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This collection of recent articles from Nature Research journals focuses on the latest efforts to understand the roles of mechanical forces in animal cells and tissues. It highlights the broad involvement of mechanical forces in different biological contexts, their roles in development, physiology and disease, and discusses how these forces are sensed and transduced to produce biologically-relevant responses. The collection also showcases new technical approaches to study and modulate mechanobiology, which in the future could be used control cell fate and behaviour for therapeutic benefits. This collection is aimed for researchers from a broad range of disciplines — biologists, physicists and theoreticians alike — and we hope that it will foster inter-disciplinary initiatives to study biological systems.
Mechanical forces are important regulators of cell function and behaviour. This role is partly achieved through the modulation of cell metabolism, which, reciprocally, affects tissue mechanics. Unravelling the mechanisms of this crosstalk will increase our understanding of how cells interact with their microenvironment.
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.
Advances in biomaterials have enabled control over desired cell responses. Here, the authors highlight key analytical and bioprocessing techniques, outlining a framework for incorporating these tools into designing functionally optimal biomaterials.
Coordinated movements of cell collectives are important for morphogenesis, tissue regeneration and cancer cell dissemination. Recent studies, mainly using novelin vitroapproaches, have provided new insights into the mechanisms governing this multicellular coordination, highlighting the key role of the mechanosensitivity of adherens junctions and mechanical cell–cell coupling in collective cell behaviours.
Mechanical forces and electrical fields are crucial for cellular signalling and can be both inducers and indicators of disease. This Review highlights advances in nanoscale, in vivo, optical probes, discussing spatial and temporal resolution, stability and stimuli sensitivity in bioimaging.
Physical cues regulate stem cell fate and function during embryonic development and in adult tissues. The biophysical and biochemical properties of the stem cell microenvironment can be precisely manipulated using synthetic niches, which provide key insights into how mechanical stimuli regulate stem cell function and can be used to maintain and guide stem cells for regenerative therapies.
Mechanical cues from the microenvironment can be efficiently transmitted to the nucleus to engage in the regulation of genome organization and gene expression. Recent technological and theoretical progress sheds new light on the relationships between cell mechanics, nuclear and chromosomal architecture and gene transcription.
Soon after their discovery in 2010, Piezo channels became a paradigm for studying mechanosensitive ion channels. These channels respond to physiologically relevant forces in diverse cellular contexts, and their dysfunction has been linked to various diseases. We are now starting to understand gating mechanisms of Piezo channels and their key roles in physiology.
The transcription factors YAP and TAZ have recently emerged as being conserved transducers of mechanical signals into cells and mediators of processes such as proliferation, migration and cell fate decision. The roles of YAP-mediated and TAZ-mediated mechanotransduction have now been documented in many physiological and pathological contexts, providing novel insights into cellular mechano-responses and their consequences.
As leukocytes travel in the bloodstream, navigate through tissues and mediate effector functions, their behaviour is influenced by mechanical forces. In this Review, Morgan Huse explains how mechanical force regulates receptor activation, cell migration, intracellular signalling and intercellular communication.
The field of active matter studies how internally driven motile components self-organize into large-scale dynamical states and patterns. This Review discusses how active matter concepts are important for understanding cell biology, and how the use of biochemical components enables the creation of new inherently non-equilibrium materials with unique properties that have so far been mostly restricted to living organisms.
The actin cytoskeleton of B cells is extensively coupled to B cell receptor (BCR) signalling pathways. This Review summarizes recent evidence that indicates that actin orchestrates BCR signalling at the plasma membrane, and discusses the role of the cytoskeleton in antigen presentation, affinity maturation and the functional specialization of B cells.
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.
Integrin extracellular matrix receptors establish contacts between the cell interior and the cell microenvironment. Integrins are subjected to complex biochemical and mechanical regulation, which allows cells to respond to extracellular matrix with different physicochemical properties and fine-tunes cell behaviour.
The mechanism by which cell geometry regulates cell signalling is reported to be modulated by lipid rafts within the plasma membrane, which are now shown to be responsible for geometry-dependent mesenchymal stem cell differentiation.
