A multimodal cross-species comparison of pancreas development

Abstract Human pancreas development remains incompletely understood due to limited sample access constrained by ethical and practical considerations. Here we investigate whether pigs resemble humans in pancreas development more closely than rodents, and as such, offer a valuable alternative large-animal model. As pig pancreas organogenesis is unexplored, we first annotated developmental hallmarks and lineage markers of pancreas differentiation and morphogenesis throughout the 114-day gestation. Building on this detailed roadmap, we further constructed a pig single-cell multiome pancreas atlas capturing temporal resolution across all three trimesters. Cross-species comparisons with human and mouse time-resolved integrated pancreas atlases accentuated that pig closely resembled human in developmental tempo, epigenetic and transcriptional regulation, gene expression patterns and gene regulatory networks (GRNs). Specifically, pig mimicked the dynamics of progenitor status, differentiation trajectories and GRNs governing endocrine fate acquisition in human. In pig multiome GRN, over 40% of transcription factors targeted by NEUROG3, the endocrine master regulator, were confirmed in human stem cell models. Most notably, we uncovered beta-cell heterogeneity arising during embryonic development, owing to endocrine induction in pancreatic progenitors with temporally altered epigenetic and transcriptional identity. Overall, our work lays the foundation for using pigs to model human pancreas biology and provides unprecedented insights into developmental principles and mechanisms across species.