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.
Highlights
Ischemic heart disease is the major cause of death globally
DHE staining demonstrated that increased intracellular reactive oxygen species (ROS) in adipose derived stem cells (ADSCs) induced by H2O2 was partially inhibited by 50 nM Exendin-4 pretreatment from 30 min to 120 min (Fig. 1B, E; p,0.05)
MTT assay showed that treatment of ADSCs with H2O2 led to significant reduction in cell proliferation, while pretreatment of ADSCs with Exendin-4 showed a significant increase in cell proliferation (Fig. 1I, p, 0.05)
Summary
Ischemic heart disease is the major cause of death globally. there are several kinds of therapeutic strategies, such as medical, interventional approaches and heart transplantation, the mortality rate of patients with acute myocardial infarction (AMI) is still very high [1]. Infarcted and peri-infarcted myocardium exhibits a hostile niche, such as largely generated reactive oxygen species (ROS), enhanced inflammatory response and vascular dysfunction. All these factors were detrimental to engrafted stem cells. Several approaches have been developed to enhance transplanted cell survival in ischemic myocardium through increasing their adhesive ability, including pretreatment before transplantation and genetically engineering [11,12,13]. Laflamme et al developed a multicomponent, prosurvival cocktail that limits cell death after transplantation and enhances function of infarcted hearts. Cho et al genetically engineered MSCs to overexpress periostin to increase cell survival and improve the cardiac function of infarcted myocardium after implantation. The method of pretreatment of stem cells before transplantation was more and suitable of clinical application
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