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The poor survival rate of stem cell transplantation in ischemic myocardial microenvironment is a major obstacle for stem cell therapy. Exendin-4 holds the potential of cardioprotective effect based on their pleiotropic activity. This study was designed to investigate whether the combination of Exendin-4 and adipose derived stem cells (ADSCs) could significantly improve the stem cells survival, engraftment and contribute to myocardial repair after myocardial infarction.
Material and Methods
The oxidative stress of cultured ADSCs was induced by H2O2 administration in vitro. The protective effect of Exendin-4 was investigated by dihydroethidium (DHE) staining and Live/Dead assay. For in vivo studies, MI was induced by the left anterior descending artery ligation in adult male Sprague-Dawley rats. ADSCs carrying dual-fusion (TF) reporter gene (fluc-mrfp) were quickly injected into border zone of myocardial infarction in rats treated with or without Exendin-4. PBS alone was injected as control. Multi-techniques were used to assess the beneficial effects after transplantation.
The results showed that exendin-4 decreased ros level and reduced the necrosis of adscs suffered from oxidative stress significantly in vitro. one week after transplantation, inflammatory cells and oxidative stress of heart in exendin-4 group were decreased markedly than that in control group. four weeks after transplantation, the cardiac function evaluated by echocardiogram and MicroPET/ct improved significantly, while the infarct size and fibrotic area decreased significantly in Exendin-4+adscs group compared with that of other groups. both exendin-4 group and adscs group also improved myocardial performance. bioluminescence imaging showed exendin-4 promoted adscs survival significantly in vivo. histology examination showed that the combination of exendin-4 and adscs could reduce myocardial fibrosis, decrease myocardial apoptosis, increase vessel density, and enhance cardiogenic differentiation of adscs. western blotting demonstrated that oxidative stress and inflammation were significantly inhibited in the border area of infarction in Exendin-4+adscs group.
Through regulating the post-infarct microenvironment, exendin-4 combined with adscs can improve the survival and therapeutic efficacy of implanted stem cells. this study suggests the potential of exendin-4 for stem cell based heart regeneration.
- 2013 American College of Cardiology Foundation