Specification of fetal liver endothelial progenitors to functional zonated adult sinusoids requires c-Maf induction [development stage]

Endothelial cell heterogeneity shapes the unique attributes of organ-specific blood vessels; however, how intra-organ vascular cell diversity is established remains unsolved. Liver vascular network is patterned by sinusoidal and hepatocyte co-zonation, however how intra-liver vessels acquire their hierarchical specialized functions is unknown. Here, we resolve the heterogeneity of hepatic vascular cells during development through functional and single-cell RNA sequencing. We show that acquisition of sinusoidal endothelial cell identity is initiated during early development and is completed postnatally, originating from a pool of undifferentiated vascular progenitors at E12. Notably, we identify the peri-natal induction of the transcription factor c-Maf as a critical switch for sinusoidal identity determination. Endothelium-restricted deletion of c-Maf disrupts liver sinusoidal development, aberrantly expands postnatal liver hematopoiesis, promotes excessive postnatal sinusoidal proliferation, and aggravates liver pro-fibrotic sensitivity to chemical insult. Notably, c-Maf overexpression in generic differentiated endothelial cells switches on a liver sinusoidal transcriptional zonation program that maintains hepatocyte function. Therefore, c-Maf represents an inducible intra-organotypic and niche-responsive molecular determinant of sinusoidal cell identity and lays the foundation for designing strategies to initiate vasculature-driven liver repair. Overall design: Single cell RNA sequencing of liver endothelial cells along developmental time points E12, E14, E16, E18, P2, P8, P15 and P30.