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利用源自人诱导多能干细胞的结肠类器官建立溃疡性结肠炎模型。

Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells.

作者信息

Yokoi Fuki, Deguchi Sayaka, Watanabe Yukio, Takayama Kazuo

机构信息

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.

出版信息

iScience. 2024 Sep 26;27(10):111049. doi: 10.1016/j.isci.2024.111049. eCollection 2024 Oct 18.

DOI:10.1016/j.isci.2024.111049
PMID:39435148
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11492162/
Abstract

The etiology of inflammatory bowel disease (IBD) is complex, with much room for a greater understanding and development of improved therapies. Therefore, establishing a reliable IBD model is crucial for future advancements. In this study, human induced pluripotent stem (iPS) cell-derived colon organoids (hiPSC-COs) were treated with a combination of tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin (IL)-1β (3 cytokines [3CK]), known to be elevated in the serum of IBD patients. Inflammatory responses in stromal cells and damage to intestinal epithelial cells were observed in the 3CK-treated hiPSC-COs. Comparison of molecular signatures of 3CK-treated hiPSC-COs with those of ulcerative colitis (UC) patient's colon revealed that 3CK-treated hiPSC-COs resemble UC patient's colon. Furthermore, the elevated production of inflammatory cytokines observed in 3CK-treated hiPSC-COs was attenuated by treatment with tofacitinib. Our UC model will be an essential tool to understand its pathologic mechanisms and identify effective therapeutic approaches.

摘要

炎症性肠病（IBD）的病因复杂，在对其进一步了解以及开发改进疗法方面仍有很大空间。因此，建立可靠的IBD模型对未来的进展至关重要。在本研究中，用人诱导多能干细胞（iPS）衍生的结肠类器官（hiPSC-COs），用肿瘤坏死因子α（TNF-α）、干扰素-γ（IFN-γ）和白细胞介素（IL）-1β（三种细胞因子[3CK]）进行处理，已知这些细胞因子在IBD患者血清中升高。在经3CK处理的hiPSC-COs中观察到基质细胞中的炎症反应和肠上皮细胞的损伤。将经3CK处理的hiPSC-COs的分子特征与溃疡性结肠炎（UC）患者结肠的分子特征进行比较，发现经3CK处理的hiPSC-COs与UC患者的结肠相似。此外，托法替布治疗可减弱经3CK处理的hiPSC-COs中观察到的炎症细胞因子产生增加的情况。我们的UC模型将成为了解其病理机制和确定有效治疗方法的重要工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/3f9076e949cf/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/7669388cd845/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/c4facccb4fed/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/955f969cdf9c/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/94709c52e2db/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/d19c4cd0c0c1/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/3affea13b070/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/3f9076e949cf/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/7669388cd845/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/c4facccb4fed/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/955f969cdf9c/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/94709c52e2db/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/d19c4cd0c0c1/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/3affea13b070/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8316/11492162/3f9076e949cf/gr6.jpg

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本文引用的文献

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Definitions of Histological Abnormalities in Inflammatory Bowel Disease: an ECCO Position Paper.炎症性肠病组织学异常的定义：ECCO 立场文件。
J Crohns Colitis. 2024 Feb 26;18(2):175-191. doi: 10.1093/ecco-jcc/jjad142.
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Ulcerative colitis.溃疡性结肠炎。
Lancet. 2023 Aug 12;402(10401):571-584. doi: 10.1016/S0140-6736(23)00966-2.
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Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease.人类炎症性肠病中单细胞空间分辨率下的巨噬细胞和中性粒细胞异质性。
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Stem cell-derived intestinal organoids: a novel modality for IBD.干细胞来源的肠道类器官：炎症性肠病的一种新疗法。
Cell Death Discov. 2023 Jul 21;9(1):255. doi: 10.1038/s41420-023-01556-1.
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A multi-mineral intervention to counter pro-inflammatory activity and to improve the barrier in human colon organoids.一种多矿物质干预措施，用于对抗促炎活性并改善人结肠类器官的屏障功能。
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Nat Biotechnol. 2024 Feb;42(2):293-304. doi: 10.1038/s41587-023-01767-y. Epub 2023 May 25.
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IBD disease-modifying therapies: insights from emerging therapeutics.炎症性肠病疾病修饰疗法：新兴疗法的见解
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Janus Kinase Inhibitors for the Management of Patients With Inflammatory Bowel Disease.用于治疗炎症性肠病患者的 Janus 激酶抑制剂
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