A single-cell time-series atlas of endothelial cell embryonic development

Endothelial cells (ECs) are essential components of the vertebrate circulatory system; however, a comprehensive atlas characterizing how ECs acquire organ-specific transcriptomic heterogeneity has not been established. Here, we generated a time-series endothelial resource covering the entirety of mouse embryonic development, including 26 time points and 8 organs. Time-series multi-organ comparison revealed emergence timing and lineage trajectory of organotypic ECs together with organ-specific genes and pathways. Using these resources, we found that most ECs showed distinguishable organ specificity before late gestation. The organotypic EC-enriched genes were associated with vascular function in the organs. Human and mouse pulmonary ECs underwent an evolutionarily conserved transcriptional transition. Endothelial-specific knockout of Casz1, a pulmonary EC-enriched transcription factor, resulted in impaired vascular growth, disturbed pulmonary endothelial organotypic differentiation, and deficient epithelial-EC crosstalk. Our work provides a powerful endothelial resource that reveals fundamental principles of organ-specific EC differentiation and uncovers previously unknown molecular mechanisms governing lung-specific vascular development.