How to make a heart: the origin and regulation of cardiac progenitor cells.

The formation of the heart is a complex morphogenetic process that depends on the spatiotemporally regulated contribution of cardiac progenitor cells. These mainly derive from the splanchnic mesoderm of the first and second heart field (SHF), with an additional contribution of neurectodermally derived neural crest cells that are critical for the maturation of the arterial pole of the heart. The origin and distinguishing characteristics of the two heart fields, as well as the relation of the SHF to the proepicardial organ and to a proposed third heart field are still subjects of debate. In the last ten years many genes that function in the SHF have been identified, leading to the establishment of a gene regulatory network in the mouse embryo. It is becoming increasingly evident that distinct gene networks control subdomains of the SHF that contribute to different parts of the heart. Although there is now extensive information about mutant phenotypes that reflect problems in the integration of progenitor cells into the developing heart, relatively little is known about the mechanisms that regulate SHF cell behavior. This important source of cardiac progenitor cells must be maintained as a proliferative, undifferentiated cell population. Selected subpopulations, at different development stages, are directed to myocardial, and also to smooth muscle and endothelial cell fates, as they integrate into the heart. Analysis of signaling pathways that impact the SHF, as well as regulatory factors, is beginning to reveal mechanisms that control cardiac progenitor cell behavior.