Aberrant Niche Signaling In The Etiopathogenesis Of Ulcerative Colitis

BACKGROUND:Primary colonic epithelial defects leading to inflammatory responses are considered central to the development of ulcerative colitis (UC). However, a systematic analysis of various colonic subcompartments in the pathogenesis of UC before inflammation remains elusive. Here, we explored changes in colonic subcompartments and their associated niche signals in patient mucosal biopsies and in an animal model of colitis. METHODS:Analysis of mucosal biopsies obtained from uninvolved and involved regions of patients with UC and Crohn's disease was performed and compared with normal subjects. Temporal analysis of colonic subcompartments was performed in mice administered with 5% dextran sodium sulphate. Phenotypic enumeration of the crypt subcompartment was complemented with flow cytometric analysis. Members of Notch and Wnt signaling pathways were analyzed by molecular, biochemical, and colocalization studies. RESULTS:Phenotypic enumeration of colonocytes' subcompartments from patients revealed significant alterations of the lower crypt, enriched in stem cell and progenitors, independent of inflammation. These changes, unique to UC, were confirmed by immunohistochemistry and molecular analysis. In parallel, a defect in proliferation and Muc2 synthesis was observed. Animal data before inflammation recapitulated human studies. Mechanistic studies revealed that changes in signaling through Wnt primarily affected colonic stem cells, whereas Notch affected progenitor function. CONCLUSIONS:Our results thus provide new insights into the development of inflammation and relapse in UC and suggest that the stem cell niche in the colon may influence pathogenesis of the disease.