The Derivation of the Myocardial, Epicardial and Endocardial Lineages from Human Pluripotent Stem Cells

The adult heart is composed of cells from three major lineages: the myocardium, the epicardium and the endocardium. The myocardium is the working muscle and comprises primarily the ventricles and atria. The epicardium represents the outer epithelial layer that surrounds the myocardium and plays a pivotal role during cardiovascular development. This cell layer supports rapid proliferation of embryonic ventricular cardiomyocytes, is the major source of coronary vascular smooth muscle cells and cardiac fibroblasts and may promote remodeling of the heart after cardiac infarct in the adult. The endocardium is the specialized inner endothelial lining of the heart chamber and contributes to the formation of valves. The endocardium also exerts paracrine effects on the adjacent myocardium, promoting the proliferation and maturation of cardiomyocytes during the formation of ventricular trabeculae. While protocols for the efficient generation of cardiomyocytes from human embryonic and induced pluripotent stem cells (collectively referred to as human pluripotent stem cells; hPSCs) have been developed, strategies for the generation of the epicardium and endocardium do not exist. In this thesis, I show that through stage-specific manipulation of the BMP, canonical WNT and BFGF pathways it is possible to successfully direct the differentiation of hPSC-derived mesoderm towards the epicardial and endocardial lineages. Access to these cell types will enable investigations on their role in human cardiovascular development, application for cardiac regenerative medicine and modeling of cardiovascular disease.Ph.D