Early pathogenesis of cystic fibrosis gallbladder disease in a porcine model

Keyan Zarei; Mallory R Stroik; Nick D Gansemer; Andrew L Thurman; Lynda S Ostedgaard; Sarah E Ernst; Ian M Thornell; Linda S Powers; Alejandro A Pezzulo; David K Meyerholz; David A Stoltz

doi:10.1038/s41374-020-0474-8

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Early pathogenesis of cystic fibrosis gallbladder disease in a porcine model

Journal article

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Peer reviewed

Early pathogenesis of cystic fibrosis gallbladder disease in a porcine model

Keyan Zarei, Mallory R Stroik, Nick D Gansemer, Andrew L Thurman, Lynda S Ostedgaard, Sarah E Ernst, Ian M Thornell, Linda S Powers, Alejandro A Pezzulo, David K Meyerholz, …

Laboratory investigation, Vol.100(11), pp.1388-1399

11/2020

DOI: 10.1038/s41374-020-0474-8

PMCID: PMC7578062

PMID: 32719544

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Abstract

Hepatobiliary disease causes significant morbidity in people with cystic fibrosis (CF), yet this problem remains understudied. We previously found that newborn CF pigs have microgallbladders with significant luminal obstruction in the absence of infection and consistent inflammation. In this study, we sought to better understand the early pathogenesis of CF pig gallbladder disease. We hypothesized that loss of CFTR would impair gallbladder epithelium anion/liquid secretion and increase mucin production. CFTR was expressed apically in non-CF pig gallbladder epithelium but was absent in CF. CF pig gallbladders lacked cAMP-stimulated anion transport. Using a novel gallbladder epithelial organoid model, we found that Cl or HCO was sufficient for non-CF organoid swelling. This response was absent for non-CF organoids in Cl /HCO -free conditions and in CF. Single-cell RNA-sequencing revealed a single epithelial cell type in non-CF gallbladders that coexpressed CFTR, MUC5AC, and MUC5B. Despite CF gallbladders having increased luminal MUC5AC and MUC5B accumulation, there was no significant difference in the epithelial expression of gel-forming mucins between non-CF and CF pig gallbladders. In conclusion, these data suggest that loss of CFTR-mediated anion transport and fluid secretion contribute to microgallbladder development and luminal mucus accumulation in CF.

Animals

Animals, Newborn

Cystic Fibrosis - complications

Cystic Fibrosis - metabolism

Cystic Fibrosis - physiopathology

Cystic Fibrosis Transmembrane Conductance Regulator - physiology

Disease Models, Animal

Epithelial Cells - metabolism

Gallbladder - metabolism

Gallbladder - physiopathology

Gallbladder Diseases - etiology

Gallbladder Diseases - metabolism

Mucin 5AC - metabolism

Mucin-5B - metabolism

Swine

Transcriptome

Details

Title: Subtitle: Early pathogenesis of cystic fibrosis gallbladder disease in a porcine model
Creators: Keyan Zarei - University of Iowa
Mallory R Stroik - University of Iowa
Nick D Gansemer - University of Iowa
Andrew L Thurman - University of Iowa
Lynda S Ostedgaard - University of Iowa
Sarah E Ernst - University of Iowa
Ian M Thornell - University of Iowa
Linda S Powers - University of Iowa
Alejandro A Pezzulo - University of Iowa
David K Meyerholz - University of Iowa
David A Stoltz - University of Iowa
Resource Type: Journal article
Publication Details: Laboratory investigation, Vol.100(11), pp.1388-1399
DOI: 10.1038/s41374-020-0474-8
PMID: 32719544
PMCID: PMC7578062
NLM abbreviation: Lab Invest
ISSN: 0023-6837
eISSN: 1530-0307
Grant note: P01 HL091842 / NHLBI NIH HHS P01 HL051670 / NHLBI NIH HHS P30 DK054759 / NIDDK NIH HHS T32 HL007638 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS
Language: English
Date published: 11/2020
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Pathology; Iowa Neuroscience Institute; Internal Medicine
Record Identifier: 9984186572502771

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