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Am J Physiol Lung Cell Mol Physiol. 2015 Feb 15;308(4):L344-57. doi: 10.1152/ajplung.00300.2014. Epub 2014 Dec 12.

Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis.

Author information

1
Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts;
2
Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts;
3
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;
4
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts;
5
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
6
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
7
Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.
8
Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; tschumperlin.daniel@mayo.edu.

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.

KEYWORDS:

Hippo; extracellular matrix; idiopathic pulmonary fibrosis; mechanotransduction; plasminogen activator inhibitor 1

PMID:
25502501
PMCID:
PMC4329470
DOI:
10.1152/ajplung.00300.2014
[Indexed for MEDLINE]
Free PMC Article

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