The Extracellular Matrix Agrin Promotes Epicardial Cells Activation and Proliferation Post Myocardial Infarction in Mice

The extracellular matrix protein (ECM) Agrin could facilitate cardiac regeneration and repair after myocardial infarction (MI), but its specific impacts on epicardial cells (EpiCs) remains unexplored. To investigate Agrin's influence on the activation and proliferation of EpiCs, we observed dynamic changes of Agrin in the heart of mice during developmental and injury periods. We also evaluated the effects of intramyocardial administration of Agrin post MI. We found that Agrin exhibited high expression in embryonic and neonatal myocardium and gradually decreased postnatally. Agrin treatment could stimulate EpiCs activation, proliferation, and migration post MI in mice. Agrin facilitated EpiCs' proliferation primarily by binding to the membrane receptor α-dystroglycan (α-DAG), with Yes-associated protein (YAP) acting as the intracellular transcriptional factor. Inhibiting the binding of Agrin to α-DAG resulted in reduced EpiCs proliferation and decreased YAP expression. Blocking YAP-TEAD activation also reduced the effects of Agrin on EpiCs proliferation. In addition, we also demonstrated that Agrin increased the survival rate of mice and improved heart function post MI. In conclusion, Agrin has the potential to promote EpiCs activation and proliferation, making it a promising candidate for heart repair post MI. The α-DAG-YAP axis is a crucial signaling pathway in Agrin-mediated EpiCs' activation, migration, and proliferation.