CFTR represses a PDX1 axis to govern pancreatic ductal cell fate
Inflammation, acinar atrophy, and ductal hyperplasia drive pancreatic remodeling in newborn cystic fibrosis (CF) ferrets lacking a functional cystic fibrosis conductance regulator (CFTR) channel. These changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. The phenotypic changes in CF ductal epithelium and their impact on islet function are unknown. Using bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3β activation. In the absence of CFTR protein, centroacinar cells adopted a bipotent progenitor-like state associated with enhanced WNT/β-Catenin, transforming growth factor β (TGF-β), and AKT signaling. We show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which <i>CFTR</i> mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
Authors
- Idil Apak-Evans
- Xingshen Sun (ORCID: https://orcid.org/0000-0003-3561-8428)
- Pavana G. Rotti (ORCID: https://orcid.org/0000-0003-1801-0269)
- Grace N. Gasser (ORCID: https://orcid.org/0000-0002-2393-2674)
- John F. Engelhardt (ORCID: https://orcid.org/0000-0003-2389-9277)
- Andrew W. Norris (ORCID: https://orcid.org/0000-0001-8396-9543)
- Nathan Cunicelli (ORCID: https://orcid.org/0000-0002-5640-3197)
- Aliye Uç (ORCID: https://orcid.org/0000-0003-2004-5743)
- Lori Sussel (ORCID: https://orcid.org/0000-0003-4672-7304)
- Feng Yuan (ORCID: https://orcid.org/0000-0001-9979-3853)
- Rosie E. Reeves
- Soon Ho Choi (ORCID: https://orcid.org/0000-0002-2351-9775)
- Kristen L. Wells (ORCID: https://orcid.org/0000-0002-7466-8164)
- Yulong Zhang (ORCID: https://orcid.org/0000-0003-3531-0052)
- Guang‐Ming Liu (ORCID: https://orcid.org/0000-0002-8689-0504)
- Yaling Yi (ORCID: https://orcid.org/0000-0001-5385-063X)
- Michael C. Winter
- Peipei Wu
- Attilina E Scioneaux
- Bo Liang (ORCID: https://orcid.org/0000-0003-4732-1488)
Institutions
- University of Iowa (US)
- Whitehead Institute for Biomedical Research (US)
- University of Colorado Anschutz Medical Campus (US)
Publication Details
- Journal
- iScience
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1016/j.isci.2024.111393
- Citations
- 4
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 2.29
Funders
- Cystic Fibrosis Foundation
- Cystic Fibrosis Foundation Therapeutics
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- NHLBI Division of Intramural Research