Journal article
CFTR Represses a PDX1 Axis to Govern Pancreatic Ductal Cell Fate
iScience, Vol.27(12), 111393
12/2024
DOI: 10.1016/j.isci.2024.111393
PMCID: PMC11647141
PMID: 39687022
Abstract
Inflammation, acinar atrophy, and ductal hyperplasia drive pancreatic remodeling in newborn cystic fibrosis (CF) ferrets lacking a functional 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-seq, scRNA-seq, and 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 bi-potent progenitor-like state associated with enhanced WNT/β-Catenin, TGFβ 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 CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
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•The lack of CFTR leads to activation of PDX1 in pancreatic ductal epithelium.•CFTR-KO (CF) duct epithelium have open chromatin at endocrine regulatory loci.•Expansion of centroacinar cells observed in CFTR-KO epithelium.•The absence of CFTR protein inhibits PTEN and activates WNT and PDX1expression.
Details
- Title: Subtitle
- CFTR Represses a PDX1 Axis to Govern Pancreatic Ductal Cell Fate
- Creators
- Pavana G. Rotti - Whitehead Institute, MIT, Cambridge, Massachusetts, USAYaling Yi - University of IowaGrace Gasser - University of IowaFeng Yuan - University of IowaXingshen Sun - University of IowaIdil Apak-Evans - University of Iowa, Molecular Physiology and BiophysicsPeipei Wu - University of IowaGuangming Liu - University of IowaSoon Choi - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USARosie Reeves - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAAttilina E. Scioneaux - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAYulong Zhang - University of IowaMichael Winter - University of IowaBo Liang - University of IowaNathan Cunicelli - University of IowaAliye Uc - Stead Family Department of Pediatrics, Carver College of Medicine, Iowa City, Iowa, Iowa, USAAndrew W. Norris - University of IowaLori Sussel - University of Colorado Anschutz Medical CampusKristen L. Wells - University of Colorado Anschutz Medical CampusJohn F. Engelhardt - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- iScience, Vol.27(12), 111393
- DOI
- 10.1016/j.isci.2024.111393
- PMID
- 39687022
- PMCID
- PMC11647141
- NLM abbreviation
- iScience
- ISSN
- 2589-0042
- eISSN
- 2589-0042
- Publisher
- Elsevier Inc
- Grant note
- NIH: P30 DK054759, RC2 DK124207 Cystic Fibrosis Foundation grant: ENGELH21XX0 Carver Chair in Molecular MedicineNHLBI: 75N92024C00008
This work was supported by NIH grants (P30 DK054759, RC2 DK124207, and NHLBI Federal Contract 75N92024C00008 to J.F.E.) ; Cystic Fibrosis Foundation grant (ENGELH21XX0 to JFE) the Carver Chair in Molecular Medicine (to J.F.E.) . Biorender was used for figure and graphical abstract schematics.
- Language
- English
- Electronic publication date
- 11/2024
- Date published
- 12/2024
- Academic Unit
- Molecular Physiology and Biophysics; Endocrinology and Diabetes; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Radiation Oncology; Gastroenterology, Hepatology, Pancreatology, and Nutrition; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984749359202771
Metrics
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