Lrig3 is Necessary for Proper Cellular Census in the Stem Cell Compartment of the Colonic Epithelium in Homeostasis and Regeneration

The cellular census of the colonic crypt is tightly regulated to provide a protective barrier from the external environment and actively renew every five-to-seven days. The crypt is formed into U-shaped invaginations that compartmentalize cell type and function through three primary regions: the stem cell compartment at the base, the transit-amplifying region in the middle, and the differentiated region at the luminal surface. This steady state of renewal requires consistent and stereotyped cell proliferation, migration, differentiation, anoikis and extrusion from the epithelium. Every year, in millions of genetically-susceptible Americans, this process goes awry, and the disruption of the epithelial barrier results in an inflammatory response to commensal microbes and pathogens, resulting in Inflammatory Bowel Disease (IBD). This inflammatory attack results in complete, localized destruction of the epithelial layer and this is repaired, over time, and restored to its original state. The etiology of IBD is not fully understood, studying the molecular mechanisms and gene expression that governs colonic cell self-renewal and crypt and regeneration will likely aid in our understanding of the regenerative process that occurs in IBD patients. In this thesis I show how Lrig3, a transmembrane protein, governs homeostatic renewal and inflammation-induced regeneration. I describe for the first time that Lrig3 is expressed in colonic crypt epithelial cells, including the stem, progenitor, and differentiated cell types. Using a novel mouse model, I show that mice missing Lrig3 have an expansion of the stem cell compartment in colonic crypts, without any obvious impact to colonic function. However, when the mice are subjected to a chemically induced inflammatory state, they lack the ability to regenerate their colonic epithelium. This thesis contributes key information in our understanding of cellular census in the colonic crypt during epithelial renewal and identifies a protein necessary for colonic crypt regeneration.2023-08-0