The epicardium, the mesothelial layer covering the heart, is a crucial cell source for cardiac development and repair. It provides cells and biochemical signals to the heart to facilitate vascularization and myocardial growth. An essential element of epicardial behavior is epicardial epithelial to mesenchymal transition (epiMT), which is the initial step for epicardial cells to become motile and invade the myocardium. To identify targets to optimize epicardium-driven repair of the heart, it is vital to understand which pathways are involved in the regulation of epiMT. Therefore, we established a cell culture model for human primary adult and fetal epiMT, which allows for parallel testing of inhibitors and stimulants of specific pathways. Using this approach, we reveal Activin A and ALK4 signaling as novel regulators of epiMT, independent of the commonly accepted EMT inducer TGF beta. Importantly, Activin A was able to induce epicardial invasion in cultured embryonic mouse hearts. Our results identify Activin A/ALK4 signaling as a modulator of epicardial plasticity which may be exploitable in cardiac regenerative medicine.Thoracic Surger
