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Perspectives FOCUS ON MECHANOTRANSDUCTION PERSPECTIVES network that can promote coordinated OPINION changes in cell, cytoskeletal and nuclear struc- ture in response to mechanical distortion14 Mechanotransduction at a (FIG. 1a). (Herein, the term hard-wired refers to cytoskeletal structures that are stable enough distance: mechanically coupling the as interconnected units to resist mechanical stresses and thereby maintain shape stabil- ity, even though they undergo continuous extracellular matrix with the nucleus dynamic remodelling at the molecular level.) This model takes into account the observa- Ning Wang, Jessica D. Tytell and Donald E. Ingber tion that individual cytoskeletal filaments can bear significant tensile and compressive loads Abstract | Research in cellular mechanotransduction often focuses on how in living cells because their structural integrity extracellular physical forces are converted into chemical signals at the cell surface. is maintained for longer than the turnover However, mechanical forces that are exerted on surface-adhesion receptors, such time of individual protein monomers15–17. as integrins and cadherins, are also channelled along cytoskeletal filaments and Key to the cellular tensegrity model is concentrated at distant sites in the cytoplasm and nucleus. Here, we explore the the idea that overall cell-shape stability and long-distance force transfer are governed by molecular mechanisms by which forces might act at a distance to induce the level of isometric tension, or ‘prestress’, mechanochemical conversion in the nucleus and alter gene activities. in the cytoskeleton that is generated through the establishment of a force balance between Mechanical forces influence the growth and For example, endothelial cells sense fluid opposing structural elements (that is, micro- shape of virtually every tissue and organ in shear through a cell–cell junctional com- tubules, contractile microfilaments and our bodies. However, little is known about the plex that contains vascular endothelial extracellular adhesions) (FIG. 1a). This occurs mechanisms by which individual cells sense (VE)-cadherin and platelet/endothelial because the cell can tense, and thereby stiffen, these mechanical signals and transduce them cell-adhesion molecule 1 (PECAM1), in load-bearing cytoskeletal filaments relative to into changes in intracellular biochemistry and addition to integrin activation4. Mechanical surrounding regions of the cytoplasm14,18,19. gene expression — a process that is known as forces that are applied directly to integrins In this type of prestressed inhomogeneous mechanotransduction. It is commonly known using micromanipulation or magnetic solid structure, mechanical signals propagate in the field that when a physical force is techniques also alter ion flux through stress- through the cytoplasm much quicker than applied to the cell surface, it distorts the mem- activated ion channels5,6 (see the Review by diffusion-based chemical signals (BOX 1) (see brane cortex and then quickly dissipates into Chalfie104 in this issue), G-protein-dependent the Review by Jaalouk and Lammerding105 the cytoplasm1. Therefore, mechanochemical cyclic AMP signalling7, binding kinetics of in this issue). However, the viscoelastic conversion must only occur in or near these structural molecules8 (for example, zyxin), properties of the cytosol that permeates sites on the cell surface. As expected, surface- protein-translation-complex formation9 and this prestressed network can also influence membrane receptors — such as integrins and activities of protein kinases, such as p130CAS stress propagation to distant cytoplasmic cadherins, which mediate cell adhesion to (also known as BCAR1) and Src3,10. Thus, sites at slower timescales, and non-covalent extracellular matrix (ECM) scaffolds and to surface-adhesion receptors and focal adhe- protein–protein interactions in the cytoplasm neighbouring cells, respectively — have a sion proteins have a key role in mechanical might govern time-dependent stiffening and central role in mechanotransduction2. signalling in various cell types, and the field of in elastic energy dissipation in the cell20. Application of a mechanical stimulus, such mechano transduction focuses mainly on the Because integrins and cadherins are as fluid shear stress, to the cell surface acti- cell surface1. But is this the whole story? physically coupled to cytoskeletal filament vates mechanosensitive ion channels, hetero- Mechanical stresses will dissipate quickly networks that, in turn, link to nuclear scaf- trimeric G proteins, protein kinases and other after passing through the plasma membrane. folds, nucleoli, chromatin and DNA inside membrane-associated signal-transduction Therefore, it makes sense to focus on surface