A glimpse of Cre-mediated controversies in epicardial signalling.

Abstract

Among the many important aspects of cardiac development, formation of the epicardium and the underlining signalling pathways that direct the mobilization and differentiation of epicardial cells have been one of the highly pursued research subjects within the past decade. These epicardium-derived cells (EPDCs) are reported to contribute to several critical cell types which include cardiac myofibroblasts and coronary smooth muscle contributing to the formation of the coronary vasculature network within the developing embryonic heart.1 Recent data suggesting that epicardial progenitor cells (EPCs) can contribute to newly formed cardiomyocytes in injured hearts2,3 has drawn further attention into the mechanisms of epicardiogenesis, as the successful use of epicardial cells in cell replacement therapies will undoubtedly have a high clinical impact on treating heart disease. To achieve this goal, a better understanding of the molecular mechanism that drive epicardiogenesis will be required. As the outermost cell layer of the vertebrate heart, the epicardium is derived from the proepicardial organ (PE), which originates from splanchnic mesenchyme within the septum transversum that is juxtaposed near the venous pole of the embryonic day 9.5 (E9.5) mouse heart (E22 for human). EPCs detach from the PE, migrate into pericardial cavity, and adhere to the myocardial surface where they rapidly spread to form a mesothelial monolayer covering the atria, atrioventricular canal, and ventricles, and in doing so, establish a primary epicardium by E10.5 in the mouse. Two days later, at E12.5, some of the primary epicardial cells undergo an epithelial to mesenchymal transition to convert into highly mobile and developmentally plastic EPDCs ( Figure 1 ). These EPDCs proceed to invade the subepicardial matrix and subsequently migrate into the myocardium, where they differentiate into interstitial …