IL-17 signaling in primary sclerosing cholangitis patient-derived organoids.

IF 8.3 2区 材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY ACS Applied Materials & Interfaces Pub Date : 2024-06-03 eCollection Date: 2024-06-01 DOI:10.1097/HC9.0000000000000454
Ana S Garcia Moreno, Maria E Guicciardi, Alexander Q Wixom, Erik Jessen, Jingchun Yang, Sumera I Ilyas, Jackie K Bianchi, Filippo Pinto E Vairo, Konstantinos N Lazaridis, Gregory J Gores
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Abstract

Background: The pathogenesis of primary sclerosing cholangitis (PSC) is unclear, although studies implicate IL-17A as an inflammatory mediator in this disease. However, a direct assessment of IL-17 signaling in PSC cholangiocytes is lacking. In this study, we aimed to investigate and characterize the response of PSC extrahepatic cholangiocyte organoids (ECO) to IL-17A stimulation.

Methods: Cholangiocytes obtained from patients with PSC and without PSC by endoscopic retrograde cholangiography were cultured as ECO. The ECO were treated with vehicle or IL-17A and assessed by transcriptomics, secretome analysis, and genome sequencing.

Results: Unsupervised clustering of all integrated single-cell RNA sequencing data identified 8 cholangiocyte clusters that did not differ between PSC and non-PSC ECO. However, PSC ECO cells demonstrated a robust response to IL-17 treatment, as noted by an increased number of differentially expressed genes by transcriptomics and more abundant chemokine and cytokine expression and secretion. After rigorous filtering, genome sequencing identified candidate somatic variants shared among PSC ECO from unrelated individuals. However, no candidate rare variants in genes regulating the IL-17 pathway were identified, but rare variants regulating the MAPK signaling pathway were present in all PSC ECO.

Conclusions: PSC and non-PSC patient-derived ECO respond differently to IL-17 stimulation, implicating this pathway in the pathogenesis of PSC.

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原发性硬化性胆管炎患者衍生器官组织中的 IL-17 信号传导。
背景:原发性硬化性胆管炎(PSC)的发病机制尚不清楚,但有研究表明,IL-17A 是该病的一种炎症介质。然而,目前还缺乏对 PSC 胆管细胞中 IL-17 信号传导的直接评估。在这项研究中,我们旨在调查和描述 PSC 肝外胆管细胞器官组织(ECO)对 IL-17A 刺激的反应:方法:将通过内镜逆行胆管造影从 PSC 患者和非 PSC 患者体内获得的胆管细胞培养成 ECO。用药物或 IL-17A 处理 ECO,并通过转录组学、分泌组分析和基因组测序对其进行评估:结果:对所有整合的单细胞 RNA 测序数据进行无监督聚类,发现了 8 个胆管细胞群,这些细胞群在 PSC 和非 PSC ECO 之间没有差异。然而,PSC ECO细胞对IL-17治疗表现出强烈的反应,这表现在转录组学中差异表达基因的数量增加,趋化因子和细胞因子的表达和分泌更加丰富。经过严格筛选,基因组测序确定了来自非亲缘关系个体的 PSC ECO 中共有的候选体细胞变异。然而,在调节IL-17通路的基因中没有发现候选罕见变异,但在所有PSC ECO中都存在调节MAPK信号通路的罕见变异:结论:PSC和非PSC患者来源的ECO对IL-17刺激的反应不同,这表明该通路与PSC的发病机制有关。
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来源期刊
ACS Applied Materials & Interfaces
ACS Applied Materials & Interfaces 工程技术-材料科学:综合
CiteScore
16.00
自引率
6.30%
发文量
4978
审稿时长
1.8 months
期刊介绍: ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.
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