Does Epicardium promote Cardiomyocyte Maturation & Cardiac Regeneration? (360G-Wellcome-203568_Z_16_Z)

Human embryonic stem cells (hESC)-derived cardiomyocytes have great potential for cardiac repair and regeneration following myocardial infarction but remain significantly challenged by graft cell survival, maturation and vascularisation. The epicardium is essential for cardiac development as it forms cardiac fibroblasts, coronary smooth muscle cells, and controversially, cardiomyocytes and endothelial cells. The epicardium has emerged as a potential cardiovascular progenitor source for vascularization and cardiomyocyte support. Signalling pathways underpinning epicardial-myocardial cross-talk are postulated to be key in cardiomyocyte maturation and regeneration. Studies based on mouse models have identified several epicardium-derived paracrine factors that increase the number of cardiomyocytes and contribute to angiogenesis, although their role in cardiac maturation is unclear. This project aims to definitively characterize the role of epicardium in promoting cardiomyocyte maturation and regeneration. Key goals are: 1) To investigate the role of hESC-derived epicardial cells in the promotion of functional integration and maturation of cardiomyocytes in an in vitro tissue-engineered cardiac construct. 2) To interrogate the role of paracrine mediators including MDK and/or FSTL1 in promoting cardiomyocyte maturation and regeneration. 3) To investigate the function of hESC-derived EPDCs in promoting the survival, maturation, electrical connectivity and function of stem cell-derived cardiomyocytes in the mammalian myocardial infarct.