A Specific Expression Signature Suggests Intrinsic Defects in the Stem Cell Compartment of Colitic Epithelium

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that affects the superficial mucosal barrier. Scant data is available about the contribution of intestinal epithelial cell (EC) dysfunction to this disease. Using a recent human gastrointestinal epithelial stem cell culture system, we investigated whether primary defects in ECs could be present in UC.

To this end, we collected biopsies from the sigmoid colon of 11 non-IBD controls and 8 UC patients. Isolated crypt units were cultured in Matrigel, and stem ECs were expanded as 3D organoids. Total RNA from stem and differentiated organoids was extracted for transcriptional analysis.

Our results show that control and UC epithelial stem organoids follow similar differentiation programs with comparable regulation of stem (i.e., Lgr5, AXIN2), proliferation (i.e., Myc, Ki67), and epithelial markers (i.e., MUC2, ANPEP). Microarray analysis, however, revealed a small panel of genes differentially expressed by UC compared to non-IBD organoids grown under the same conditions. Several of the UC up-regulated genes are characteristic of the upper regions of the intestine, while UC-derived organoids showed a marked down-regulation of genes normally expressed by the distal colon.

Overall, we demonstrate that sigmoid ECs from colitic patients show a unique transcriptional signature including the acquisition of an upper intestinal tract phenotype. We hypothesize that this could ultimately drive permanent changes in colitic epithelium with implications on mucus composition and the nature of antimicrobial response.