Özkan Alican, Merry Gwenn, Chou David B, Posey Ryan R, Stejskalova Anna, Calderon Karina, Sperry Megan, Horvath Viktor, Ferri Lorenzo E, Carlotti Emanuela, McDonald Stuart A C, Winton Douglas J, Riccardi Rocco, Bordeianou Lilianna, Hall Sean, Goyal Girija, Ingber Donald E
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA.
Department of Pathology, Massachusetts General Hospital, Boston, MA.
medRxiv. 2024 Dec 8:2024.12.05.24318563. doi: 10.1101/2024.12.05.24318563.
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.
炎症性肠病（IBD）患者表现出肠道屏障功能受损、黏液积累减少，以及炎症、纤维化和癌症风险增加，且症状在孕期女性中往往会加剧。在此，我们表明，使用由IBD患者来源的结肠上皮细胞衬里并与在流动条件下培养的匹配成纤维细胞相连接的人体器官芯片，可以重现这些IBD特征。使用异型组织重组体表明，IBD成纤维细胞是多种IBD症状的主要驱动因素。IBD芯片中的类蠕动运动以及雌性IBD芯片暴露于妊娠相关激素时，炎症和纤维化会加剧。致癌物暴露也会增加IBD芯片中的炎症、基因突变和染色体复制，但在健康芯片中则不会。人体器官芯片技术所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驱动男性和女性IBD患者的炎症和疾病进展中起关键作用。
