Myocardial heterogeneity in permissiveness for epicardium-derived cells and endothelial precursor cells along the developing heart tube at the onset of coronary vascularization

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Abstract
The coronary vasculature develops from mesothelial and endothelial precursor cells (EPCs) derived from the proepicardial organ (PEO), which migrate over the heart to form the epicardium. By epithelial‐mesenchymal transition (EMT), the subepicardium and epicardium‐derived cells (EPDCs) are formed. EPDCs migrate into the myocardium, where they differentiate into smooth muscle cells and fibroblasts that stabilize the developing coronary vasculature and contribute to myocardial architecture. Complete PEO ablation results in embryonic lethality due to cardiac defects, including a looping disorder with a too wide inner curvature. To investigate the behavior of early coronary contributors, we analyzed normal quail embryos and found lumenized endothelial vessels in the subepicardium already at stage HH19. Furthermore, EPCs had penetrated into the myocardium of the inner curvature. To confirm that the myocardium of the inner curvature is specifically permissive for EPCs and to study early EPDC migration in more detail, chimeric chicken embryos harboring a quail PEO were analyzed. Lateral epicardial outgrowth and EMT were observed throughout, but migration into the myocardium was restricted to the inner curvature between HH19 and 22. The permissive myocardial area expanded to the atrium, atrioventricular canal, and trabeculated ventricle at stage HH23–24. In contrast, outflow tract myocardium was never found to be permissive for EPDCs and EPCs until HH30, not even when the quail PEO was attached directly onto it. We conclude that early coronary formation starts in the inner curvature and hypothesize that the presence of PEO‐derived cells is essential for the maturation of the inner curvature and subsequent looping of the heart tube.