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Cell behaviour is governed by the mechanical environment, which influences not only cell-intrinsic properties, but also cellular interactions at the tissue and organism level. Thus, the sensing and transduction of mechanical forces has become an intensely studied aspect of cell biology. Nature Cell Biology presents a series of commissioned Reviews discussing recent advances in the field of mechanobiology, which will be published in the journal over several months. An accompanying online library presents recent research and review articles published in Nature Cell Biology and other Nature journals.
Mechanical forces influence both cytoplasmic and nuclear events. Kirby and Lammerding discuss recent evidence suggesting that the nucleus itself is a mechanosensor and methods to study nuclear mechanotransduction.
Physical forces influence the growth and development of all organisms. In the second Review in the Series on Mechanobiology, Trepat and co-authors describe techniques to measure forces generated by cells, and discuss their use and limitations.
In this Review, we will discuss how the interplay and feedback between mechanical and biochemical signals control tissue morphogenesis and cell fate specification in embryonic development.
Tumours are often more stiff than normal tissue. In this Review, Mohammadi and Sahai discuss recent insights into how such altered tumour mechanics arise and how this affects tumorigenesis.
Mechanobiology — the study of how physical forces control the behaviour of cells and tissues — is a rapidly growing field. In this issue, we launch a Series of specially commissioned Review articles that discuss exciting recent developments in this area.
Kronenberg et al. develop a system to record cell–substrate interactions allowing the measurement of horizontal and vertical forces at high resolution, and demonstrate its use by monitoring podosome protrusion and other cell behaviours.
Cortical tension is thought to be generated by myosin II, and little is known about the role of actin network properties. Chugh et al. demonstrate that actin cortex thickness, determined by actin filament length, influences cortical tension.
Bays et al. demonstrate that application of force to E-cadherin leads to LKB1-dependent activation of AMPK and recruitment of AMPK to E-cadherin complexes to increase glucose uptake and ATP production and re-enforce cell–cell junctions.
Epithelial cells form energetically costly cell–cell adhesions in response to mechanical forces. How cells obtain their energy during this event is unclear. Activity of a key regulator of cell metabolism, the AMP-activated protein kinase (AMPK), is now shown to be mechanoresponsive, and thus can bridge adhesion mechanotransduction and energy homeostasis.
Lilja et al. find that SHANK proteins inhibit the signalling of Ras and Rap G-proteins by restricting their availability at the plasma membrane. This leads to restricted integrin activation, affecting cell spreading, migration and invasion.
Acetylation of α-tubulin on lysine 40 is associated with microtubule stability. In vitro experiments by Portran et al. show that tubulin acetylation reduces lateral interactions, increasing microtubule flexibility and resistance to mechanical stress.
Cancer-associated fibroblasts (CAFs) promote metastasis by creating tracks for cancer cell migration. Labernadie et al. now show that heterotypic adhesions between E-cadherin on cancer cells and N-cadherin on CAFs transmit forces to drive invasion.
Weaver and colleagues report that enrichment of the extracellular matrix with tenascin C promotes aggressiveness of IDH1-mutant glioblastoma by activating a HIF1α-controlled mechanosignalling feedback loop.
Two studies by Pasakarnis et al. and Ducuing and Vincent show that the actin cable does not drive dorsal closure, but facilitates closure of the epidermis by providing zipping integrity and homogenizing mechanical tension along the leading edge.
Two studies by Pasakarnis et al. and Ducuing and Vincent show that the actin cable does not drive dorsal closure, but facilitates closure of the epidermis by providing zipping integrity and homogenizing mechanical tension along the leading edge.
Wickström and colleagues describe how mechanical forces applied to epidermal stem cells lead to relocation of emerin to the nuclear envelope and reduced nuclear actin levels, resulting in chromatin changes that influence lineage commitment.
At sites of cell adhesion to the matrix, integrins are coupled to the actin cytoskeleton through proteins such as talin. Sun et al. now identify Kank2 as an activator of talin that reduces force transmission across focal adhesions.
