Charting Endocrine Progenitors Across Species and Organs.

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.