人体器官芯片揭示炎症性肠病驱动因素

Alican Özkan, Gwenn Merry, David B Chou, Ryan R Posey, Anna Stejskalova, Karina Calderon, Megan Sperry, Viktor Horvath, Lorenzo E Ferri, Emanuela Carlotti, Stuart A C McDonald, Douglas J Winton, Rocco Riccardi, Lilianna Bordeianou, Sean Hall, Girija Goyal, Donald E Ingber
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摘要

炎症性肠病(IBD)患者表现出肠道屏障功能受损、粘液积聚减少以及炎症、纤维化和癌症风险增加,妊娠期妇女的症状往往会加重。在这里,我们展示了这些 IBD 标志可以通过使用由 IBD 患者来源的结肠上皮细胞与在流动条件下培养的匹配成纤维细胞连接而成的人体器官芯片来复制。使用异型组织重组物发现,IBD 成纤维细胞是多种 IBD 症状的主要驱动因素。IBD 芯片的蠕动和女性 IBD 芯片暴露于妊娠相关激素时,炎症和纤维化会加剧。在 IBD 芯片中,接触致癌物质也会增加炎症、基因突变和染色体重复,但在健康芯片中则不会。利用人体器官芯片技术获得的这些数据表明,肠道基质和与蠕动相关的机械变形在推动男性和女性 IBD 患者的炎症和疾病进展方面起着关键作用。
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Inflammatory Bowel Disease Drivers Revealed in Human Organ Chips.

Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis, and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here, we show that these IBD hallmarks can be replicated using human Organ Chips lined by IBD patient-derived colon epithelial cells interfaced with matched fibroblasts cultured under flow. Use of heterotypic tissue recombinants revealed that IBD fibroblasts are the primary drivers of multiple IBD symptoms. Inflammation and fibrosis are accentuated by peristalsis-like motions in IBD Chips and when exposed to pregnancy-associated hormones in female IBD Chips. Carcinogen exposure also increases inflammation, gene mutations, and chromosome duplication in IBD Chips, but not in Healthy Chips. These data enabled by human Organ Chip technology suggest that the intestinal stroma and peristalsis-associated mechanical deformations play a key role in driving inflammation and disease progression in male and female IBD patients.

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