Abstract
The pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown. No model exists that adequately recapitulates the complexity of clinical UC. Here, we take advantage of induced pluripotent stem cells (iPSCs) to develop an induced human UC-derived organoid (iHUCO) model and compared it with the induced human normal organoid model (iHNO). Notably, iHUCOs recapitulated histological and functional features of primary colitic tissues, including the absence of acidic mucus secretion and aberrant adherens junctions in the epithelial barrier both in vitro and in vivo. We demonstrate that the CXCL8/CXCR1 axis was overexpressed in iHUCO but not in iHNO. As proof-of-principle, we show that inhibition of CXCL8 receptor by the small-molecule non-competitive inhibitor repertaxin attenuated the progression of UC phenotypes in vitro and in vivo. This patient-derived organoid model, containing both epithelial and stromal compartments, will generate new insights into the underlying pathogenesis of UC while offering opportunities to tailor interventions to the individual patient.
Highlights
The pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown
We provide evidence linking recent advances in stem cell biology[19] with intestinal development[10,11,12,15,20,21,22] to reprogram colonic fibroblasts isolated from UC patients to induced pluripotent stem cells (iPSCs), followed by directed differentiation to induced human UC organoids
We reprogrammed UC fibroblasts to iPSCs; UC fibroblasts were isolated from 6 patients with established chronic colitis along with samples from 4 participants with normal colonic fibroblasts and one from a commercially available source (Supplementary Table 1, Supplementary Fig. 1a, 1b)
Summary
The pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown. As proof-ofprinciple, we show that inhibition of CXCL8 receptor by the small-molecule non-competitive inhibitor repertaxin attenuated the progression of UC phenotypes in vitro and in vivo This patient-derived organoid model, containing both epithelial and stromal compartments, will generate new insights into the underlying pathogenesis of UC while offering opportunities to tailor interventions to the individual patient. Pluripotent stem cell (PSC)-derived human intestinal organoids have been developed for the normal mid/hind gut[10,11] and colon[12,13] and have distinct advantages in advancing precision medicine[14] These organoids can be derived from the individual patient and exhibit recapitulation of physiological responses both in vitro and in vivo[10,12,15]. The roles of the inflammatory chemokine CXCL8 and chemotactic cytokine CXCL1 were highlighted in the transcriptome and mesenchymal secretome of iHUCOs and their parental fibroblasts
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