The embryonic epicardial layer of the heart, which originates from the proe
picardium, gives rise to a set of invasive pluripotent epicardially-derived
cells (EPDCs) that contribute to the development of 1) subepicardial mesen
chyme, 2) coronary vessels, 3) intermyocardial fibrous tissue, and 4) mesen
chyme of the atrioventricular cardiac valve primordia. Here we report that
chimeric tracing of proepicardial cells as well as a new experimental proce
dure reveal a non-proepicardial origin for the epicardial-like cells of the
more distal part of the outflow tract of the heart (OFT). This observation
is supported by the fact that the expression pattern of mesothelial antige
ns in the epicardial-like cells of the distal outflow tract is different fr
om the expression pattern in the pro epicardially-derived epicardium. The d
elay of epicardium and EPDC development using diverse microsurgical procedu
res leads to abnormal cardiac phenotypes in all cardiac areas colonized by
proepicardially-derived epicardium and EPDCs. These results suggest the exi
stence of a signaling role for epicardium and EPDCs in cardiac development
and support the hypothesis that ontogenetical diversity of cardiac epicardi
um is involved in heart chamber morphogenesis and remodeling.