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Key Points Under steady state conditions, cells must actively maintain the mechanical properties of the extracellular matrix (ECM) to maintain the normal function of many, if not all, tissues. Cells control ECM mechanics through degradation, synthesis, organization and pre-stress of its components. Mechanical cues from the ECM trigger signalling cascades that alter gene expression and affect various processes, including cell motility and fate. Elucidating the feedback mechanisms between cells and the ECM that maintain mechanical properties is a key question for future work. In soft connective tissues at the steady state, cells continually read environmental cues and respond to promote mechanical homeostasis of the extracellular matrix and ensure cellular and tissue health. Progress has been made into our understanding of the molecular, cellular and tissue scale responses to mechanical load that promote mechanical homeostasis. Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix (ECM) that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function. Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.

The form of vertebrates is shaped by the sensing and relaying of mechanical forces that are applied between cells and their microenvironment. Mechanobiology has emerged as a field of research dedicated to studying these forces and their communication through signalling processes, which are collectively known as mechanotransduction. Although the shapes of organisms are encoded in their genome, the developmental processes that lead to the final form of vertebrates involve a constant feedback between dynamic mechanical forces, and cell growth and motility. Mechanobiology has emerged as a discipline dedicated to the study of the effects of mechanical forces and geometry on cell growth and motility — for example, during cell–matrix adhesion development — through the signalling process of mechanotransduction.

The ability of animal cells to sense, adhere to and remodel their local extracellular matrix (ECM) is central to control of cell shape, mechanical responsiveness, motility and signalling, and hence to development, tissue formation, wound healing and the immune response. Cell–ECM interactions occur at various specialized, multi-protein adhesion complexes that serve to physically link the ECM to the cytoskeleton and the intracellular signalling apparatus. This occurs predominantly via clustered transmembrane receptors of the integrin family. Here we review how the interplay of mechanical forces, biochemical signalling and molecular self-organization determines the composition, organization, mechanosensitivity and dynamics of these adhesions. Progress in the identification of core multi-protein modules within the adhesions and characterization of rearrangements of their components in response to force, together with advanced imaging approaches, has improved understanding of adhesion maturation and turnover and the relationships between adhesion structures and functions. Perturbations of adhesion contribute to a broad range of diseases and to age-related dysfunction, thus an improved understanding of their molecular nature may facilitate therapeutic intervention in these conditions.Cell–extracellular matrix (ECM) interactions occur at specialized, multi-protein adhesion complexes, with clustered integrins as the predominant ECM receptors. Progress in characterization of adhesion composition, organization and dynamics in response to force has improved understanding of adhesion maturation and turnover and the relationships between adhesion structures and functions.

Integrins, and integrin-mediated adhesions, have long been recognized to provide the main molecular link attaching cells to the extracellular matrix (ECM) and to serve as bidirectional hubs transmitting signals between cells and their environment. Recent evidence has shown that their combined biochemical and mechanical properties also allow integrins to sense, respond to and interact with ECM of differing properties with exquisite specificity. Here, we review this work first by providing an overview of how integrin function is regulated from both a biochemical and a mechanical perspective, affecting integrin cell-surface availability, binding properties, activation or clustering. Then, we address how this biomechanical regulation allows integrins to respond to different ECM physicochemical properties and signals, such as rigidity, composition and spatial distribution. Finally, we discuss the importance of this sensing for major cell functions by taking cell migration and cancer as examples.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.

Dynamics of epithelial tissues determine key processes in development, tissue healing and cancer invasion. These processes are critically influenced by cell–cell adhesion forces. However, the identity of the proteins that resist and transmit forces at cell–cell junctions remains unclear, and how these proteins control tissue dynamics is largely unknown. Here we provide a systematic study of the interplay between cell–cell adhesion proteins, intercellular forces and epithelial tissue dynamics. We show that collective cellular responses to selective perturbations of the intercellular adhesome conform to three mechanical phenotypes. These phenotypes are controlled by different molecular modules and characterized by distinct relationships between cellular kinematics and intercellular forces. We show that these forces and their rates can be predicted by the concentrations of cadherins and catenins. Unexpectedly, we identified different mechanical roles for P-cadherin and E-cadherin; whereas P-cadherin predicts levels of intercellular force, E-cadherin predicts the rate at which intercellular force builds up. Trepat and colleagues conduct a systematic analysis of how key cell–cell adhesion molecules affect intercellular forces and epithelial monolayer dynamics.

Integrins are the major family of adhesion molecules that mediate cell adhesion to the extracellular matrix. They are essential for embryonic development and influence numerous diseases, including inflammation, cancer cell invasion and metastasis. In this Perspective, we discuss the current understanding of how talin, kindlin and mechanical forces regulate integrin affinity and avidity, and how integrin inactivators function in this framework. In this Perspective, Fässler and co-authors describe current models of how integrin adhesion molecules are activated and stabilised, and the importance of forces in this process.

