Lineage-enriched cell proliferation code underlies spatio-temporal regulation of cell cycle dynamics in lymphatic vessels

Abstract Cell proliferation is central to the proper formation of functional and healthy organs. Although cells divide in all tissues during embryogenesis, how the spatio-temporal control of lymphatic endothelial cell (LEC) number expansion is achieved, remains to be determined. Our comprehensive whole organism time-course analysis has uncovered that spatially restricted LEC proliferation bursts contribute to the morphogenesis of distinct lymphatic vascular beds in zebrafish during embryonic and larval development. Mechanistically, Vegfc-Vegfr3 signalling is necessary and sufficient for LEC proliferation and regulates cell cycle length. Using single-cell transcriptomics, we discover a cohort of genes that generate the unique LEC proliferation code, which is lineage-enriched during the cell proliferation bursts. We confirmed that FKBP1A and LBR are required for endothelial cell proliferation in human primary cell lines. Similarly, the conservation of the lineage-enriched cell proliferation code is present in mouse endothelial cells, whereas in Pik3ca-driven endothelial cell pathologies the cell proliferation code loses its cell type specificity. Thus, our data uncover promising new candidates behind the mechanisms regulating lineage cell number expansion, which could be relevant to future strategies for modulating lymphatic cell proliferation in homeostasis or disease.