CFTR represses a PDX1 axis to govern pancreatic ductal cell fate

CFTR represses a PDX1 axis to govern pancreatic ductal cell fate

Summary: 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...

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Main Authors: Pavana G. Rotti, Yaling Yi, Grace Gasser, Feng Yuan, Xingshen Sun, Idil Apak-Evans, Peipei Wu, Guangming Liu, Soon Choi, Rosie Reeves, Attilina E. Scioneaux, Yulong Zhang, Michael Winter, Bo Liang, Nathan Cunicelli, Aliye Uc, Andrew W. Norris, Lori Sussel, Kristen L. Wells, John F. Engelhardt
Format: Article
Language:English
Published: Elsevier 2024-12-01
Series:iScience
Subjects:
Physiology
Molecular biology
Cell biology
Transcriptomics
Online Access:http://www.sciencedirect.com/science/article/pii/S258900422402618X
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Summary:Summary: 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 CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.
ISSN:2589-0042

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