Deciphering cryptic calcium signals in the human colonic epithelium.

Pelaez Llaneza, Nicolas (2019) Deciphering cryptic calcium signals in the human colonic epithelium. Doctoral thesis, University of East Anglia.

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The colonic epithelium is constantly exposed to a harsh luminal environment. A monolayer of epithelial cells is organised into millions of blind ending flask-like invaginations called crypts. The regulation of the epithelial barrier is key in maintaining tissue integrity; failure to do so can result in the development of intestinal conditions such as inflammatory bowel diseases and cancer.

Stem cells residing at each crypt-base constantly proliferate to maintain tissue renewal and integrity. Physical barrier function provided by the epithelial monolayer is supported by goblet cells which secrete mucus and other antimicrobial proteins to protect the epithelium from noxious substances and the luminal microbiota. The regulation of this dynamic epithelial barrier and the associated physiological functions requires the complex integration of different signalling pathways. Calcium is a versatile intracellular messenger capable of integrating different signals to modulate cell biology and physiological function.

The aim of this thesis was to determine the molecular mechanism of cholinergic-induced intracellular calcium signals in the colonic epithelium and study the implications for tissue renewal and barrier function.

This thesis demonstrates that in the colonic epithelium intracellular calcium signals couple muscarinic receptors to the modulation of short-term and long-term physiological responses. In the stem cell niche, muscarinic receptor activation results in the generation of an intracellular calcium signal mediated by the endolysosomal Two-pore channels. The cholinergic calcium signal initiates in stem cells and results in the translocation of transcription factors to the nucleus and, over the long-term, stimulation of stem/progenitor cell proliferation and tissue regeneration. After a short delay, the stem cell-calcium signal registers in neighbouring goblet cells, hereby defined as Guardian goblet cells because they protect adjacent intestinal stem cells. Activation of the calcium signalling pathway in goblet cells induces mucus secretion and expansion in the crypt lumen which is accompanied by stimulated fluid secretion from neighbouring stem/progenitor cells; these short-term physiological responses culminate in flushing of the crypt luminal contents.

Taken together, these findings demonstrate a central role for intracellular calcium signalling in maintaining the fitness of the human intestinal stem cell niche and in promoting gut barrier function.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Chris White
Date Deposited: 12 Apr 2021 13:56
Last Modified: 30 Sep 2022 01:38


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