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
Background: 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 act...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396421002450 |
| _version_ | 1831794307758030848 |
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| author | Weijun Ou Weimin Xu Fangyuan Liu Yuegui Guo Zhenyu Huang Tienan Feng Chen-Ying Liu Peng Du |
| author_facet | Weijun Ou Weimin Xu Fangyuan Liu Yuegui Guo Zhenyu Huang Tienan Feng Chen-Ying Liu Peng Du |
| author_sort | Weijun Ou |
| collection | DOAJ |
| description | Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: 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). |
| first_indexed | 2024-12-22T15:48:18Z |
| format | Article |
| id | doaj.art-307201ae785e48a88966186b64eb07d9 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-22T15:48:18Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-307201ae785e48a88966186b64eb07d92022-12-21T18:20:58ZengElsevierEBioMedicine2352-39642021-07-0169103452Increased expression of yes-associated protein/YAP and transcriptional coactivator with PDZ-binding motif/TAZ activates intestinal fibroblasts to promote intestinal obstruction in Crohn's diseaseWeijun Ou0Weimin Xu1Fangyuan Liu2Yuegui Guo3Zhenyu Huang4Tienan Feng5Chen-Ying Liu6Peng Du7Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, ChinaDepartment of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, ChinaDepartment of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, ChinaDepartment of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, ChinaDepartment of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, ChinaClinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaDepartment of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; Corresponding author: Peng Du, Department of Colorectal Surgery, Xinhua Hospital, 1665 Kongjiang Road, Shanghai 200092, China; Tel: 086-021-25077858Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; Corresponding author: Peng Du, Department of Colorectal Surgery, Xinhua Hospital, 1665 Kongjiang Road, Shanghai 200092, China; Tel: 086-021-25077858Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: 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).http://www.sciencedirect.com/science/article/pii/S2352396421002450Crohn's diseaseintestinal fibroblastsYAPTAZROCK1 |
| spellingShingle | Weijun Ou Weimin Xu Fangyuan Liu Yuegui Guo Zhenyu Huang Tienan Feng Chen-Ying Liu Peng Du 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 EBioMedicine Crohn's disease intestinal fibroblasts YAP TAZ ROCK1 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Crohn's disease intestinal fibroblasts YAP TAZ ROCK1 |
| url | http://www.sciencedirect.com/science/article/pii/S2352396421002450 |
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