A multimodal cross-species comparison of pancreas development

A multimodal cross-species comparison of pancreas development | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article A multimodal cross-species comparison of pancreas development Heiko Lickert, Kaiyuan Yang, Hannah Spitzer, Michael Sterr, Karin Hrovatin, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4151759/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Oct, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version 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. Biological sciences/Developmental biology Biological sciences/Computational biology and bioinformatics Full Text Additional Declarations Yes there is potential Competing Interest. F.J.T. consults for Immunai Inc., Singularity Bio B.V., CytoReason Ltd, Cellarity, Curie Bio Operations, LLC and has an ownership interest in Dermagnostix GmbH and Cellarity. The remaining authors declare no competing interests. Supplementary Files SupplementaryTable1Nextgenerationsequencingsampleinventory.xlsx Dataset 1 SupplementaryTable2Markergenesofcellclustersinhumanpigandmouse.xlsx Dataset 2 SupplementaryTable3DEGofeachcellclusterinhumanpigandmouse.xlsx Dataset 3 SupplementaryTable4CellRankAlphaandBetalineagedrivers.xlsx Dataset 4 SupplementaryTable5NEUROG3targetsfrompigGRNandhumanstemcells.xlsx Dataset 5 SupplementaryTable6DEGsandpathwaysofpighumanbetacells.xlsx Dataset 6 SupplementaryTable7CellOracleinferredGRNsofpigBeta0andBeta1.xlsx Dataset 7 SupplementaryTable8TradeSeqgenegroupsandenrichedpathways.xlsx Dataset 8 SupplementaryTable9DEGsofpigEPs.xlsx Dataset 9 SupplementaryTable10AntibodiesandhiPSCdifferentiationreagents.xlsx Dataset 10 SupplementaryTable11ImprovedgenomeannotationfortheSusscrofa.xlsx Dataset 11 SupplementaryTable12Sequencingrawdatafilteringthresholds.xlsx Dataset 12 Cite Share Download PDF Status: Published Journal Publication published 22 Oct, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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