Origin and functional implications of coro-nary endothelial heterogeneity in development and post-ischemic regeneration
The heart is one of the most vascularized organs in mammals, forming the coronary vascular network to continuously support the high metabolic activity of the myocardium. The coronary vasculature forms during embryogenesis when the luminal supply of oxygen through the endocardium is no longer sufficient for the growing myocardial wall. At present, there is no consensus on the developmental mechanisms and cellular origin of the coronary endothelium. Various contradictory reports claim different developmental origins for the coronary endothelium and propose distinct cardiac vascularization processes. Our preliminary data identified that the coronary vasculature is formed by different subpopulation of endothelial progenitors originating from different embryonic sources. Endothelial cells of distinct origins contribute differentially in terms of spatial distribution, exhibit distinct morphological features and transcriptional profiles, and are incorporated into the plexus through diverse mechanisms. Our aim is to unravel the genetic and functional heterogeneity of coronary endothelial cells. We hypothesize, that coronary endothelium comprises a diversity of specialized differentiated endothelial cell types with distinct endogenous gene expression programs, defined during developmental stages, which persist during postnatal life.
Using 3D imaging for lineage tracing and fate mapping, combined with single cell sequencing, we will map the origins of coronary endothelial heterogeneity in mice, establish their spatial and temporal distribution pattern in the maturing coronary vasculature and identify their genetic profiles and possible transitions thereof in adulthood. We will also determine whether and how cells of different developmental origin show divergent capacity and plasticity in response to reactivation.
A deeper understanding of the heterogeneity of coronary endothelium in terms of gene expression, developmental origin and adaptive plasticity has the potential to rewrite current concepts on cardiac homeostasis and repair.