Key Points In many biological situations in vivo , including tissue shaping during morphogenesis, tissue repair and cancer invasion, cells do not move as single bodies but as a collective. Two main mechanisms support collective dynamics: polarized collective cell migration and coordinated contractile processes of cell groups that involve multicellular actomyosin-based structures. In vitro wound-healing assays exploiting microfabricated devices have been models of choice to study collective cell behaviours. Such in vitro approaches are the most important methods to achieve multiscale analysis from the molecular to the multicellular level. In contrast to a single cell, collective cell migration relies not only on the interactions with the extracellular matrix but also with neighbouring cells. Coordinated movements strongly depend on intercellular interactions via mechanosensitive cadherin-based adhesions. Cellular coordination is a mechanoregulated multiscale process integrating events at the molecular, cellular and multicellular scales, and it occurs at a wide range of timescales, from milliseconds to minutes to days. Coordinated movements of cell collectives are important for morphogenesis, tissue regeneration and cancer cell dissemination. Recent studies, mainly using novel in vitro approaches, 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. The way in which cells coordinate their behaviours during various biological processes, including morphogenesis, cancer progression and tissue remodelling, largely depends on the mechanical properties of the external environment. In contrast to single cells, collective cell behaviours rely on the cellular interactions not only with the surrounding extracellular matrix but also with neighbouring cells. Collective dynamics is not simply the result of many individually moving blocks. Instead, cells coordinate their movements by actively interacting with each other. These mechanisms are governed by mechanosensitive adhesion complexes at the cell–substrate interface and cell–cell junctions, which respond to but also further transmit physical signals. The mechanosensitivity and mechanotransduction at adhesion complexes are important for regulating tissue cohesiveness and thus are important for collective cell behaviours. Recent studies have shown that the physical properties of the cellular environment, which include matrix stiffness, topography, geometry and the application of external forces, can alter collective cell behaviours, tissue organization and cell-generated forces. On the basis of these findings, we can now start building our understanding of the mechanobiology of collective cell movements that span over multiple length scales from the molecular to the tissue level.

Cell function depends on tissue rigidity, which cells probe by applying and transmitting forces to their extracellular matrix, and then transducing them into biochemical signals. Here we show that in response to matrix rigidity and density, force transmission and transduction are explained by the mechanical properties of the actin–talin–integrin–fibronectin clutch. We demonstrate that force transmission is regulated by a dynamic clutch mechanism, which unveils its fundamental biphasic force/rigidity relationship on talin depletion. Force transduction is triggered by talin unfolding above a stiffness threshold. Below this threshold, integrins unbind and release force before talin can unfold. Above the threshold, talin unfolds and binds to vinculin, leading to adhesion growth and YAP nuclear translocation. Matrix density, myosin contractility, integrin ligation and talin mechanical stability differently and nonlinearly regulate both force transmission and the transduction threshold. In all cases, coupling of talin unfolding dynamics to a theoretical clutch model quantitatively predicts cell response. 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.

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. During cell migration, the forces generated in the actin cytoskeleton are transmitted across transmembrane receptors to the extracellular matrix or other cells through a series of mechanosensitive, regulable protein–protein interactions termed the molecular clutch. In integrin-based focal adhesions, the proteins forming this linkage are organized into a conserved three-dimensional nano-architecture. Here we discuss how the physical interactions between the actin cytoskeleton and focal-adhesion-associated molecules mediate force transmission from the molecular clutch to the extracellular matrix.

The transmembrane domain of NOTCH1 plays a key role in the assembly of adherens junctions and the non-transcriptional regulation of vascular permeability that links transcriptional programs with adhesive and cytoskeletal remodelling. Vascular barrier formation The interaction between the Notch receptor and its ligands causes proteolysis of the receptor's intracellular domain, which then relocates to the nucleus and regulates transcription of a battery of genes. William Polacheck et al . show that ligand binding to the Notch receptor in the endothelium—the layer of cells that line the interior of blood and lymphatic vessels—triggers a non-canonical signalling cascade that is mediated by the receptor's transmembrane domain. This domain catalyses the formation of a complex composed of vascular endothelial cadherin, the transmembrane protein tyrosine phosphatase LAR, and the RAC1 guanidine-exchange factor TRIO. This complex drives the assembly of adherens junctions and is crucial for the establishment and maintenance of the endothelial barrier, which is essential to vascular health. The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and haemostasis 1 . Haemodynamic shear stress plays a critical role in maintaining endothelial barrier function 2 , but how this occurs remains unknown. Here we use an engineered organotypic model of perfused microvessels to show that activation of the transmembrane receptor NOTCH1 directly regulates vascular barrier function through a non-canonical, transcription-independent signalling mechanism that drives assembly of adherens junctions, and confirm these findings in mouse models. Shear stress triggers DLL4-dependent proteolytic activation of NOTCH1 to expose the transmembrane domain of NOTCH1. This domain mediates establishment of the endothelial barrier; expression of the transmembrane domain of NOTCH1 is sufficient to rescue defects in barrier function induced by knockout of NOTCH1 . The transmembrane domain restores barrier function by catalysing the formation of a receptor complex in the plasma membrane consisting of vascular endothelial cadherin, the transmembrane protein tyrosine phosphatase LAR, and the RAC1 guanidine-exchange factor TRIO. This complex activates RAC1 to drive assembly of adherens junctions and establish barrier function. Canonical transcriptional signalling via Notch is highly conserved in metazoans and is required for many processes in vascular development, including arterial–venous differentiation 3 , angiogenesis 4 and remodelling 5 . We establish the existence of a non-canonical cortical NOTCH1 signalling pathway that regulates vascular barrier function, and thus provide a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodelling.