A human arteriovenous differentiation roadmap reveals vein developmental mechanisms and vascular effects of viruses

We map human artery and vein endothelial cell (EC) differentiation from pluripotent stem cells, and employ this roadmap to discover new mechanisms of vascular development (vein differentiation) and disease (viral infection). We discovered vein development unfolds in two steps driven by opposing signals: VEGF differentiates mesoderm into “pre-vein” ECs, but surprisingly, VEGF/ERK inhibition subsequently specifies vein ECs. Pre-vein ECs co-expressed certain arterial ( SOX17 ) and venous ( APLNR ) markers, harbored poised chromatin at future venous genes, but completed venous differentiation only upon VEGF inhibition. Intersectional lineage tracing revealed that early Sox17 + Aplnr + ECs also formed veins in vivo . Next, we compared how Ebola, Andes, and Nipah viruses infect artery and vein ECs under biosafety-level-4 containment. Each virus distinctly affected ECs. Interestingly, artery and vein ECs also responded divergently to the same virus, thus revealing that developmentally-specified cell identity impacts viral infection. Collectively, this arteriovenous differentiation roadmap illuminates vascular development and disease.