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Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease
Jinghua Liu, … , Ashlee M. Strubberg, Lane L. Clarke
Jinghua Liu, … , Ashlee M. Strubberg, Lane L. Clarke
Published February 2, 2015
Citation Information: J Clin Invest. 2015;125(3):1056-1068. https://doi.org/10.1172/JCI73193.
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Research Article Gastroenterology

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

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Abstract

Cystic fibrosis (CF) intestinal disease is associated with the pathological manifestation mucoviscidosis, which is the secretion of tenacious, viscid mucus that plugs ducts and glands of epithelial-lined organs. Goblet cells are the principal cell type involved in exocytosis of mucin granules; however, little is known about the exocytotic process of goblet cells in the CF intestine. Using intestinal organoids from a CF mouse model, we determined that CF goblet cells have altered exocytotic dynamics, which involved intrathecal granule swelling that was abruptly followed by incomplete release of partially decondensated mucus. Some CF goblet cells exhibited an ectopic granule location and distorted cellular morphology, a phenotype that is consistent with retrograde intracellular granule movement during exocytosis. Increasing the luminal concentration of bicarbonate, which mimics CF transmembrane conductance regulator–mediated anion secretion, increased spontaneous degranulation in WT goblet cells and improved exocytotic dynamics in CF goblet cells; however, there was still an apparent incoordination between granule decondensation and exocytosis in the CF goblet cells. Compared with those within WT goblet cells, mucin granules within CF goblet cells had an alkaline pH, which may adversely affect the polyionic composition of the mucins. Together, these findings indicate that goblet cell dysfunction is an epithelial-autonomous defect in the CF intestine that likely contributes to the pathology of mucoviscidosis and the intestinal manifestations of obstruction and inflammation.

Authors

Jinghua Liu, Nancy M. Walker, Akifumi Ootani, Ashlee M. Strubberg, Lane L. Clarke

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Figure 1

Incomplete mucin release by Cftr-KO goblet cells.

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Incomplete mucin release by Cftr-KO goblet cells.
(A) PAS-stained sectio...
(A) PAS-stained section of 100 μM CCH-stimulated intestine from WT (left) and Cftr-KO (right) mice. White arrows, Cftr-KO goblet cells with attached luminal mucus. (B) Transverse view of WT enteroid crypt during 100 μM CCH stimulation of goblet cell exocytosis. Arrows, goblet cells; L, crypt lumen. (C) Transverse view of Cftr-KO enteroid crypt during CCH stimulation of goblet cell exocytosis. White arrows, goblet cells with attached luminal mucus blebs; arrowhead, luminal extension of released mucus connected to granule cluster in theca. (D) Time-lapse microscopy of WT enteroid showing orderly progression of CCH-stimulated exocytosis by 2 goblet cells (white arrows). Top panel, goblet cells 2.25 minutes after CCH; panel 2, early exocytosis; panel 3, cupping at the apical aspect of the goblet cell during exocytosis; panel 4, ongoing exocytosis. (E) Time-lapse microscopy of Cftr-KO enteroid during CCH stimulation of goblet cell exocytosis. White arrows indicate the perimeter of granule cluster. Top panel, goblet cell 1.25 minutes after CCH; panel 2, enlarged granule cluster and enlargement of individual granule within theca (arrowhead); panel 3, exocytosis of enlarged granule (arrowhead); and panel 4, formation of a mucus bleb protruding into lumen (arrowhead). Note reduced size of granule cluster. Scale bars: 50 μm (A); 10 μm (B–E).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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