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Matrix viscoelasticity regulates cell behavior in a stiffness-dependent manner. Here, the authors reveal that the mechanosensitive channel Piezo1 transduces soft matrix viscoelastic cues, through a coordinated interaction with molecular clutch mechanisms.

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

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.

Cells convert mechanical forces into biochemical signals through mechanotransduction, a process which can now be synthetically engineered. In this Review, we examine engineered artificial mechanotransduction mechanisms, from gene circuits responsive to mechanical cues to synthetic force-generating systems that reshape tissue behaviour and cellular function.

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.

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.

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.

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.

The crosstalk between cell-cell and cell-matrix adhesions regulates stem cell fate. Here, the authors reveal a critical role for matrix viscosity in controlling this crosstalk, which they explain via a modified molecular clutch model.

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.

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.

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.

By maximizing cell–substrate force transmission, cancer cells can migrate towards either stiffer or softer substrate regions.

Cells can sense the mechanical properties of their environment. By adjusting the ruffling of their membranes, cells respond to different viscosities of their surrounding liquid medium.

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.

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.

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.

The rate at which proteins are imported into the nucleus of a cell is shown to be regulated by their mechanical unfolding, a mechanism that identifies the nuclear pore machinery as a highly sensitive force detector.

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.

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.

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.

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.

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.

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

This study provides key mechanistic insights into how direct coupling of ECM to actin through talin has specific and critical roles in controlling adhesion dynamics required for early mammalian development.

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.

The formation of cellular adhesion complexes is important in normal and pathological cell activity, and is determined by the force imposed by the combined effect of the distribution of extracellular matrix molecules and substrate rigidity.

A growing body of evidence suggests that the mechanical functions of cardiac fibroblasts are an active and necessary component of myocardial growth and homeostasis. In this Review, Van Linthout and colleagues describe cell mechanosensation as a regulator of cardiac maturation and disease, and summarize the evidence showing that remodelling of the cardiac extracellular matrix, as a result of disease, can induce changes in the mechanical properties of the myocardium.

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.

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.