Molecular regulation of endocardial heterogeneity during semilunar valve development and disease

Abstract

A critical event in cardiac morphogenesis is differentiation of heterogenous endocardial subpopulations with distinctive developmental capabilities. However, little is known about the factors that regulate endocardial differentiation. We have utilized NFATc‐Cre mediated lineage tracing in vivo to identify a subpopulation of valvular endocardial cells within the outflow tract that is resistant to transformation and is required for semilunar valve formation. Bacterial artificial chromosome (BAC) transgenesis containing endogenous regulatory elements of the NFATc1 locus was used to study the earliest events of endocardial differentiation. These studies have defined the endocardium as a unique subpopulation of endothelium during early mesodermal differentiation. Further analysis of in vitro endocardium differentiation utilizing ES cells derived from transgenic animals confirms that in vitro differentiation mirrors the temporal and spatial organization seen in vivo. Furthermore, manipulation of tissue specific culture conditions suggests that endocardial differentiation is not dependent on vascular or hematopoietic differentiation but is more closely associated and regulated by myocardial differentiation in a Wnt dependent process. These studies will be discussed in the context of developing a renewable resource of endocardial cells as mediators of tissue regeneration and repair.