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Xavier Trepat highlights the first approach to measurement of forces exerted by cells

Haptotaxis was traditionally seen as migration up protein gradients. It is now shown that cells can also oscillate or migrate down the gradient.

Engineering approaches allow biological structures and behaviours to be reconstituted in vitro. A biologist and a physicist discuss the potential and limitations of this bottom-up philosophy in providing insights into complex biological processes.

Trepat and colleagues conduct a systematic analysis of how key cell–cell adhesion molecules affect intercellular forces and epithelial monolayer dynamics.

The mechanical stresses within and between cells inside an advancing cellular monolayer are mapped experimentally. Cellular migration is found to be oriented in the direction of maximum principal stress indicating that cells collectively migrate to maintain minimal local intercellular shear stress.

Pérez-González et al. explore the mechanical properties of intestinal organoids, and report the existence of distinct mechanical domains and that cells are pulled out of the central crypt along a gradient of increasing tension.

Cell clusters mechanically reorganize viscoelastic collagen networks, resulting in transient gradients in collagen density, alignment and stiffness that promote spontaneous persistent migration.

Modelling the tumour immune microenvironment in vitro is a valuable tool to test immunotherapy efficiency but capturing its complexity is challenging. Here authors present a fully humanised in vitro platform representing tumour/stroma interface and demonstrate how modulation by IL2 may allow immune cells to overcome stromal barriers.

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.

Marin-Llaurado and colleagues engineer curved epithelial monolayers of controlled geometry and develop a new technique to map their state of stress. They show that pronounced stress anisotropies influence cell alignment.

The mechanical properties of heterogeneous cell populations in colorectal tumors and the relevance to cancer metastasis remain not fully understood. Here, the authors suggest that the variations in malignant phenotypes between LGR5-positive cancer stem cells and LGR5-negative cells could be due to their distinct mechanical phenotypes observed in vitro, determined by the membrane to cortex attachment proteins Ezrin/Radixin/Moesin.

The formation of body segments in vertebrate embryos has long been attributed to the spatio-temporal patterning of molecular signals. But segment length in zebrafish is now found to be adjusted by tissue mechanics.

Tissue growth and regrowth rely on the collective migration of sheets of cells. Gradients in tension established through intercellular forces guide this migration, but the mechanism driving the gradients has remained unclear. Innovative experiments now reveal their origin—in a mechanical wave set up by sequential cell reinforcement and fluidization.

Amphiphysin BAR proteins reshape membranes, but the dynamics of the process remained unexplored. Here, the authors show through experiment and modelling that reshaping depends on the initial template shape, occurs even at low initial curvature, and involves the coexistence of isotropic and nematic states.

The most abundant proteins in our cells are there to generate mechanical forces, and measurement of these forces has just become possible.

A poor prognosis gene programme in patients with colorectal cancer is expressed by a unique tumour cell population that we name high-relapse cells (HRCs), and ablation of cells expressing the HRC marker EMP1 or neoadjuvant immunotherapy prevented metastatic recurrence in mice.

Leader cells play an important role in guiding migratory clusters in various biological processes. Now, the mechanical organization of leader and followers within a cell cluster is shown to enable collective migration.

Andreu et al. show that force regulates nucleocytoplasmic transport by weakening the permeability barrier of nuclear pore complexes, affecting passive and facilitated diffusion in different ways.

Cells sense mechanical forces from their environment, but the precise mechanical variable sensed by cells is unclear. Here, the authors show that cells can sense the rate of force application, known as the loading rate, with effects on YAP nuclear localization and cytoskeletal stiffness remodelling.

Although the collective cellular motion involved in, for example, wound healing and tumour invasion is suspected to be driven by mechanical stresses within the advancing cell monolayer, how motion and stress relate has remained elusive. Now, stress-microscopy observations of an epithelial cell sheet advancing towards a region where cells cannot adhere reveal that the cells located nearby such a region exert forces that pull them towards the unfilled space, regardless of whether the cells approach or recede from it.

How the cell goes about its routine mechanical business of stretching, contracting, and remodelling has implications for understanding excessive airway narrowing in asthma, cell invasion in cancer and vessel constriction in vascular disease. Surprisingly, the cell is an intermediate form of matter, neither solid nor fluid but retaining features of both - that responds to stretch by fluidizing, much as do common pastes, foams, clays, and colloids.

It has been thought that sheets of cells move by traction forces exerted by the cells at the leading edge of the sheet. Using traction microscopy to create a map of physical forces, it is now shown that in fact it is cells many rows from the front that do most of the work.

