Department of Biosciences, Durham University, Durham, United Kingdom.
Reprocell Europe Ltd, West of Scotland Science Park, Glasgow, United Kingdom.
Front Immunol. 2024 Feb 12;15:1357690. doi: 10.3389/fimmu.2024.1357690. eCollection 2024.
At present, preclinical models of inflammatory bowel disease (IBD) are insufficient, limiting translation between research and new therapeutics. This is especially true for fistulising Crohn's disease (CD), as the severe lack of relevant models hinders research progression. To address this, we present human IBD mucosal models that recapitulate multiple pathological hallmarks of IBD simultaneously in one model system - immune cell infiltration, stromal remodelling and epithelial disruption. Stimulation of models induces epithelial aberrations common in IBD tissue including altered morphology, microvilli abnormalities, claudin gene expression changes and increased permeability. Inflammatory biomarkers are also significantly increased including cytokines and chemokines integral to IBD pathogenesis. Evidence of extracellular matrix remodelling, including upregulated matrix-metalloproteinases and altered basement membrane components, suggests the models simulate pathological stromal remodelling events that closely resemble fistulising CD. Importantly, MMP-9 is the most abundant MMP and mimics the unique localisation observed in IBD tissue. The inflamed models were subsequently used to elucidate the involvement of TNF-α and IFN- γ in intestinal stromal remodelling, in which TNF-α but not IFN- γ induced MMP upregulation, specifically of MMP-3 and MMP-9. Collectively, our results demonstrate the potential of the IBD models for use in preclinical research in IBD, particularly for fistulising CD.
目前,炎症性肠病(IBD)的临床前模型还不够完善,这限制了研究与新疗法之间的转化。对于瘘管性克罗恩病(CD)尤其如此,因为严重缺乏相关模型阻碍了研究进展。为了解决这个问题,我们提出了一种人类 IBD 黏膜模型,该模型在一个模型系统中同时再现了 IBD 的多个病理特征——免疫细胞浸润、基质重塑和上皮破坏。刺激模型可诱导上皮出现 IBD 组织中常见的异常,包括形态改变、微绒毛异常、紧密连接基因表达变化和通透性增加。炎症生物标志物也显著增加,包括对 IBD 发病机制至关重要的细胞因子和趋化因子。细胞外基质重塑的证据,包括基质金属蛋白酶的上调和基底膜成分的改变,表明这些模型模拟了与瘘管性 CD 非常相似的病理基质重塑事件。重要的是,MMP-9 是最丰富的 MMP,模拟了在 IBD 组织中观察到的独特定位。随后,对炎症模型进行了研究,以阐明 TNF-α 和 IFN-γ 在肠道基质重塑中的作用,结果表明 TNF-α 而非 IFN-γ 可诱导 MMP 上调,特别是 MMP-3 和 MMP-9。总之,我们的研究结果表明,这些 IBD 模型具有在 IBD 的临床前研究中应用的潜力,特别是对于瘘管性 CD。