Integrins and talin are parts of a ‘molecular clutch’ that mechanically links the actin cytoskeleton to the extracellular matrix. Elosegui-Artola et al. now reveal a tunable rigidity threshold, above which talin unfolds to mediate force transduction.
Using mathematical simulations and a FRET tension sensor inserted into the microtubule-binding complex Ndc80, Suzuki and colleagues obtain insights into how force is generated at the budding yeast kinetochore.
By culturing rat hepatocyte doublets in microwells with controlled ECM environments, Viasnoff and colleagues show that the lumen between the cells extends anisotropically towards regions of lower intercellular tension.
Nowell et al. report that chronic inflammation of the corneal epithelium activates β-catenin signalling through YAP/TAZ-dependent mechanotransduction, leading to epidermal differentiation on the ocular surface and corneal squamous cell metaplasia.
Sheetz and colleagues use micropillar arrays to report that the regulation of rigidity sensing involves the tropomyosin-dependent control of the stepwise contractions needed to reach a force level sufficient for integrin adhesion reinforcement.
Case and Waterman discuss how integrating extracellular-matrix-bound integrins and the actin cytoskeleton into a mechanosensitive molecular clutch transmits actin-cytoskeleton-generated forces to the extracellular matrix through focal adhesions.
Yap and Lecuit review the interplay of E-cadherin-mediated adhesion and actomyosin-based contractility, and discuss the functional effects of their crosstalk at the cellular and tissue level.
Roman et al. demonstrate that crosslinking and contraction of myofibrils mediate the movement of nuclei to the periphery of myofibres, and describe a role for Arp2/3 in organizing desmin.
Ingallina et al. show that mutant p53 is protected from degradation in response to matrix stiffness in a manner dependent on RhoA geranylgeranylation and actomyosin dynamics.
Mechanics of epidermal differentiation Miroshnikova et al. find that during embryonic development, epidermal basal layer crowding generates local changes in cell shape, cortical tension, and adhesion that initiate differentiation and delamination
Using nanopillars with increased spatial resolution, Shiu et al. identify high perinuclear forces that originate from contractile apical actin filaments that span across the nucleus and are dependent on lamin A and the LINC complex.
Monitoring growing epithelial cells through the cell cycle, Uroz et al. find that cell–cell tension and cell–matrix traction forces differ across the cell cycle and affect cell cycle duration, the G1–S transition and mitotic rounding.
Duan et al. find that the membrane skeleton protein spectrin is required for myoblast fusion in Drosophila, accumulating in a mechanosensitive manner in the receiving partner during cell–cell fusion to modulate adhesion and protrusion events.
The transcriptional co-activator YAP is known to operate downstream of mechanical signals arising from the cell niche. Here the authors demonstrate that YAP controls cell mechanics, force development and adhesion strength by promoting the transcription of genes related to focal adhesions.
Large-scale tissue reorganization requires the generation of directional tension, which requires orientation of the cytoskeleton. Here Chanetet al. alter tissue shape and tension in the Drosophilaembryo to show that geometric and mechanical constraints act as cues to orient the cytoskeleton and tension.
Epidermal growth factor receptor and its isoform HER2 are recruited to nascent cellular adhesion sites and play an important role in the rigidity sensing of cells on stiff substrates, this activity being dependent on Src-mediated phosphorylation.
Under physiological forces, resulting from cytokinesis, the mechanosensitivity of adherens junction arises from a local decrease in E-cadherin concentration and results in actomyosin flows.
Plant cell growth requires cell wall extension. Here, the nanoscale movement of cellulose microfibrils in onion primary cell wall is imaged by atomic force microscopy and compared under mechanical extension versus enzymatic loosening.
Molecular motor dynein-2, involved in retrograde intraflagellar transport, adopts an autoinhibited conformation, in which the mechanical linker and track-binding stalk are trapped via a newly described motor–motor interface.