Wound repair is thought to involve cell migration and the contraction of a tissue-level biopolymer ring—invoking analogy with the pulling of purse strings. Traction-force measurements now show that this ring engages the tissue's surroundings to steer migration, prompting revision of the purse-string mechanism.

Measurements in stretched epithelial cell sheets show that epithelial cracks are independent of tension and that epithelial fracture is caused by the hydraulic pressure that builds up in the extracellular matrix during stretching.

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.

Apical constriction is a force-generating process required during embryonic development; there is a lack of tools to manipulate 3D shapes of mammalian tissues. Here the authors report the optogenetic method, OptoShroom3, to achieve fast spatiotemporal control of apical constriction in mammalian epithelia.

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.

The collective migration of cell clusters is modulated by substrate geometry through a combination of velocity and polarity alignment.

Laminin, an important component of the extracellular matrix supporting the epithelium, hinders the typical mechanoresponse of epithelial cells to an increase in substrate stiffness, by protecting the cell nucleus from mechanical deformation.

Theoretical modelling in combination with measurements of tension and shape in epithelial domes of controlled geometry reveals a plateau of tension in tissue that is maintained by heterogeneous strain across cells.

Lolo et al. show caveolin-1 functions in non-caveolae structures termed dolines. Whereas caveolae respond to high forces over a mechanical threshold, dolines transduce low and medium mechanical forces gradually in a complementary buffering system.

Variations in cell shape must be accommodated by the cell membrane, but how the membrane adjusts to changes in area and volume is not known. Here the authors show that the membrane responds in a nearly instantaneous, purely physical manner involving the flattening or generation of membrane invaginations.

Closure of epithelial gaps such as wounds is thought to involve contraction of an actomyosin ‘purse-string’. By creating non-adherent gaps to exclude contributions of adhesive protrusion, the authors find that large-scale tension, more than purse-string contraction, mediates closure.

Cancer-associated fibroblasts (CAFs) can produce ECM and form a physical barrier around the tumour. Here, the authors show in transgenic mouse models and in vitro systems that CAFs are able to actively compress cancer cells using actomyosin contractility and this leads to a modulation of cancer cell mechanosensing and tumour reorganisation.

The generation of aligned extracellular matrices by fibroblasts is shown to depend on cell reorientation following collision, leading to closer alignment of the cells’ long axes. This cell collision guidance depends on the transcription factor TFAP2C and localized regulation of actomyosin contractility.

A method to accelerate the generation of kidney organoids from human pluripotent stem cells cultured in a three-dimensional environment and exposed to inductive stimuli has been developed, with the organoids capable of recapitulating kidney organogenesis.

The mechanism of cytokinetic failure in the migrating zebrafish epicardium leading to multinucleated cells is shown to be driven by the interaction of the cytokinetic ring and the extracellular matrix through adhesion reinforcement by high traction forces.

Changes in membrane curvature influence how migrating cells navigate their environment. Experiments and modelling reveal that dynamic reorganization of the actin cytoskeleton in response to these changes provides cells with a sensing mechanism.

Plasma membrane tension is an important factor that regulates many key cellular processes. Here authors show that a specific dynamin-independent endocytic pathway is modulated by changes in tension via the mechano-transducer vinculin.

Substrate stiffness influences cellular cluster migration through collective durotaxis. Now, the underlying mechanism of this process is explained by considering the wetting dynamics of the clusters.

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.

Cell behaviour is in part regulated by the rigidity of their environment, yet the underlying mechanisms have remained unclear. It is now shown for breast myoepithelial cells expressing two types of integrin that rigidity sensing and adaptation can be explained by a clutch-bond model that considers the different rates of binding and unbinding between the integrins and the extracellular matrix.

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.

Epithelial wound closure proceeds through both crawling into the wound and by constricting an actomyosin cable in a so-called purse-string mechanism. Here the authors show that the two mechanisms are mechanically coupled and the curvature of the wound regulates the overall dynamics of wound closure.

In wound healing, skin cells collectively migrate to maintain tissue cohesion despite the existence of inhomogeneities in the extracellular environment within the wound bed. Yet how the cell collective responds to heterogeneities in the extracellular matrix is not well understood. Now, it is shown that migrating human keratinocyte cell sheets form suspended multicellular bridges over non-adhesive regions on micropatterned substrates comprising alternating strips of fibronectin and non-adherent polymer.

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.