The effect of mechanical cues on the behaviour of cells in culture is well documented, but such effects are more difficult to study in vivo. Norbert Perrimon and colleagues find that stem cells of the Drosophila gut sense mechanical signals in vivo through the stretch-activated ion channel Piezo. Piezo is expressed in a subset of enteroendocrine precursor cells. Loss of Piezo reduces the differentiation of the enteroendocrine lineage in adults, while the over expression of this gene in gut stem cells has the reverse effect. Further analysis shows that Piezo activates the calcium signalling pathway in response to mechanical stimuli.
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.
Mesenchymal stem cell (MSC) fate can be mechanically regulated by substrate stiffness but this is difficult to control in a 3D hydrogel. Here the authors identify miRNAs that change expression in response to substrate stiffness and RhoA signalling and show that they can bias MSC fate in a 3D soft hydrogel.
Mechanosensitive cation channels convert external mechanical stimuli into various biological actions, including touch, hearing, balance and cardiovascular regulation. The eukaryotic Piezo proteins are mechanotransduction channels, although their structure and gating mechanisms are not well elucidated. In related papers in this issue of Nature, two groups report cryo-electron microscopy structures of the full-length mouse Piezo1 and reveal three flexible propeller blades. Each blade is made up of at least 26 helices, forming a series of helical bundles, which adopt a curved transmembrane region. A kinked beam and anchor domain link these Piezo repeats to the pore, giving clues as to how the channel responds to membrane tension and mechanical force.
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
Mechanosensitive Piezo channels are important for a wide range of mechanotransduction processes. Here the authors show that Piezos interact with sarcoplasmic /endoplasmic-reticulum Ca2+ ATPases (SERCA) and give mechanistic insights into mechanogating and SERCA2-mediated regulation of Piezo1.
Integrins play an important role in the adhesion of cells to their matrix. Here, the authors investigate how fibroblasts respond to mechanical loads, at the onset of cell adhesion to fibronectin, in distinct phases that are modulated by integrins.
In multi-layered epithelia tight junctions (TJ) are confined to the most suprabasal viable layer. Here the authors show that this is regulated by ubiquitously localized E-cadherin tuning junctional tension and EGFR activity to inhibit TJ formation in lower layers while promoting TJ stability in the granular layer 2.
How soft tissues respond to mechanical load is essential to their biological function. Here, the authors discover that – contrary to predictions of poroelasticity – fluid mobility in collagenous tissues induces drastic volume decrease with tensile loading and pronounced chemo-mechanical coupling.
Adenomatous polyposis coli (APC) regulates the localization of some mRNAs at cellular protrusions but the underlying mechanisms and functional roles are not known. Here the authors show that APC-dependent RNAs are enriched in contractile protrusions, via detyrosinated microtubules, and enhance cell migration.
The mechanical properties of biomaterials affect cell growth through mechanotransduction signals. Here, hydrogels with fast stress relaxation were developed and showed increased cartilage matrix formation by cartilage cells compared to slow relaxation hydrogels.
At tissue boundaries, cellular repulsive events are manifested as deformation waves that result from an oscillatory pattern of traction forces and intracellular stress that pull cellular adhesions away from the boundary.
Determining how cellular activity affects the collective properties of growing tissues is key to understanding morphogenesis. An epithelial tissue model shows how active tension can give rise to striking mechanical behaviours seen in experiments.
Studying polarity establishment in C. elegans zygotes, Wang et al. find, by imaging GFP-tagged proteins, that clusters of the PAR-3 polarity protein assemble in response to membrane tension created by actomyosin contractility.
Cells in the connective tissue are surrounded by a heterogeneous network of biopolymers. Here, the authors investigate how such heterogeneity affects cellular mechanosensing by simulating the deformation response of experimental and modelled biopolymer networks to locally applied forces.
Inner ear hair cells detect sound through deflection of stereocilia that harbor mechanically-gated channels. Here the authors show that protein responsible for Usher syndrome, CIB2, interacts with these channels and is essential for their function and hearing in mice.
