Spatiotemporal dissection of vascular heterogeneity

Endothelial cells (ECs) are essential for organ development, homeostasis and regeneration, yet we still know relatively little about the early steps of their formation. I have shown that ECs from different embryonic lineages preferentially contribute to distinct parts of the vasculature; paraxial mesoderm (PXM) is the major source of lymphatic ECs, but its contribution to blood vessel endothelium is restricted to certain organs. This finding establishes a new model of how the vasculature is formed, however the underlying molecular mechanisms are unknown. Here I propose experiments to test the hypothesis that EC heterogeneity is underpinned by an intrinsic molecular memory established during differentiation from distinct embryonic sources. Building on my recent findings, we will the use the formation of lymphatic (PXM-derived), liver (partial PXM contribution) and coronary ECs (no PXM contribution) as paradigms to dissect the impact of lineage history on EC heterogeneity. Specifically, we will decipher the transcriptional and epigenetic mechanisms that control EC differentiation from distinct embryonic sources, and determine the impact of lineage history on the regenerative/fibrotic response of ECs. These analyses will provide insight into what makes ECs from distinct lineages different, and determine whether these differences impact organ development, function or regeneration.