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Goblet Cell Hyperplasia is not Epithelial-Autonomous in the Cftr Knockout Intestine.

Authors
  • Walker, Nancy M1
  • Liu, Jinghua1
  • Young, Sarah M1, 2
  • Woode, Rowena A1, 3
  • Clarke, Lane L1, 3
  • 1 Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, United States. , (United States)
  • 2 Department of Pathobiology, Columbia, MO, United States. , (United States)
  • 3 Department of Biomedical Sciences, University of Missouri, Columbia, MO, United States. , (United States)
Type
Published Article
Journal
AJP Gastrointestinal and Liver Physiology
Publisher
American Physiological Society
Publication Date
Dec 08, 2021
Identifiers
DOI: 10.1152/ajpgi.00290.2021
PMID: 34878935
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Goblet cell hyperplasia is an important manifestation of cystic fibrosis (CF) disease in epithelial-lined organs. Explants of CF airway epithelium show normalization of goblet cell numbers; therefore we hypothesized that small intestinal enteroids from Cftr knockout (KO) mice would not exhibit goblet cell hyperplasia. Toll-like receptors 2 and 4 (Tlr2, Tlr4) were investigated as markers of inflammation and influence on goblet cell differentiation. Ex vivo studies found goblet cell hyperplasia in Cftr KO jejunum as compared to wild-type (WT). IL-13, SAM pointed domain-containing ETS transcription factor (Spdef), Tlr2 and Tlr4 protein expression was increased in Cftr KO intestine relative to WT. In contrast, WT and Cftr KO enteroids did not exhibit differences in basal or IL-13-stimulated goblet cell numbers, or differences in expression of Tlr2, Tlr4 and Spdef. Ileal goblet cell numbers in Cftr KO/Tlr4 KO and Cftr KO/Tlr2 KO mice were not different from Cftr KO mice, but enumeration was confounded by altered mucosal morphology. Treatment with Tlr4 agonist LPS did not affect goblet cell numbers in WT or Cftr KO enteroids, whereas the Tlr2 agonist Pam3Csk4 stimulated goblet cell hyperplasia in both genotypes. Pam3Csk4 stimulation of goblet cell numbers was associated with suppression of Notch1 and Neurog3 expression and upregulated determinants of goblet cell differentiation. We conclude that goblet cell hyperplasia and inflammation of the Cftr KO small intestine are not exhibited by enteroids, indicating that this manifestation of CF intestinal disease is not epithelial-automatous but secondary to the altered CF intestinal environment.

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