The stem cell adjuvant with Exendin‐4 repairs the heart after myocardial infarction via STAT 3 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 E xendin‐4 in conjunction with adipose‐derived stem cells ( ADSC s) 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 S prague‐ D awley rats. ADSC s carrying double‐fusion reporter gene [firefly luciferase and monomeric red fluorescent protein (fluc‐m RFP )] were quickly injected into border zone of MI in rats treated with or without E xendin‐4. Exendin‐4 enhanced the survival of transplanted ADSC s, as demonstrated by the longitudinal in vivo bioluminescence imaging. Moreover, ADSC s adjuvant with E xendin‐4 decreased oxidative stress, apoptosis and fibrosis. They also improved myocardial viability and cardiac function and increased the differentiation rates of ADSC s into cardiomyocytes and vascular smooth muscle cells in vivo . Then, ADSC s were exposed to hydrogen peroxide/serum deprivation ( H 2 O 2 / SD ) to mimic the ischaemic environment in vitro . Results showed that E xendin‐4 decreased the apoptosis and enhanced the paracrine effect of ADSC s. In addition, E xendin‐4 activated signal transducers and activators of transcription 3 ( STAT 3) through the phosphorylation of Akt and ERK 1/2. Furthermore, E xendin‐4 increased the anti‐apoptotic protein Bcl‐2, but decreased the pro‐apoptotic protein B ax of ADSC s. In conclusion, E xendin‐4 could improve the survival and therapeutic efficacy of transplanted ADSC s through STAT 3 activation via the phosphorylation of Akt and ERK 1/2. This study suggests the potential application of E xendin‐4 for stem cell–based heart regeneration.