Epicardial function of canonical Wnt-, Hedgehog-, Fgfr1/2-, and Pdgfra-signalling.

AIMS The embryonic epicardium is a source of smooth muscle cells and fibroblasts of the coronary vasculature and of the myocardium, but the signalling pathways that control mobilization and differentiation of epicardial cells are only partly known. We aimed to (re-)evaluate the relevance of canonical Wnt-, Hedgehog (Hh)-, Fibroblast growth factor receptor (Fgfr)1/2-, and platelet-derived growth factor receptor alpha (Pdgfra)-signalling in murine epicardial development. METHODS AND RESULTS We used a T-box 18 (Tbx18)(cre)-mediated conditional approach to delete and to stabilize, respectively, the downstream mediator of canonical Wnt-signalling, beta-catenin (Ctnnb1), to delete and activate the mediator of Hh-signalling, smoothened (Smo), and to delete Fgfr1/Fgfr2 and Pdgfra in murine epicardial development. We show that epicardial loss of Ctnnb1, Smo, or Fgfr1/Fgfr2 does not affect cardiac development, whereas the loss of Pdgfra prevents the differentiation of epicardium-derived cells into mature fibroblasts. Epicardial expression of a stabilized version of Ctnnb1 results in the formation of hyperproliferative epicardial cell clusters; epicardial expression of a constitutively active version of Smo leads to epicardial thickening and loss of epicardial mobilization. CONCLUSION Canonical Wnt-, Hh-, and Fgfr1/Fgfr2-signalling are dispensable for epicardial development, but Pdgfra-signalling is crucial for the differentiation of cardiac fibroblasts from epicardium-derived cells.