in SD rats. Autologous ADSCs with or without Exendin-4 pretreatment were injected into the border area of infarcted hearts, respectively. Multi-techniques were used to assess the beneficial effects after transplantation. Longitudinal bioluminescence imaging and histological staining revealed that Exendin-4 pretreatment enhanced the survival and differentiation of engrafted ADSCs in ischemic myocardium, accompanied with significant benefits in cardiac function, matrix remodeling, and angiogenesis compared with non-pretreated ADSCs 4 weeks post-transplantation. In conclusion, transplantation of Exendin-4 pretreated ADSCs significantly improved cardiac performance and can be an innovative approach in the clinical perspective.
authors.affiliation: Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences; Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, P.R. China; Department of Cardiology, Medical school of Chinese PLA, Chinese PLA General Hospital, Beijing, P.R. China; Department of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences; Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, P.R. China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences; Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Transfusion Medicine, Academy of Military Medical Sciences, Beijing, P.R China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences; Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, P.R. China.
authors.forename: Liman
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences; Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, P.R. China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Medical school of Chinese PLA, Chinese PLA General Hospital, Beijing, P.R. China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Medical school of Chinese PLA, Chinese PLA General Hospital, Beijing, P.R. China.
authors.forename: Yundai
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences; Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, P.R. China.
authors.forename: Changyong
authors.initials: C
authors.lastname: Wang
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077270:Exenatide; D006334:Heart Function Tests / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016023:Integrins / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D014463:Ultrasonography; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016023:Integrins; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D006861:Hydrogen Peroxide