Charting Endocrine Progenitors Across Species and Organs

Abstract

ABSTRACT Hormone‐producing cells in the pancreas and intestine regulate whole‐body metabolism and are dysregulated in obesity and diabetes. A deeper understanding of endocrine lineage formation (endocrinogenesis) in these organs is essential to elucidate the healthy state and disease trajectories. Here, we performed cross‐species (mouse and human) and cross‐system (in vivo and in vitro) comparisons of pancreatic endocrine progenitors (EPs), complemented by cross‐organ (pancreas and intestine) analyses, using single‐cell transcriptomics and epigenomics, together with mouse bulk proteomics. We uncovered conserved and distinct gene regulatory networks (GRNs) and cell‐cell communication patterns during lineage allocation across species, systems, and organs. Additionally, we identified diabetes‐associated genes restricted to embryonic pancreatic EPs but largely absent in the adult pancreas, suggesting that dysregulation during development may predispose to diabetes. Furthermore, our multi‐source EP profiling resolved the transcriptional programs underlying the aberrant, in vitro‐enriched enterochromaffin cell formation during differentiation toward human islet cells, suggesting that these cells may not correspond to a naturally occurring cell type present in vivo development. Finally, we revealed conserved, dynamic shifts in the cell cycle and cytoskeletal organization, alongside divergent mRNA translation, during endocrinogenesis. Collectively, this multi‐source EP profiling establishes a resource mapping the molecular landscape of endocrinogenesis across two major metabolic‐endocrine organs.