Single cell and spatial characterization of the human pancreas reveals drivers of beta cell dysfunction in cystic fibrosis

Cystic fibrosis (CF) causes severely damaged pancreas morphology and results in high rates of cystic fibrosis-related diabetes (CFRD), but the cellular pathways and regulatory programs driving CFRD pathogenesis in the pancreas are not understood. 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.

• Publication year

  2025

• Venue

  bioRxiv

• Publication date

  2025-12-16

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.64898/2025.12.14.694120PMID 41446239PMCID 12724667
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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