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Contribution of Stroma to Inflammatory Bowel Disease Progression Revealed in Patient-Derived Human Colon Chips

ABSTRACT: Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function, enhanced inflammation, and increased cancer risk, with symptoms sometimes being exacerbated in women during pregnancy. To investigate the IBD phenotype and disease progression in human intestine, we leveraged organ-on-a-chip (Organ Chip) technology to engineer human Colon Chips lined by homotypic or heterotypic recombinants of intestinal epithelium interfaced with stromal fibroblasts isolated from Healthy or IBD patient-derived colon resections. Chips created with both epithelial and stromal cells from the same ulcerative colitis or Crohn's disease patient showed increased IBD-associated gene pathway activation, elevated pro-inflammatory cytokines, reduced mucus layer thickness, increased intestinal barrier permeability, compared to homotypic Healthy Colon Chips. When heterotypic tissue recombinants were created, the IBD stromal fibroblasts induced the IBD phenotype in healthy epithelium, and healthy colonic fibroblasts partially reduced inflammation in the IBD epithelium. Using this system, we discovered that peristalsis-like mechanical deformations directly impact colon tissue physiology by increasing mucin gene expression, mucus thickness, and barrier permeability in both Healthy and IBD Chips, and that they only stimulate a fibrotic response in IBD Chips. We also found that both inflammation and fibrosis were accentuated in IBD Chips created with cells from a female patient that were exposed to pregnancy-associated hormones. Interestingly, exposure to a carcinogen (N-ethyl-N-nitrosourea) for 3 weeks in vitro induced histological changes and gene duplication in the IBD Chips, but not in the Healthy Chips. These data suggest that the stroma plays a key role in driving inflammation and disease progression in IBD patients and that human Organ Chip technology may represent a new preclinical tool to gain insight into these mechanisms as well as to identify novel diagnostic biomarkers and therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277964 | GEO | 2025/01/02

REPOSITORIES: GEO

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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).

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Contribution of Stroma to Inflammatory Bowel Disease Progression Revealed in Patient-Derived Human Colon Chips

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