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In this study, we performed single cell multiomic and spatial profiling of 2.04M cells in the pancreas from 23 non-disease and CF donors and defined regulatory programs and tissue niches of specific cell types and sub-types in CF. A high-mucin sub-type of ductal cells had relatively preserved abundance, altered localization and up-regulated stress, secretion and pro-fibrotic activity in CF, and conventional ductal cells showed evidence for transition to the high-mucin state. Increased inflammatory and fibrotic pathway activity in CF was linked to closer proximity and crosstalk between immune and stellate cells in specific niches. Beta cells had extensive genomic changes in CF, including increased stress and insulin secretion-related processes, and these changes were broadly distinct from those in type 1 and type 2 diabetes. Islets in CF preferentially localized near large adipose tissue and collagen structures, and both areas were strongly linked to beta cell loss in CF due to signaling from adipocytes, macrophages, stellate, and high-mucin ductal cells. Overall, our results reveal cellular drivers of pancreatic dysfunction in CF and offer new in-roads to preserving beta cells in CFRD.<\/jats:p>","DOI":"10.64898\/2025.12.14.694120","type":"posted-content","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T04:51:11Z","timestamp":1765947071000},"source":"Crossref","is-referenced-by-count":3,"title":["Single cell and spatial characterization of the human pancreas reveals drivers of beta cell dysfunction in cystic fibrosis"],"prefix":"10.64898","author":[{"given":"Hannah M.","family":"Mummey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sierra","family":"Corban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacinta","family":"Lucero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L.","family":"Melton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine","family":"Pittigher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria C.","family":"Johnston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail H.","family":"Deutsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"D\u2019Antonio-Chronowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L.","family":"Hull-Meichle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle J.","family":"Gaulton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025121811550937000_2025.12.14.694120v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2475911"},{"key":"2025121811550937000_2025.12.14.694120v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90148-8"},{"key":"2025121811550937000_2025.12.14.694120v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2745"},{"key":"2025121811550937000_2025.12.14.694120v1.4","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200509-1377OC"},{"key":"2025121811550937000_2025.12.14.694120v1.5","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1089\/jpm.2013.9515","article-title":"Palliative Care for Patients with Cystic Fibrosis #265","volume":"16","year":"2013","journal-title":"J. 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