Revolutionizing IBD Research with Innovative In Vitro Models

When examining the existing landscape of pharmaceutical interventions for inflammatory bowel disease (IBD), the inherent limitations of current pre-clinical models and how it is hampering the translation of research findings into new therapeutic approaches are readily apparent. These models, employed to study disease mechanisms and evaluate potential therapies, often fail to closely replicate the complex pathophysiology of IBD, particularly in clinically distinct subsets like fistulizing Crohn’s disease. This flaw poses a significant barrier to the development of effective treatments that can adequately address the diverse manifestations of the disease.

To address this gap, we introduce an in vitro human IBD mucosal model built using our Alvetex Scaffold, which is capable of simultaneously recapitulating multiple pathological features of the disease within a single model system. The model is designed to recreate three key aspects of IBD pathogenesis: immune cell activation, compromised epithelial barrier integrity, and stromal remodelling dynamics. To achieve this, researchers at REPROCELL and Durham University have cultured different types of cells involved in these processes, including immune cells such as macrophages and T cells, epithelial cells lining the gut mucosa, and stromal cells that provide structural support to the tissue.

By culturing these cells together in a controlled environment, we aimed to replicate the complex cellular crosstalk observed in IBD. Inflammation and epithelial damage can be induced using various stimuli, such as pro-inflammatory cytokines or bacterial components, to simulate disease conditions.

Upon stimulation, the models exhibit epithelial abnormalities that are characteristic of IBD, including morphological alterations, microvilli abnormalities, changes in claudin gene expression, and increased permeability. Furthermore, the inflammatory response in the stimulated models results in significant elevation of key biomarkers such as cytokines and chemokines crucial to IBD pathogenesis. Evidence of extracellular matrix remodelling, marked by upregulated matrix-metalloproteinases and altered basement membrane components, suggests that the models effectively simulate pathological stromal remodelling events closely resembling those seen in fistulizing CD. Notably, MMP-9 emerges as the most abundant matrix-metalloproteinase in the inflamed models, exhibiting a localization pattern akin to that observed in actual IBD tissue.

Subsequent investigation using the inflamed models sheds light on the involvement of TNF-α and IFN-γ in intestinal stromal remodelling. Interestingly, TNF-α, but not IFN-γ, induces the upregulation of specific matrix-metalloproteinases, notably MMP-3 and MMP-9. Together, these findings underscore the potential of our Alvetex-based IBD models for preclinical research.

The validity and utility of the inflamed IBD models are underscored by their ability to replicate critical aspects of IBD pathophysiology observed in patients. These include histopathological changes, upregulation of inflammatory biomarkers, and alterations in cytokine expression profiles reminiscent of those seen in clinical settings. Notably, the models also successfully mimic epithelial dysfunction, a hallmark feature of IBD characterized by increased permeability and structural abnormalities.

While the models presented in the study represent a significant advancement in IBD research, they are not without limitations. Further refinement and validation efforts are underway to further enhance the utility of the model for pre-clinical drug testing and mechanistic studies. Overall, the development of this innovative in vitro model holds immense promise for advancing our understanding of IBD pathophysiology and accelerating the discovery of novel therapeutic interventions.

More information about our IBD assays can be found here:

• Anti-inflammatory drug responses in human fresh IBD tissues
• 3D Bioengineered IBD model
• Pharmacology-AI: IBDiscovery

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