Cellular precursors of the coronary arteries.

Coronary vessels develop from a primary vascular network that differentiates in the subepicardium through a process of vasculogenesis, that is, self-assembly of mesenchymal vascular progenitors. Further growth of the subepicardial vascular plexus through a complex process of angiogenesis, vascular remodeling, and arterialization of specific branches gives rise to the definitive coronary system. This report is intended to summarize current knowledge on the origin of the coronary vascular progenitors and to provide new insights suggested by recent findings. It has been established that the mesenchymal precursors of the vascular smooth muscle cells and the adventitial fibroblasts originate from an epithelial-mesenchymal transformation of the epicardial mesothelium. We report herein experimental evidence that the precursors of the coronary endothelium are also epicardium-derived cells (EPDCs). The evidence shown includes co-localization of mesothelial and endothelial molecular markers as well as cell lineage studies performed through direct labeling of the epicardial cells. If this proposal is confirmed, the early EPDCs might be found to have a competence similar to that shown by the recently discovered bipotential vascular progenitor cells, which are able to differentiate into endothelium or smooth muscle depending on their exposure to VEGF or PDGF-BB. It is conceivable that the earliest EPDCs differentiate into endothelial cells in response to myocardially secreted VEGF, while subsequent EPDCs, recruited by the nascent capillaries via PDGFRbeta signaling, differentiate into percytes and smooth muscle cells.

[The epicardium and epicardial-derived cells: multiple functions in cardiac development]. / El epicario y las células derivadas del epicardio: múltiples funciones en el desarrollo cardíaco.

The epicardium develops from an extracardiac primordium, the proepicardium, which is constituted by a cluster of mesothelial cells located on the cephalic and ventral surface of the liver-sinus venosus limit (avian embryos) or on the pericardial side of the septum transversum (mammalian embryos). The proepicardium contacts the myocardial surface and gives rise to a mesothelium, which grows and progressively lines the myocardium. The epicardium generates, through a process of epithelial-mesenchymal transition, a population of epicardial-derived cells (EPDC). EPDC contribute to the development of cardiac connective tissue, fibroblasts, and the smooth muscle of cardiac vessels. Recent data suggest that EPDC can also differentiate into endothelial cells of the primary subepicardial vascular plexus. If this is confirmed, EPDC would show the same developmental properties that characterize the stem-cell-derived bipotential vascular progenitors recently described, whose differentiation into endothelium and smooth muscle is regulated by exposure to VEGF and PDGF-BB, respectively. Aside from their function in the development of cardiac connective and vascular tissue, EPDC also play an essential modulating role in the differentiation of the compact ventricular layer of the myocardium, a role which might be regulated by the transcription factor WT1 and the production of retinoic acid.

El epicardio y las células derivadas del epicardio: múltiples funciones en el desarrollo cardíaco / The epicardium and epicardial-derived ells: multiple functions in cardiac development

Durante el desarrollo cardíaco, el epicardio deriva de un primordio externo al corazón, denominado proepicardio, que está formado por un acúmulo de células mesoteliales situado en la superficie ventral y cefálica del límite hígado-seno venoso (aves) o en la cara pericárdica del septo transverso (mamíferos). El proepicardio entra en contacto con la superficie miocárdica y da lugar a un mesotelio que crece y recubre progresivamente al miocardio. El epicardio genera, por un proceso localizado de transición epitelio-mesénquima, una población de células mesenquimáticas, las células derivadas de epicardio (CDEP). Las CDEP contribuyen al desarrollo del tejido conectivo del corazón y también dan lugar a los fibroblastos y las células musculares lisas de los vasos coronarios. Existen evidencias que sugieren la diferenciación de las CDEP en células endoteliales del plexo subepicárdico primitivo. De confirmarse esto, las CDEP mostrarían propiedades similares a los precursores vasculares bipotenciales derivados de células madre recientemente descritos, cuya diferenciación en endotelio y músculo liso se regula por exposición a VEGF y PDGF-BB, respectivamente. Además de las funciones señaladas en la formación de los tejidos vascular y conectivo del corazón, las CDEP podrían desempeñar un papel modulador esencial para la formación de la capa compacta ventricular del miocardio, un papel que podría estar regulado por el factor de transcripción WT1 y la producción de ácido retinoico (AU)

Origin of coronary endothelial cells from epicardial mesothelium in avian embryos.

It has been established that coronary vessels develop through self-assembly of mesenchymal vascular progenitors in the subepicardium. Mesenchymal precursors of vascular smooth muscle cells and fibroblasts are known to originate from an epithelial-to-mesenchymal transformation of the epicardial mesothelium, but the origin of the coronary endothelium is still obscure. We herein report that at least part of the population of the precursors of the coronary endothelium are epicardially-derived cells (EPDCs). We have performed an EPDC lineage study through retroviral and fluorescent labelling of the proepicardial and epicardial mesothelium of avian embryos. In all the experiments onlythe surface mesothelium was labelled after 3 h of reincubation. However, endothelial cells from subepicardial vessels were labelled after 24-48 h and endothelial cells of intramyocardial vessels were also labelled after 48-96 h of reincubation. In addition, the development of the coronary vessels was studied in quail-chick chimeras, obtaining results which also support a mesothelial origin for endothelial and smooth muscle cells. Finally, quail proepicardial explants cultured on Matrigel showed colocalization of cytokeratin and QH1 (mesothelial and endothelial markers, respectively) after 24 h. These results, taken together, suggest that EPDC show similar competence to that displayed by bipotential vascular progenitor cells [Yamashita et al., Nature 408: 92-96 (2000)] which are able to differentiate into endothelium or smooth muscle depending on their exposure to VEGF or PDGF-BB. It is conceivable that the earliest EPDC differentiate into endothelial cells in response to myocardially-secreted VEGF, while further EPDC would be recruited by the nascent capillaries via PDGFR-beta signalling, giving rise to mural cells.