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

• Published in: EBioMedicine Vol. 69; p. 103452
• Main Authors: Ou, Weijun, Xu, Weimin, Liu, Fangyuan, Guo, Yuegui, Huang, Zhenyu, Feng, Tienan, Liu, Chen-Ying, Du, Peng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2021; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adult; Animals; Cells, Cultured; Crohn Disease - complications; Crohn Disease - metabolism; Crohn Disease - pathology; Crohn's disease; Female; Fibroblasts - metabolism; Fibrosis; Humans; intestinal fibroblasts; Intestinal Obstruction - etiology; Intestinal Obstruction - metabolism; Intestinal Obstruction - pathology; Intestines - cytology; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Mice; Mice, Inbred C57BL; Middle Aged; Research paper; rho-Associated Kinases - metabolism; ROCK1; TAZ; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP; YAP-Signaling Proteins; intestinal fibroblasts; YAP; Crohn's disease; ROCK1; TAZ
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2021.103452

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).