{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:53:51Z","timestamp":1787748831402,"version":"build-2784847793"},"reference-count":45,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000849","name":"National Centre for the Replacement, Refinement and Reduction of Animals in Research","doi-asserted-by":"publisher","award":["NC\/V002260\/1"],"award-info":[{"award-number":["NC\/V002260\/1"]}],"id":[{"id":"10.13039\/501100000849","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Trust PhD programme PhD studentship"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>\n                    The pancreas has vital endocrine and exocrine functions that can be affected by life-threatening diseases such as diabetes and pancreatic cancer. Although animal models are essential for understanding pancreatic development and disease, they are limited by their low throughput and major species-specific molecular and physiological differences. Generating 3D\n                    <ns3:italic>in vitro<\/ns3:italic>\n                    models, such as organoids, that are physiologically relevant is essential for investigating pancreatic development and disease in the human context. However, the production of human stem cell-derived pancreatic organoids with a proper branched architecture and correct patterning of cell domains remains challenging. Here, we successfully developed a protocol that efficiently and reproducibly generated organoids from human induced pluripotent stem cells (hiPSCs) by optimizing organoid culture format and media. Our differentiation protocol promotes acinar cell differentiation and generates organoids with branches patterned into the central trunk and peripheral tip domains without relying on animal-derived matrices for organoid culture. This platform opens the door to high-throughput investigations of human pancreatic development in a system that recapitulates the most important aspects of pancreatic tissue architecture. Lastly, we anticipate that this system will contribute to the replacement of animal models used to investigate diseases, such as pancreatic cancer.\n                  <\/ns3:p>","DOI":"10.12688\/f1000research.162496.1","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T04:40:08Z","timestamp":1753764008000},"page":"575","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Generation of human iPSC-derived pancreatic organoids to study pancreas development and disease"],"prefix":"10.12688","volume":"14","author":[{"given":"Jean-Francois","family":"Darrigrand","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Isaacson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7094-8188","authenticated-orcid":false,"given":"Francesca Maria","family":"Spagnoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"9946","DOI":"10.3390\/ijms24129946","article-title":"Acinar-to-Ductal Metaplasia (ADM): On the Road to Pancreatic Intraepithelial Neoplasia (PanIN) and Pancreatic Cancer.","volume":"24","author":"L Marstrand-Dauc\u00e9","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"530-565","DOI":"10.1002\/dvdy.22584","article-title":"Pancreas organogenesis: From bud to plexus to gland.","volume":"240","author":"F Pan","year":"2011","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"171-180","DOI":"10.1016\/j.gde.2015.03.004","article-title":"Islet formation in mice and men: Lessons for the generation of functional insulin-producing \u03b2-cells from human pluripotent stem cells.","volume":"32","author":"G Nair","year":"2015","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"4295-4305","DOI":"10.1242\/dev.052993","article-title":"Epithelial dynamics of pancreatic branching morphogenesis.","volume":"137","author":"A Villasenor","year":"2010","journal-title":"Dev. Camb. Engl."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"81-105","DOI":"10.1146\/annurev-cellbio-101512-122405","article-title":"Pancreas organogenesis: From lineage determination to morphogenesis.","volume":"29","author":"H Shih","year":"2013","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"51-68","DOI":"10.1016\/j.semcdb.2017.01.005","article-title":"The molecular and morphogenetic basis of pancreas organogenesis.","volume":"66","author":"H Larsen","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"103-114","DOI":"10.1016\/j.devcel.2007.06.001","article-title":"A multipotent progenitor domain guides pancreatic organogenesis.","volume":"13","author":"Q Zhou","year":"2007","journal-title":"Dev. Cell."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"143-190","DOI":"10.1016\/bs.ctdb.2018.02.009","article-title":"Recapitulating and Deciphering Human Pancreas Development From Human Pluripotent Stem Cells in a Dish.","volume":"129","author":"M Petersen","year":"2018","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1022-1029","DOI":"10.1016\/j.devcel.2010.05.015","article-title":"Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors.","volume":"18","author":"A Schaffer","year":"2010","journal-title":"Dev. Cell."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"5354","DOI":"10.1038\/s41467-023-40893-8","article-title":"Deciphering early human pancreas development at the single-cell level.","volume":"14","author":"Z Ma","year":"2023","journal-title":"Nat. Commun."},{"key":"ref11","first-page":"3126-3137","article-title":"Human pancreas development.","volume":"142","author":"R Jennings","year":"2015","journal-title":"Dev. Camb. Engl."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"571-584","DOI":"10.1038\/s41580-020-0259-3","article-title":"Human organoids: Model systems for human biology and medicine.","volume":"21","author":"J Kim","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref13","first-page":"dev201004","article-title":"Pancreas organoid models of development and regeneration.","volume":"149","author":"A Grapin-Botton","year":"2022","journal-title":"Dev. Camb. Engl."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"692","DOI":"10.3389\/fbioe.2020.00692","article-title":"Exploiting CRISPR Cas9 in Three-Dimensional Stem Cell Cultures to Model Disease.","volume":"8","author":"S Gopal","year":"2020","journal-title":"Front. Bioeng. 