Abstract
Epicardial derivatives, including vascular smooth muscle cells and cardiac fibroblasts, are crucial for proper development of the coronary vasculature and cardiac fibrous matrix, both of which support myocardial integrity and function in the normal heart. Epicardial formation, epithelial-to-mesenchymal transition (EMT), and epicardium-derived cell (EPDC) differentiation are precisely regulated by complex interactions among signaling molecules and transcription factors. Here we review the roles of critical transcription factors that are required for specific aspects of epicardial development, EMT, and EPDC lineage specification in development and disease. Epicardial cells and subepicardial EPDCs express transcription factors including Wt1, Tcf21, Tbx18, and Nfatc1. As EPDCs invade the myocardium, epicardial progenitor transcription factors such as Wt1 are downregulated. EPDC differentiation into SMC and fibroblast lineages is precisely regulated by a complex network of transcription factors, including Tcf21 and Tbx18. These and other transcription factors also regulate epicardial EMT, EPDC invasion, and lineage maturation. In addition, there is increasing evidence that epicardial transcription factors are reactivated with adult cardiac ischemic injury. Determining the function of reactivated epicardial cells in myocardial infarction and fibrosis may improve our understanding of the pathogenesis of heart disease.
Highlights
Epicardial derivatives, including vascular smooth muscle cells and cardiac fibroblasts, are crucial for proper development of the coronary vasculature and cardiac fibrous matrix, both of which support myocardial integrity and function in the normal heart
epicardium-derived cell (EPDC) transcription factors have been used as markers for progenitor cells and epicardial activation, specific information related to transcriptional targets and cell lineage regulation is limited
Wt1, Tcf21, and Tbx18, are expressed in a variety of mesothelial progenitor lineages, and it is likely that they have similar roles in fibroblast and smooth muscle (SM) development in multiple organs
Summary
The proepicardium (PE) is derived from the splanchnic mesoderm and forms as a cluster of mesothelial cells located between the liver and cardiac sinus venosus [19]. Retroviral labeling lineage studies and quail-chick chimera experiments indicated that EPDCs contribute to fibroblast, SM, and coronary endothelial cell lineages [1,2]. While it is known that multiple cell types arise from epicardial progenitors, the timing and regulation of SMC, fibroblast, and endothelial cell lineage determination is not fully characterized. In addition it is not known if the various epicardial derivatives arise from common or distinct progenitor pools. EPDC lineages arise from distinct populations located at the venous pole of the heart and are specified prior to epicardial EMT [6,13]
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