A Mechanical Checkpoint Controls Multicellular Growth through YAP/TAZ Regulation by Actin-Processing Factors

Aragona, Mariaceleste; Panciera, Tito; Manfrin, Andrea; Giulitti, Stefano; Michielin, Federica; Elvassore, Nicola; Dupont, Sirio; Piccolo, Stefano

doi:10.1016/j.cell.2013.07.042

Cited by 1,391 publications

(1,629 citation statements)

References 43 publications

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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%

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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Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…Finally, Ca 2+ dynamics and actin remodeling have been shown to play an important role in regulating the nuclear transport of several transcription factors, including nuclear factor of activated T cells, myocardin-like protein, and Yes-associated protein (16,(45)(46)(47)(48). This property suggests that the force/Ca 2+ -mediated perinuclear actin remodeling may serve as a mechanism of mechanotransduction by enabling the delivery of mechanical signals from the cytoplasm to the nucleus.…”

Section: Discussionmentioning

confidence: 96%

Mechanical stimulation induces formin-dependent assembly of a perinuclear actin rim

Shao

Mogilner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

126

129

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Cells constantly sense and respond to mechanical signals by reorganizing their actin cytoskeleton. Although a number of studies have explored the effects of mechanical stimuli on actin dynamics, the immediate response of actin after force application has not been studied. We designed a method to monitor the spatiotemporal reorganization of actin after cell stimulation by local force application. We found that force could induce transient actin accumulation in the perinuclear region within ∼2 min. This actin reorganization was triggered by an intracellular Ca 2+ burst induced by force application. Treatment with the calcium ionophore A23187 recapitulated the force-induced perinuclear actin remodeling. Blocking of actin polymerization abolished this process. Overexpression of Klarsicht, ANC-1, Syne Homology (KASH) domain to displace nesprins from the nuclear envelope did not abolish Ca 2+ -dependent perinuclear actin assembly. However, the endoplasmic reticulum-and nuclear membrane-associated inverted formin-2 (INF2), a potent actin polymerization activator (mutations of which are associated with several genetic diseases), was found to be important for perinuclear actin assembly. The perinuclear actin rim structure colocalized with INF2 on stimulation, and INF2 depletion resulted in attenuation of the rim formation. Our study suggests that cells can respond rapidly to external force by remodeling perinuclear actin in a unique Ca 2+ -and INF2-dependent manner.force | mechanotransduction | calcium | formin | perinuclear actin rim C ells can sense and adapt to their physical microenvironment through specific mechanosensing mechanisms. These properties are often mediated by the actin cytoskeleton, which can be modulated by a wide range of forces. Fluid shear stress, for example, induces actin stress fiber assembly and realignment along the direction of flow (1-4), whereas the cyclic stretch of an elastic substrate induces a reorientation of stress fibers under some angle to the direction of stretch (5-8). Applying mechanical force to cells by a microneedle results in focal adhesion growth and activation of formin-type actin nucleators (9, 10). Similarly, local application of force through fibronectin or collagen-coated beads trapped by optical or magnetic tweezers leads to the local reorganization of the actin cytoskeleton. This response is associated with reinforcement of bead attachment (11), recruitment of additional actin-associated proteins (12), and activation of a variety of signaling pathways (13)(14)(15)(16)(17). Most studies to date have explored the effects of force on actin structures directly associated with the sites of force application, such as focal adhesions and stress fibers. However, the immediate effect of force on the assembly of actin structures distal from the sites of force application has not been assessed. Such process is despite distal effects having potential implications in the transduction of local forces from the cell periphery to nuclear events (18).In this study, we used a local mecha...

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“…Contact inhibition is a well‐recognized cell biological process whereby cell proliferation ceases when cultured cells come into contact as a confluent monolayer (Abercrombie, 1967) and is mediated through the Hippo signalling pathway involving the target transcription factors YAP/TAZ (Tariki et al ., 2014) which are responsive to mechanical forces (Aragona et al ., 2013). Sparse cultures of RPE cells in vitro proliferate extensively and adopt an EMT‐like spindle shape morphology (Newsome, 1983; Chen et al ., 2012), but under appropriate conditions differentiate into a typical hexagonal nonproliferating RPE monolayer (Newsome, 1983).…”

Section: Discussionmentioning

confidence: 99%

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

et al. 2016

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SummaryRetinal pigment epithelial (RPE) cells are central to retinal health and homoeostasis. Dysfunction or death of RPE cells underlies many age‐related retinal degenerative disorders particularly age‐related macular degeneration. During aging RPE cells decline in number, suggesting an age‐dependent cell loss. RPE cells are considered to be postmitotic, and how they repair damage during aging remains poorly defined. We show that RPE cells increase in size and become multinucleate during aging in C57BL/6J mice. Multinucleation appeared not to be due to cell fusion, but to incomplete cell division, that is failure of cytokinesis. Interestingly, the phagocytic activity of multinucleate RPE cells was not different from that of mononuclear RPE cells. Furthermore, exposure of RPE cells in vitro to photoreceptor outer segment (POS), particularly oxidized POS, dose‐dependently promoted multinucleation and suppressed cell proliferation. Both failure of cytokinesis and suppression of proliferation required contact with POS. Exposure to POS also induced reactive oxygen species and DNA oxidation in RPE cells. We propose that RPE cells have the potential to proliferate in vivo and to repair defects in the monolayer. We further propose that the conventionally accepted ‘postmitotic’ status of RPE cells is due to a modified form of contact inhibition mediated by POS and that RPE cells are released from this state when contact with POS is lost. This is seen in long‐standing rhegmatogenous retinal detachment as overtly proliferating RPE cells (proliferative vitreoretinopathy) and more subtly as multinucleation during normal aging. Age‐related oxidative stress may promote failure of cytokinesis and multinucleation in RPE cells.

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A Mechanical Checkpoint Controls Multicellular Growth through YAP/TAZ Regulation by Actin-Processing Factors

Cited by 1,391 publications

References 43 publications

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

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

Mechanical stimulation induces formin-dependent assembly of a perinuclear actin rim

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

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