The epicardium signals the way towards heart regeneration

Abstract

From historical studies of developing chick hearts to recent advances in regenerative injury models, the epicardium has arisen as a key player in heart genesis and repair. The epicardium provides paracrine signals to nurture growth of the developing heart from mid-gestation, and epicardium-derived cells act as progenitors of numerous cardiac cell types. Interference with either process is terminal for heart development and embryogenesis. In adulthood, the dormant epicardium reinstates an embryonic gene programme in response to injury. Furthermore, injury-induced epicardial signalling is essential for heart regeneration in zebrafish. Given these critical roles in development, injury response and heart regeneration, the application of epicardial signals following adult heart injury could offer therapeutic strategies for the treatment of ischaemic heart disease and heart failure.

Graphical abstract

Figure 1

Key epicardial signals conserved in mammalian heart muscle development and lower vertebrate heart muscle regeneration: epicardial–myocardial retinoic acid (RA), fibroblast growth factor (FGF) and extracellular matrix (ECM) signalling are key mitogenic events during the formation and growth of mammalian heart muscle (left) and the restoration of lost muscle during zebrafish heart regeneration (right). Curved arrows indicate reciprocal epicardial (derived cell) signals (green) and myocardium-derived signals (red).