Project description:RNAseq1: Single cell analysis of human liver CD31+ CD45- cells RNAseq2: Comparison of human umbilical vein endothelial cells from Control and MAF knockout conditions.
Project description:The kidney vasculature is specialized to filter waste products from the blood, regulate blood pressure, and balance electrolytes. Although recent advances in stem cell studies have enabled the partial generation of kidney tissues in vitro, recapitulating the complex vascular structures of the kidney remains a daunting task. The molecular pathways that specify and sustain kidney vascular heterogeneity to perform these diverse tasks are not well characterized. Here, we have employed high throughput bulk and single-cell RNA sequencing of the non-lymphatic vasculature of the kidney to uncover the progression of pathways that dictate the developmental transition of nephrogenesis and vascular zonation from embryos to adulthood. We show that glomeruli and its associated vessels, manifest vascular-specific signatures expressing defined transcription factors, ion channels, solute transporters, and paracrine factors choreographing kidney functions. Notably, the ontology of the glomerulus coincides with induction of several unique transcription factors, including Tbx3, Gata5, Prdm1, and Pbx1. Selective deletion of Tbx3 in endothelial cells result in glomerular hypoplasia, microaneurysms and regressed fenestrations leading to fibrosis. Unraveling the molecular determinants of kidney vascular signatures will lay the foundation for rebuilding nephrons and understanding the pathogenesis of kidney diseases.
Project description: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.
Project description: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.