Increased expression of yes-associated protein/YAP and transcriptional coactivator with PDZ-binding motif/TAZ activates intestinal fibroblasts to promote intestinal obstruction in Crohn's disease.
Increased expression of yes-associated protein/YAP and transcriptional coactivator with PDZ-binding motif/TAZ activates intestinal fibroblasts to promote intestinal obstruction in Crohn's disease.
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Yes相关蛋白/YAP以及含PDZ结合基序的转录共激活因子/TAZ表达增加可激活肠道成纤维细胞，从而促进克罗恩病中的肠梗阻。
DOI：
10.1016/j.ebiom.2021.103452
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发表时间：
2021-07
期刊：
影响因子：
11.1
通讯作者：
Du P
中科院分区：
文献类型：
--
作者：
Ou W;Xu W;Liu F;Guo Y;Huang Z;Feng T;Liu CY;Du P
肠纤维化引起的肠梗阻是克罗恩病（CD）常见而严重的并发症。肠成纤维细胞是介导胃肠道纤维化的主要效应细胞，在慢性炎症过程中被激活。然而，CD中成纤维细胞活化的机制尚未得到很好的阐明。从CD患者的狭窄和非狭窄肠分离的成纤维细胞用于RNA测序。进行免疫组织化学和免疫荧光染色以评估我们的CD组群和DSS诱导的慢性结肠炎小鼠模型中肠纤维化和雅普/TAZ表达之间的相关性。采用Rho相关卷曲螺旋蛋白激酶1（ROCK 1）抑制剂，研究ROCK 1-雅普/TAZ轴在体外肠成纤维细胞和DSS诱导的慢性结肠炎小鼠模型中的表达。雅普/TAZ的表达在狭窄成纤维细胞中显著上调，这与雅普/TAZ靶基因标签相关。雅普/TAZ敲低抑制肠成纤维细胞的活化。在肠道成纤维细胞中，雅普/TAZ被Rho-ROCK 1信号通路激活。高雅普/TAZ表达与ROCK 1表达呈正相关，ROCK 1是CD患者肠梗阻的预后标志物。CD中雅普/TAZ激活可导致成纤维细胞激活和肠梗阻。ROCK 1抑制剂减轻肠纤维化的作用与雅普/TAZ抑制有关。靶向抑制成纤维细胞中的雅普/TAZ可能是抑制CD肠纤维化的潜在治疗策略。本课题得到了国家重点研发计划（2019 YFC 1316002）、国家自然科学基金（81873547、82073201、81874177、82000481）和上海帆船计划（20 YF 1429400）的资助。
Intestinal obstruction caused by intestinal fibrosis is a common and serious complication of Crohn's disease (CD). Intestinal fibroblasts, the main effector cells mediating gastrointestinal fibrosis, are activated during chronic inflammation. However, the mechanism of fibroblast activation in CD has not been well elucidated. Fibroblasts isolated from stenotic and nonstenotic intestines of CD patients were used for RNA sequencing. Immunohistochemical and immunofluorescent staining was performed to evaluate the correlation between intestinal fibrosis and YAP/TAZ expression in our CD cohort and a DSS-induced chronic colitis murine model. A Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) inhibitor was used to explore the ROCK1-YAP/TAZ axis in intestinal fibroblasts in vitro and DSS-induced chronic colitis murine model in vivo. The expression of YAP/TAZ was significantly upregulated in stenotic fibroblasts, which was associated with the YAP/TAZ target gene signature. YAP/TAZ knockdown suppressed the activation of intestinal fibroblasts. In intestinal fibroblasts, YAP/TAZ were activated by the Rho-ROCK1 signalling pathway. High YAP/TAZ expression was positively correlated with ROCK1 expression, which is a prognostic marker for intestinal obstruction in CD patients. YAP/TAZ activation can lead to fibroblast activation and intestinal obstruction in CD. The effect of ROCK1 inhibitor on alleviating intestinal fibrosis is associated with YAP/TAZ inhibition. Targeted inhibition of YAP/TAZ in fibroblasts may be a potential therapeutic strategy to suppress intestinal fibrosis in CD. This work was supported by the National Key R&D Program of China (2019YFC1316002), the NSFC (81873547, 82073201, 81874177, 82000481) and the Shanghai Sailing Program (20YF1429400).
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影响因子：
3.9
作者：
Piersma B;Bank RA;Boersema M
通讯作者：
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影响因子：
64.8
作者：
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DOI：
10.1186/s12964-018-0232-3
发表时间：
2018-04-25
期刊：
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影响因子：
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DOI：
10.1165/rcmb.2003-0063oc
发表时间：
2003-09-01
影响因子：
6.4
作者：
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通讯作者：
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