Generating Epicardial Cells from Human Pluripotent Stem Cells in a Defined, Growth-Factor Free Manner

The epicardium contributes both multi-lineage descendants and paracrine factors to the heart during cardiogenesis and cardiac repair, underscoring its potential for cardiac regenerative medicine. Despite significant advances in animal models, little is known about the cellular and molecular mechanisms that regulate human epicardial development and regeneration. To assess the roles of developmental pathways in epicardial formation, self-renewal, and differentiation we developed a robust method for differentiating human pluripotent stem cells to epicardial cells via stage-specific modulation of cardiac developmental pathway under chemically-defined, animal component-free conditions. The hPSC-derived epicardial cells were expandable and exhibited properties of primary epicardial cells both in vitro and in vivo. These findings improve our understanding of differentiation and self-renewal mechanisms of the epicardium and have implications for stimulating epicardial regeneration via cellular or small-molecule therapies.