Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis

• Published in: JCI insight Vol. 7; no. 4
• Main Authors: He, Xiaolin, Tolosa, Monica F, Zhang, Tianzhou, Goru, Santosh Kumar, Ulloa Severino, Luisa, Misra, Paraish S, McEvoy, Caitríona M, Caldwell, Lauren, Szeto, Stephen G, Gao, Feng, Chen, Xiaolan, Atin, Cassandra, Ki, Victoria, Vukosa, Noah, Hu, Catherine, Zhang, Johnny, Yip, Christopher, Krizova, Adriana, Wrana, Jeffrey L, Yuen, Darren A
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 22-02-2022; American Society for Clinical investigation
• Subjects: Adaptor Proteins, Signal Transducing - biosynthesis; Adaptor Proteins, Signal Transducing - genetics; Animals; Cell Cycle Proteins - biosynthesis; Cell Cycle Proteins - genetics; Disease Models, Animal; Fibrosis - genetics; Fibrosis - metabolism; Gene Expression Regulation; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myofibroblasts - metabolism; Myofibroblasts - pathology; Nephrology; Organ Transplantation; Pulmonology; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; RNA - genetics; Signal Transduction; Transcription Factors; YAP-Signaling Proteins - biosynthesis; YAP-Signaling Proteins - genetics; Pulmonology; Nephrology; Chronic kidney disease; Fibrosis
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.146243

Fibrotic diseases account for nearly half of all deaths in the developed world. Despite its importance, the pathogenesis of fibrosis remains poorly understood. Recently, the two mechanosensitive transcription cofactors YAP and TAZ have emerged as important profibrotic regulators in multiple murine tissues. Despite this growing recognition, a number of important questions remain unanswered, including which cell types require YAP/TAZ activation for fibrosis to occur and the time course of this activation. Here, we present a detailed analysis of the role that myofibroblast YAP and TAZ play in organ fibrosis and the kinetics of their activation. Using analyses of cells, as well as multiple murine and human tissues, we demonstrated that myofibroblast YAP and TAZ were activated early after organ injury and that this activation was sustained. We further demonstrated the critical importance of myofibroblast YAP/TAZ in driving progressive scarring in the kidney, lung, and liver, using multiple transgenic models in which YAP and TAZ were either deleted or hyperactivated. Taken together, these data establish the importance of early injury-induced myofibroblast YAP and TAZ activation as a key event driving fibrosis in multiple organs. This information should help guide the development of new antifibrotic YAP/TAZ inhibition strategies.