Epicardial cell transformation

Abstract

The embryonic epicardium, which invests all the heart surface by midgestation, derives from an extracardiac progenitor tissue called the proepicardium. The embryonic epicardium gives rise to a population of mesenchymal cells called the epicardially‐derived cells (EPDCs) that populate the space between the myocardium and the epicardium and later invade the ventricular myocardium. EPDCs contribute to the connective and vascular tissue of the heart. The transformation of epicardial cells into EPDCs is a critical step of the cardiac development, and it can be regarded as an epithelial‐mesenchymal transition (EMT), the same cellular process that accounts for the origin of the neural crest cells or the valvuloseptal tissue of the heart. We have just started to know how epicardial EMT is controlled at the molecular level, as well as the differences between the epicardial transformation and other embryonic EMTs. The Wilms' tumor suppressor gene Wt1 is probably a main element regulating epicardial EMT, since it is able to repress E‐cadherin and to activate Snail expression, regulating in this way the switch between epithelial and mesenchymal states in EPDCs. Wt1 also directly activates Raldh2 expression in the epicardium, thus controlling the retinoic acid synthesis in this tissue. We think that epicardial EMT should be regarded as a two‐step process, with a triggering signal in the proepicardium and the acquisition of an invasive behaviour when the primitive epicardium spreads over the heart surface. Later, a process of mesenchymal‐epithelial transformation in the most external epicardial cell layer gives rise to the definitive epicardial mesothelium.