Charting endocrine progenitors across species and organs

A deeper understanding of endocrine lineage formation (endocrinogenesis) in these organs is essential to elucidate disease mechanisms and develop improved therapies. Here, we performed cross-species (mouse-human) and cross-system (in vivo-in vitro) comparisons of pancreatic endocrine progenitors (EPs), complemented by cross-organ (pancreas-intestine) analyses, using single-cell transcriptomics and epigenomics integrated with bulk proteomics.

We uncovered shared and distinct gene regulatory networks (GRNs) and cell-cell communication patterns during lineage allocation across species, systems, and organs. Additionally, we identified cardiometabolic risk-associated genes restricted to embryonic pancreatic EPs but largely absent in the adult pancreas, implicating developmental origins of disease. Furthermore, our integrated, multi-source EP profiling resolved the transcriptional programs underlying off-target enterochromaffin cell formation during in vitro differentiation toward human islet cells.