Uncovering the heterogeneity of pancreatic endothelial cells using integrative and comparative single cell gene expression analysis

The pancreatic islet vasculature displays tissue-specific physiological and functional adaptations that support rapid glucose sensing and insulin response by β-cells. To uncover the transcriptomic basis of this specialization, we performed a meta-analysis of multi-organ single cell RNA sequencing atlases employing a unique strategy to avoid transcriptomic contamination. We identified biologically relevant genes involved in sphingosine-1-phosphate-mediated insulin-secretion ( PLPP1, RDX, CDC42EP1 ), islet basement membrane formation ( SPARC, COL15A1 ), endothelial cell (EC) permeability ( PLVAP, EHD4 ), membrane transporters ( CD320, SLCO2A1) and developmental transcription factors ( NKX2-3, AHR) . These were validated in silico in independent datasets. We further established the first integrated transcriptomic atlas of human pancreatic ECs and described two unique capillary subpopulations: exocrine and endocrine pancreas ECs. We validated the spatial localization of key markers using RNAscope™ and immunofluorescence staining on mouse pancreatic tissue cross-sections. Our findings provide novel insights into pancreatic EC heterogeneity and islet EC function with potential implications in therapeutic strategies.