Role of the cell cycle in controlling epicardial contribution to the developing and regenerating heart

Our group investigates embryonic mechanisms of cardiovascular development, to inform cardiac regenerative strategies, through reactivating of developmental processes in the adult heart1. The epicardium plays a crucial role in the embryo, to stimulate growth of the coronary vasculature and maturation of the myocardium (1). A key first step is epithelial to mesenchymal transition (EMT) to yield migratory cells which invade the myocardium and secrete potent paracrine factors. The adult mammalian epicardium is reactivated in response to myocardial infarction and contributes to repair (2), albeit sub-optimally, a major limitation being the extent of endogenous EMT. Based on our knowledge of ‘optimal’ embryonic mechanisms, we seek to enhance epicardial-based regeneration of the injured adult heart. Our preliminary data suggest a novel cell cycle-dependent mechanism controlling EMT and differentiation of epicardial cells, in line with the emerging paradigm of cell cycle control of stem cell fate (3). We will explore this exciting hypothesis by assessing how pharmacological and genetic perturbation of the cell cycle impacts EMT and fate, using functional assays, candidate and unbiased (e.g. RNA-Seq) approaches in cell culture, primary explant and genetic mouse models.

1). Redpath and Smart (2020). Stem Cells Transl Med. doi.org/10.1002/sctm.20-0352.

2). Smart et al. (2011) Nature. 474(7353):640-4.

3). Pauklin & Vallier (2013) Cell 155, 135.