the nucleus, mechanical forces that are molecules; these trigger downstream signal- signalling if one views the cell as an elastic applied at the surface do more than activate ling cascades that lead to force-dependent membrane that surrounds a viscous or visco- membrane-signalling events — they also changes in gene expression3 (see the Review elastic cytoplasm that is filled with cytoskel- promote structural rearrangements deep in by Hahn and Schwartz103 in this issue). etal filaments that continuously depolymerize the cytoplasm and nucleus21,22. This raises the But these responses are usually mediated by and repolymerize11–13 (BOX 1). However, an intriguing possibility that mechanical forces the distortion of specific adhesion receptors alternative model of cell structure suggests applied at the cell surface might act at a that link to the cytoskeleton, rather than that this dynamically remodelling cyto- distance to promote mechanochemical by deformation of the lipid bilayer alone. skeleton is also a ‘hard-wired’ tensegrity conversion in the nucleus23, in addition NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 10 | JANUARY 2009 | 75 © 2009 Macmillan Publishers Limited. All rights reserved PERSPECTIVES Box 1 | Mechanotransduction on the fast track cell, the cytoplasm and the nucleus are due to direct mechanical force transfer and not to Stress-wave propagation predicts rapid signal transduction in the cytoplasm associated chemical signalling events28. These A small chemical, such as calcium (which has a diffusion coefficient of <100 µm2 per s), that is findings also have physiological relevance moving by diffusion takes ~25 s to reach a distance of 50 µm in the cytoplasm, and a molecule that is transported by a motor-based translocation mechanism in the cytoplasm takes ~50 s (at a as they can explain how mitochondria that velocity of ~1 µm per s) to migrate the same distance. By contrast, mechanical stresses that are are located far from the surface membrane propagated along tensed cytoskeletal filaments move the same distance in ~2 µs (at a velocity of on cytoplasmic microtubules can sense and ~30 m per s). respond to mechanical strain by releasing Only prestressed cell models predict long-distance force propagation reactive oxygen species and activating The homogeneous solid (elastic or viscoelastic) model. Physiological local loads of <100 Pa, or signalling molecules (such as nuclear surface local deformation of <0.5 µm, decay to insignificant magnitudes within 10 µm of the site factor-κB (NF-κB) and vascular cell-adhesion of force application in the cell. This is because induced stress or strain decays according to the mole cule 1 (VCAM1)) that contribute to equation 1/R2, of which R is the distance from the site of mechanical load application. inflammation and atherosclerosis29. The prestressed inhomogeneous solid (tensegrity) model. Induced deformation that is produced Recent technological developments that by physiological load application at the cell surface is approximately ten times larger than that enable stress mapping in the cytoplasm of predicted by the homogeneous solid model. Forces applied in this manner can lead to living cells29,30 confirm that even small physiologically relevant distortion of molecular structures that are ~100 µm away, inside the mechanical deformations of surface integrins cytoplasm and nucleus. can result in long-range force propagation, Intracellular stiffness differentials are required for distant force propagation and stress concentrations can be visualized When all stress-supporting elements in a structure have the same stiffness, as in the homogeneous many micrometres away from sites of force elastic or viscoelastic cell models, stress decays rapidly as the reciprocal of the distance squared application (FIG. 2a), including locations near (as according to St Venant’s principle) because the input mechanical energy must be equally the nucleus and at the opposite pole of the distributed among all elements. By contrast, in a prestressed inhomogeneous material (that is, cell30,31. Most importantly, these mechanical a tensegrity cell model), the stresses are preferentially channelled over structural elements that signals induce rapid (<300 ms) mechano- are stiffened owing to prestress and, hence, they decay at a slower rate than forces that are transferred over soft elements in the same structure18. High nuclear stiffness relative to chemical conversion, as detected by focal cytoplasmic stiffness22,101, and the higher stiffness of some intranuclear structures, might also activation of Src kinase in regions of the cyto- facilitate long-distance force propagation in the nucleus, as stresses tend to dissipate less in stiffer plasm that are distant from the site of force structures.
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