Pulsatile actomyosin contractility during tissue morphogenesis has been mainly studied in apical domains but less is known about the contribution of the basal domain. Here the authors show differential influence of cell-matrix and cell-cell adhesions in regulating oscillations and tissue elongation.
The stretch-activated channel Piezo1 controls homeostatic epithelial cell numbers by activating cells to divide rapidly when under stretch strain from low density, and by activating cells to extrude and die when cells are under crowding strain.
Many cellular processes rely on cells generating or responding to nanoscale mechanical forces. This protocol describes STED–traction force microscopy (STFM), which allows these forces to be measured with higher resolution and accuracy than standard TFM.
Actin polymerization in lamellipodia of cells is regulated by the Arp2/3 complex and FMNL family formins. Here the authors show that both FMNL2 and FMNL3 contribute to lamellipodium protrusion and structure, and abolishing FMNL2/3 reduces protrusion force generation and migration, without affecting Arp2/3 incorporation.
Cellular mechanical forces are regulated by Rho GTPases. Here the authors develop an optogenetic system to control the spatiotemporal activity of RhoA, and show that directing a RhoA activator to the plasma membrane causes contraction and YAP nuclear localization, whereas directing it to the mitochondria causes relaxation.
Increased cellular expression of RAB5A, an important regulator of endocytic processes, brings epithelial cells from a jammed state to coordinated motion, and can facilitate wound closure, gastrulation and migration in constrained environments.
Interaction of fibronectin with αv-class and α5β1 integrins results in formation of cell adhesion complexes, but the initial events (<120 s) remain unclear. Here, the authors show that αv-class integrins bind fibronectin faster than α5β1 integrins and subsequently signal to α5ß1 integrins to strengthen the adhesion.
The mechanical properties of tissues can be measured by deforming magnetically responsive microdroplets that are implanted in the tissue. Serwane et al. apply this method to study the mechanical properties of tissues in the living zebrafish embryo.
The role of force in activating integrin cell adhesion receptors is not known. Here the authors develop fluorescent tension sensors for αL and β2 integrins and show that in migrating T cells force is transduced across the β2 integrin, and that this correlates with an active conformational state.
Light-scattering kinetics and atomic force and electron microscopy analyses show that Hsp70-mediated disassembly of clathrin cages occurs via a collision-pressure mechanism consistent with the entropic pulling model.
Mechanosensation by biological membranes can be relayed by mechanical tension to ion channels. Here the authors show that phospholipase D (PLD) is activated by mechanical disruption of lipid rafts which allows PLD to mix with its substrate in the lipid membrane, and propose a kinetic model of force transduction.
Mesenchymal stem cells primed on soft silicone substrates suppress fibrogenesis and are desensitized against subsequent mechanical activation in vitro and in vivo.
N-cadherin can alter how the stiffening extracellular microenvironment is interpreted by mesenchymal stem cells, leading to subsequent changes in downstream cell proliferation and differentiation.
Here, a combination of biophysical measurement, modelling, and genetic and experimental manipulation of cell contractile components is used to analyse the formation of the inner cell mass in the early mouse embryo.
Impaired TGF-β signaling due to SMAD4 mutation in PDAC tumors initiates a STAT3-dependent signaling cascade that leads to increased stromal stiffening and disease progression.
There is a growing appreciation that mechanical forces have important roles in many aspects of biology. This review provides a survey of methods for measuring the forces exerted by cells and discusses technical barriers to their implementation.
Measuring the forces generated by cells is not trivial in materials that behave in a nonlinear fashion. An equation that captures this behavior and finite-element modeling can be used to derive these forces from the material deformations around cells.
This protocol describes how to immobilize living cells into polydimethylsiloxane stamps, generating an array of living cells that can undergo atomic force microscopy, with no chemical or physical denaturation.
Optomechanical actuator nanoparticles collapse upon illumination with near-infrared light. Appropriately coated, they can be used to mechanically trigger cellular processes such as focal adhesion formation or T cell activation.