Alterations in the epithelial stem cell compartment could contribute to permanent changes in the mucosa of patients with ulcerative colitis

Abstract

ObjectiveUC is a chronic inflammatory disease of the colonic mucosa. Growing evidence supports a role for epithelial cell defects in driving pathology. Moreover, long-lasting changes in the epithelial barrier have been reported in quiescent UC. Our aim was to investigate whether epithelial cell defects could originate from changes in the epithelial compartment imprinted by the disease.DesignEpithelial organoid cultures (EpOCs) were expanded ex vivo from the intestinal crypts of non-IBD controls and patients with UC. EpOCs were induced to differentiate (d-EpOCs), and the total RNA was extracted for microarray and quantitative real-time PCR (qPCR) analyses. Whole intestinal samples were used to determine mRNA expression by qPCR, or protein localisation by immunostaining.ResultsEpOCs from patients with UC maintained self-renewal potential and the capability to give rise to differentiated epithelial cell lineages comparable with control EpOCs. Nonetheless, a group of genes was differentially regulated in the EpOCs and d-EpOCs of patients with UC, including genes associated with antimicrobial defence (ie, LYZ, PLA2G2A), with secretory (ie, ZG16, CLCA1) and absorptive (ie, AQP8, MUC12) functions, and with a gastric phenotype (ie, ANXA10, CLDN18 and LYZ). A high rate of concordance was found in the expression profiles of the organoid cultures and whole colonic tissues from patients with UC.ConclusionsPermanent changes in the colonic epithelium of patients with UC could be promoted by alterations imprinted in the stem cell compartment. These changes may contribute to perpetuation of the disease.

Intestinal epithelial claudins: expression and regulation in homeostasis and inflammation

“…Increased claudin‐18 expression has been noted in the intestinal mucosa of ulcerative colitis patients and in mice with trinitrobenzenesulfonic acid (TNBS) colitis . Since claudin‐18 is predominantly expressed in the stomach, its induction (along with expression of some other markers of gastric epithelium) suggests localized shifts in intestinal stem cell differentiation toward the gastric program in ulcerative colitis patients . The increase of claudin‐18 was also recently demonstrated in epithelial organoid cultures from ulcerative colitis patients (Table ).…”

Intestinal organoid culture model is a valuable system to study epithelial barrier function in IBD

“…With great interest, we have read the article by Dotti et al ,1 who analysed the transcriptional signature of epithelial organoid cultures (EpOCs) generated from patients with UC and non-IBD controls. They identified a set of genes that were differentially expressed between UC and control EpOCs, among which several were associated with epithelial secretory and antimicrobial defense.…”

Epithelial organoid cultures from patients with ulcerative colitis and Crohn's disease: a truly long-term model to study the molecular basis for inflammatory bowel disease?

“…With great interest we read the paper by Dotti et al ,1 who identified a set of differentially expressed genes in epithelial organoid cultures (EpOCs) derived from patients with UC compared with EpOCs from healthy controls.…”