Mechanosensation forms the basis of many of our senses, including touch, balance, hearing and pain. Mechanically gated ion channels are responsible for transmitting mechanical force into electrical signals. However, how this occurs is not well understood at the molecular level. Here the authors report the structure of the Drosophila mechanotransduction channel NOMPC by single-particle cryo-electron microscopy. The channel contains a long, helical domain of ankyrin repeats, which appears to undergo a spring-like motion. This motion allows the mechanical movement of the cytoskeleton to be relayed into opening the channel.
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.
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.
Notch signalling is a fundamental negative regulator of epidermal stemness. Here, the authors show that cell mechanics through YAP/TAZ activity prevent primary human keratinocytes from differentiating by inhibiting cell-autonomous Notch signals.
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.
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.
Zebrafish neuroectoderm morphogenesis is influenced by the mesoderm germ layer. Smutny et al. now show that friction forces between cells moving in opposite directions, mediated by E-cadherin adhesion, determine the position of the neural anlage.
Cytokinesis, which physically separates the dividing cells at the end of epithelial cell division, involves the remodelling of adhesive junctions between the dividing cell and its neighbours. This process depends on the cytoskeletal protein myosin II (MyoII) in the non-dividing neighbouring cells. Yohanns Bellaïche and team investigated how cytokinesis in the dividing cell is coordinated with MyoII activity in its neighbours in living fly tissue and find that mechanical communication is the answer. Specifically, the cytokinetic ring pulls at local adherens junctions causing their elongation, which results in decreased levels of E-cadherin protein at these sites. This is sensed by the contracting neighbouring cells, which then promote actomyosin flows and MyoII accumulation at the base of the ingressing junctions. The authors propose that this mechano-sensing mechanism drives remodelling of adherens junction and highlight the role of actomyosin flows in epithelial cell dynamics.
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.
Epithelial cell layers serve as barriers for the organs they cover, yet they continuously undergo cell division and cell death. So how do these dynamic processes avoid compromising the barrier function of epithelia? Jody Rosenblatt and colleagues previously reported in Nature that when epithelial cells become too crowded they trigger the stretch-activated channel Piezo1 to effect extrusion of cells that later die. They now ask how epithelia deal with the opposite situation—cell death. It emerges that, following cell death, the low density of surrounding cells also activate Piezo1, driving cell division to rebalance the cell numbers. The authors provide insights into the molecular mechanism through which stretch triggers cell division, and propose that whether Piezo1 signals for cell division or cell extrusion depends on the type of mechanical forces that it experiences.
An ultrathin, needle-shaped piezoelectric microsystem that can be injected or mounted onto conventional biopsy needles measures variations in tissue modulus in real time and can thus be used to distinguish abnormal from healthy tissue.
A microtechnology involving force sensors embedded in elastomers for cell culture enables the high-throughput measurement of single-cell force generation from contractile cells in a scalable and highly parallelized manner.
Purely elastic biomimetic soft materials are used to characterize the mechanical response of cells, but do not resemble real tissues. Here the authors develop a viscoelastic solid hydrogel, based on polyacrylamide, that can be tuned to closely resemble soft tissue, and show the influence of viscous dissipation on cellular mechanical sensing.
Molecular force microscopy employs a combination of fluorescence polarization microscopy and molecular tension sensors to determine the orientation of cellular forces. The technology is demonstrated for integrin-mediated forces in platelets and fibroblasts.
Angiogenesis has been implicated in fibrotic diseases of the liver. Here, the authors developed microniches that mimic angiogenesis during different stages of liver fibrosis, and demonstrate the role of mechanotransduction in fibrogenesis.
A genetically encoded tension sensor module for measuring molecular forces at 3–5 pN along with tools for multiplexed tension sensing and data analysis reveal an intramolecular tension gradient across talin-1 during cell adhesion.
Mechanical forces can trigger a variety of biological responses in cells and tissues. This protocol describes how to combine 3D magnetic twisting cytometry with confocal fluorescence microscopy to study these force responses in greater detail.
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.
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.
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.