期刊
BIOLOGICAL & PHARMACEUTICAL BULLETIN
卷 43, 期 7, 页码 1088-1095出版社
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.b20-00088
关键词
induced pluripotent stem cell; intestinal organoid; inflammatory bowel disease; tumor necrosis factor (TNF)-alpha; transforming growth factor (TGF)-beta
资金
- Japan Society for the Promotion of Science [16K15164, 17108421]
- Research on Development of New Drugs from Japan Agency for Medical Research and Development [17937834]
- Japan Research Foundation for Clinical Pharmacology
- Nagoya City University
- Grants-in-Aid for Scientific Research [16K15164] Funding Source: KAKEN
Inflammatory bowel disease, which typically manifests as Crohn's disease and ulcerative colitis, is caused by the abnormal production of cytokines such as tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta. These cytokines damage intestinal epithelial cells and trigger fibrosis, respectively, for which the current in vitro models have many limitations. Therefore, we tested whether human induced pluripotent stem cell-derived intestinal organoids (HiOs) can mimic inflammatory bowel disease (IBD), and whether such a model is suitable for drug screening. HiOs were treated with TNF-alpha and TGF-beta to construct mucosal damage and fibrosis models. TNF-alpha diminished the mRNA expression of intestinal epithelial cell and goblet cell markers in HiOs. TNF-alpha also induced epithelial cell damage and degradation of tight junctions but not in the presence of infliximab, an antibody used in the clinic to deplete TNF-alpha. Furthermore, permeation of the non-absorbable marker FD-4 was observed in HiOs treated with TNF-alpha or ethylene glycol tetraacetic acid (EGTA), but not in the presence of infliximab. In contrast, TNF-alpha and TGF-beta induced mRNA expression of mesenchymal and fibrosis markers, as well as epithelial mesenchymal transition. SB431542, a TGF-beta inhibitor, significantly reversed these events. The data indicate that HiOs mimic mucosal damage and fibrosis due to IBD and are thus suitable models for drug screening.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据