Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis

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.

Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion

“…Indeed, we find that aged fibroblasts display an increased nuclear translocation of YAP/TAZ (Fig 4D). The increased nuclear YAP/TAZ of isolated aged fibroblasts is consistent with our findings of increased muscle stiffness with aging (Fig 1) and is in accordance with previous reports demonstrating an increased nuclear YAP/TAZ expression in response to a pathologically stiffened ECM (Liu et al ., 2015). …”

Myocardin-related Transcription Factor Regulates Nox4 Protein Expression

“…In any case, this finding further confirms that the intact epithelium remains responsive to TGF␤ (although EMyT does not develop) and that TGF␤ may prime the cells for injury-induced Nox4 expression through this indirect pathway, too. Importantly, TAZ/YAP are regulated by many fibrogenic conditions, including matrix stiffness (77,78) and hyperglycemia (79). Clearly, the involvement of TAZ and YAP in the regulation of the redox state of the cell warrants further mechanistic studies.…”

Unifying mechanism for different fibrotic diseases

“…It is not known whether similar molecular mechanisms are responsible for the fibrotic response in different diseases, and some studies came to conflicting conclusions (6). The molecular processes driving fibrogenesis are not well-understood, involving but not limited to transforming growth factor B (TGFB), platelet-derived growth factor (PDGF), connective-tissue growth factor (CTGF), vasoactive peptide, integrin signaling, and increased tissue stiffness (7,8). At the cellular level, efforts have been made to characterize fibroblasts by molecular markers (9), and fibrosis is thought to involve the crosstalk of hematopoietic and mesenchymal stroma cells (4,6).…”