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.
Xiaolin He, Monica F. Tolosa, Tianzhou Zhang, Santosh Kumar Goru, Luisa Ulloa Severino, Paraish S. Misra, Caitríona M. McEvoy, Lauren Caldwell, Stephen G. Szeto, Feng Gao, Xiaolan Chen, Cassandra Atin, Victoria Ki, Noah Vukosa, Catherine Hu, Johnny Zhang, Christopher Yip, Adriana Krizova, Jeffrey L. Wrana, Darren A. Yuen
Progressive myofibroblast YAP/TAZ activation occurs during human kidney fibrogenesis.