Application of Human Induced Pluripotent Stem Cell-Derived Intestinal Organoids as a Model of Epithelial Damage and Fibrosis in Inflammatory Bowel Disease

Inflammatory bowel disease, which typically manifests as Crohn's disease and ulcerative colitis, is caused by the abnormal production of cytokines such as tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta. These cytokines damage intestinal epithelial cells and trigger fibrosis, respectively, for which the current in vitro models have many limitations. Therefore, we tested whether human induced pluripotent stem cell-derived intestinal organoids (HiOs) can mimic inflammatory bowel disease (IBD), and whether such a model is suitable for drug screening. HiOs were treated with TNF-alpha and TGF-beta to construct mucosal damage and fibrosis models. TNF-alpha diminished the mRNA expression of intestinal epithelial cell and goblet cell markers in HiOs. TNF-alpha also induced epithelial cell damage and degradation of tight junctions but not in the presence of infliximab, an antibody used in the clinic to deplete TNF-alpha. Furthermore, permeation of the non-absorbable marker FD-4 was observed in HiOs treated with TNF-alpha or ethylene glycol tetraacetic acid (EGTA), but not in the presence of infliximab. In contrast, TNF-alpha and TGF-beta induced mRNA expression of mesenchymal and fibrosis markers, as well as epithelial mesenchymal transition. SB431542, a TGF-beta inhibitor, significantly reversed these events. The data indicate that HiOs mimic mucosal damage and fibrosis due to IBD and are thus suitable models for drug screening.