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Mech."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"324-338","DOI":"10.1016\/j.cell.2014.12.021","article-title":"Organoid models of human and mouse ductal pancreatic cancer.","volume":"160","author":"S Boj","year":"2015","journal-title":"Cell."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"239-255.e12","DOI":"10.1016\/j.neuron.2019.07.014","article-title":"CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons.","volume":"104","author":"R Tian","year":"2019","journal-title":"Neuron."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"101711","DOI":"10.1016\/j.xpro.2022.101711","article-title":"Differentiating functional human islet-like aggregates from pluripotent stem cells.","volume":"3","author":"T Barsby","year":"2022","journal-title":"STAR Protoc."},{"key":"ref21","article-title":"Image Processing with ImageJ.","author":"M Abr\u00e0moff"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"402-408","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.","volume":"25","author":"K Livak","year":"2001","journal-title":"Methods San Diego Calif."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"426-437","DOI":"10.1016\/S0012-1606(03)00326-9","article-title":"Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development.","volume":"260","author":"J Hald","year":"2003","journal-title":"Dev. 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USA."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1435-1440","DOI":"10.1101\/gad.1412806","article-title":"Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation.","volume":"20","author":"T Miyatsuka","year":"2006","journal-title":"Genes Dev."},{"key":"ref27","doi-asserted-by":"crossref","first-page":"9301382","DOI":"10.1155\/2019\/9301382","article-title":"Pancreatic Progenitors and Organoids as a Prerequisite to Model Pancreatic Diseases and Cancer.","volume":"2019","author":"M Hohwieler","year":"2019","journal-title":"Stem Cells Int."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"16-29","DOI":"10.1016\/j.molmet.2019.09.005","article-title":"Establishment of a high-resolution 3D modeling system for studying pancreatic epithelial cell biology in vitro.","volume":"30","author":"M Bakhti","year":"2019","journal-title":"Mol. Metab."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1090-1104.e6","DOI":"10.1016\/j.stem.2021.03.022","article-title":"Commitment and oncogene-induced plasticity of human stem cell-derived pancreatic acinar and ductal organoids.","volume":"28","author":"L Huang","year":"2021","journal-title":"Cell Stem Cell."},{"key":"ref30","first-page":"861-871","article-title":"Stage-specific signaling through TGF\u03b2 family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells.","volume":"138","author":"M Nostro","year":"2011","journal-title":"Dev. Camb. Engl."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1121-1133","DOI":"10.1038\/nbt.3033","article-title":"Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells.","volume":"32","author":"A Rezania","year":"2014","journal-title":"Nat. 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Biotechnol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1105-1124.e19","DOI":"10.1016\/j.stem.2021.03.005","article-title":"Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.","volume":"28","author":"M Breunig","year":"2021","journal-title":"Cell Stem Cell."},{"key":"ref45","doi-asserted-by":"publisher","DOI":"10.6084\/m9.figshare.28559300.v4","article-title":"Generation of human iPSC-derived pancreatic organoids to study pancreas development and disease.","author":"J Darrigrand","year":"2025","journal-title":"Figshare."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/14-575\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/14-575\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/14-575\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T04:55:07Z","timestamp":1753937707000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/14-575\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,10]]},"references-count":45,"URL":"https:\/\/doi.org\/10.12688\/f1000research.162496.1","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.178705.r393060","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.178705.r391177","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.178705.r391175","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.178705.r391179","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.178705.r391177","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.178705.r391180","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.178705.r391175","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.178705.r393060","asserted-by":"object"}],"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.10.24.620102","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,10]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/14-575\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.178705.r393060, Christof Westenfelder, Division of Nephrology, Department of Internal Medicine, University of Utah Medical Centers, Salt Lake City, UT, 84112, 29 Jul 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-575\/v1#referee-response-393060","order":0,"name":"referee-response-393060","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.178705.r391175, Ilse Rooman, Universiteit Brussel, Brussels, 29 Jul 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-575\/v1#referee-response-391175","order":1,"name":"referee-response-391175","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.178705.r391177, Maria Cristina Nostro, McEwen Stem Cell Institute, Toronto, 31 Jul 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-575\/v1#referee-response-391177","order":2,"name":"referee-response-391177","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by a fellowship from NC3Rs (grant reference NC\/V002260\/1) to Jean-Francois Darrigrand. Abigail Isaacson was funded by the Wellcome Trust PhD programme \u2018\u2018Cell therapies and regenerative medicine\u2019\u2019 (grant #108874\/Z\/15\/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}