Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis

Fei Liu, David Lagares, Kyoung Moo Choi, Lauren Stopfer, Aleksandar Marinković, Vladimir Vrbanac, Clemens K. Probst, Samantha E. Hiemer, Thomas H. Sisson, Jeffrey C. Horowitz, Ivan O. Rosas, Laura E. Fredenburgh, Carol Feghali-Bostwick, Xaralabos Varelas, Andrew M. Tager, Daniel J. Tschumperlin

Research output: Contribution to journalArticle

239 Scopus citations

Abstract

Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis.

Original languageEnglish (US)
Pages (from-to)L344-L357
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume308
Issue number4
DOIs
StatePublished - 2015

Keywords

  • Extracellular matrix
  • Hippo
  • Idiopathic pulmonary fibrosis
  • Mechanotransduction
  • Plasminogen activator inhibitor 1

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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    Liu, F., Lagares, D., Choi, K. M., Stopfer, L., Marinković, A., Vrbanac, V., Probst, C. K., Hiemer, S. E., Sisson, T. H., Horowitz, J. C., Rosas, I. O., Fredenburgh, L. E., Feghali-Bostwick, C., Varelas, X., Tager, A. M., & Tschumperlin, D. J. (2015). Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. American Journal of Physiology - Lung Cellular and Molecular Physiology, 308(4), L344-L357. https://doi.org/10.1152/ajplung.00300.2014