Role of YAP/TAZ in mechanotransduction

Dupont, Sirio; Morsut, Leonardo; Aragona, Mariaceleste; Enzo, Elena; Giulitti, Stefano; Cordenonsi, Michelangelo; Zanconato, Francesca; Digabel, Jimmy Le; Forcato, Mattia; Bicciato, Silvio; Elvassore, Nicola; Piccolo, Stefano

doi:10.1038/nature10137

Cited by 4,557 publications

(5,641 citation statements)

References 82 publications

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“…Recent investigations have shown that YAP/TAZ behaves as cellular rheostats, which largely influence mechanosensing and affect cell function and fate 2, 40. For hMSCs in elastic hydrogels, YAP/TAZ mainly remained in the cytoplasm throughout the 7 d culture (Figure 5a,f and more representative images in Figure S11, Supporting Information), reminiscent of previous findings in slowly relaxing9 or nondegradable gels 38.…”

supporting

confidence: 78%

Adaptable Fast Relaxing Boronate‐Based Hydrogels for Probing Cell–Matrix Interactions

et al. 2018

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Hydrogels with tunable viscoelasticity hold promise as materials that can recapitulate many dynamic mechanical properties found in native tissues. Here, covalent adaptable boronate bonds are exploited to prepare hydrogels that exhibit fast relaxation, with relaxation time constants on the order of seconds or less, but are stable for long‐term cell culture and are cytocompatible for 3D cell encapsulation. Using human mesenchymal stem cells (hMSC) as a model, the fast relaxation matrix mechanics are found to promote cell–matrix interactions, leading to spreading and an increase in nuclear volume, and induce yes‐associated protein/PDZ binding domain nuclear localization at longer times. All of these effects are exclusively based on the hMSCs' ability to physically remodel their surrounding microenvironment. Given the increasingly recognized importance of viscoelasticity in controlling cell function and fate, it is expected that the synthetic strategies and material platform presented should provide a useful system to study mechanotransduction on and within viscoelastic environments and explore many questions related to matrix biology.

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supporting

confidence: 78%

Adaptable Fast Relaxing Boronate‐Based Hydrogels for Probing Cell–Matrix Interactions

et al. 2018

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“…To first investigate this hypothesis, old and young fibroblasts were cultured on collagen‐coated plates for 3–4 days and then fixed for evaluation of YAP/TAZ expression. YAP/TAZ are transcriptional regulators that relay mechanical signals imposed by the matrix and act as mediators of mechanotransductive signaling (Dupont et al ., 2011; Aragona et al ., 2013). Indeed, we find that aged fibroblasts display an increased nuclear translocation of YAP/TAZ (Fig 4D).…”

Section: Resultsmentioning

confidence: 99%

“…These age‐related alterations affect stem cell behavior, and both the aged ECM and matricellular proteins secreted by aged fibroblasts drive MuSC differentiation toward a fibrogenic lineage. Aged fibroblasts display an increased nuclear translocation of Yes‐associated protein (YAP)/transcriptional coactivator with PDZ‐binding motif (TAZ), mechanotransductive transcriptional regulators that are activated in response to a stiff microenvironment (Dupont et al ., 2011). Accordingly, seeding young fibroblasts onto a substrate engineered to mimic the stiffness of aged muscle drives YAP/TAZ nuclear translocation and promotes a secretory profile that favors MuSC fibrogenesis at the expense of myogenicity.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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SummaryAge‐related declines in skeletal muscle regeneration have been attributed to muscle stem cell (MuSC) dysfunction. Aged MuSCs display a fibrogenic conversion, leading to fibrosis and impaired recovery after injury. Although studies have demonstrated the influence of in vitro substrate characteristics on stem cell fate, whether and how aging of the extracellular matrix (ECM) affects stem cell behavior has not been investigated. Here, we investigated the direct effect of the aged muscle ECM on MuSC lineage specification. Quantification of ECM topology and muscle mechanical properties reveals decreased collagen tortuosity and muscle stiffening with increasing age. Age‐related ECM alterations directly disrupt MuSC responses, and MuSCs seeded ex vivo onto decellularized ECM constructs derived from aged muscle display increased expression of fibrogenic markers and decreased myogenicity, compared to MuSCs seeded onto young ECM. This fibrogenic conversion is recapitulated in vitro when MuSCs are seeded directly onto matrices elaborated by aged fibroblasts. When compared to young fibroblasts, fibroblasts isolated from aged muscle display increased nuclear levels of the mechanosensors, Yes‐associated protein (YAP)/transcriptional coactivator with PDZ‐binding motif (TAZ), consistent with exposure to a stiff microenvironment in vivo. Accordingly, preconditioning of young fibroblasts by seeding them onto a substrate engineered to mimic the stiffness of aged muscle increases YAP/TAZ nuclear translocation and promotes secretion of a matrix that favors MuSC fibrogenesis. The findings here suggest that an age‐related increase in muscle stiffness drives YAP/TAZ‐mediated pathogenic expression of matricellular proteins by fibroblasts, ultimately disrupting MuSC fate.

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“…Recent studies have elucidated two independent signal transduction pathways that are regulated by the state of actin polymerization. The effectors of these pathways are transcription factors YAP and MRTF (Olson & Nordheim, 2010; Dupont et al ., 2011; Janmey et al ., 2013; Maller et al ., 2013). Both transcription factors are sequestered in the cytoplasm when bound to separate protein complexes that associate with monomeric G‐actin.…”

Section: Discussionmentioning

confidence: 99%

“…Both transcription factors are sequestered in the cytoplasm when bound to separate protein complexes that associate with monomeric G‐actin. Mechanical force generation through recruitment of G‐actin to actin filaments results in release of YAP or MRTF, which translocate to the nucleus to regulate expression of target gene (Olson & Nordheim, 2010; Dupont et al ., 2011; Maller et al ., 2013). …”

Section: Discussionmentioning

confidence: 99%

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

et al. 2015

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SummaryThe structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix (ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced size, with decreased elongation and a more rounded, collapsed morphology. Here, we show that reduced size of fibroblasts in mechanically unrestrained three‐dimensional collagen lattices coincides with reduced mechanical force, measured by atomic force microscopy. Reduced size/mechanical force specifically down‐regulates TGF‐β type II receptor (TβRII) and thus impairs TGF‐β/Smad signaling pathway. Both TβRII mRNA and protein were decreased, resulting in 90% loss of TGF‐β binding to fibroblasts. Down‐regulation of TβRII was associated with significantly decreased phosphorylation, DNA‐binding, and transcriptional activity of its key downstream effector Smad3 and reduced expression of Smad3‐regulated essential ECM components type I collagen, fibronectin, and connective tissue growth factor (CTGF/CCN2). Restoration of TβRII significantly increased TGF‐β induction of Smad3 phosphorylation and stimulated expression of ECM components. Reduced expression of TβRII and ECM components in response to reduced fibroblast size/mechanical force was fully reversed by restoring size/mechanical force. Reduced fibroblast size was associated with reduced expression of TβRII and diminished ECM production, in aged human skin. Taken together, these data reveal a novel mechanism that provides a molecular basis for loss of dermal ECM, with concomitant increased fragility, which is a prominent feature of human skin aging.

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Role of YAP/TAZ in mechanotransduction

Cited by 4,557 publications

References 82 publications

Adaptable Fast Relaxing Boronate‐Based Hydrogels for Probing Cell–Matrix Interactions

Adaptable Fast Relaxing Boronate‐Based Hydrogels for Probing Cell–Matrix Interactions

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

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

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