Outside insight; using the epicardium to improve the function of the damaged heart

The epicardium forms the outside layer of the heart and harbours an easily accessible source of progenitor cells. During the development of the heart, part of this layer undergoes a process of epithelial-to-mesenchymal transition (EMT), giving rise to epicardial derived cells (EPDCs) that readily migrate into the myocardium to become fibroblasts, smooth muscle cells, endothelial cells and cardiomyocytes. In the adult EPDCs respond to damage by recapitulating their embryonic activation. After myocardial infarction (MI), the activation of the epicardium leads to partial regeneration of damaged heart tissue and formation of a scar. However, in cardiac fibrosis, resulting from prolonged overload of the heart, the role of the epicardium is likely detrimental; EMT contributes to an increased number of myofibroblasts and therefore to excessive production of extracellular matrix resulting in organ failure. The aim of this proposal is to define the role of the epicardial layer in MI and cardiac fibrosis using several well-defined transgenic mouse models that allow tracing and elimination of EPDCs in vivo. This will establish if the epicardium has a beneficial (MI) or detrimental (cardiac fibrosis) contribution to cardiac function in disease. I will determine whether stimulating or inhibiting EMT in these disease models affects the function of the heart. In collaboration with Oxford University I will identify new regulators of EMT by performing a high-throughput screen on cultured EPDCs. Novel factors will be validated in both MI and cardiac fibrosis (hypertrophy) models. As an initial target I will investigate a pathway known to influence EMT: Transforming growth factor-beta. Together, these experiments are expected to result in a novel approach to prevent the progression to heart failure after cardiac damage. Influencing EMT of the epicardial layer can lead to cardiac repair after MI, or alternatively, reduce cardiac fibrosis in hypertrophic hearts, thereby influencing cardiac function.