Cellular adhesions are modulated by cytoskeletal forces or external stresses and adapt to the mechanical properties of the extracellular matrix. We propose that this mechanosensitivity can be driven at least in part by the elastic, cell-contractility-induced deformations of protein molecules that form the adhesion. The model accounts for observations of anisotropic growth and shrinkage of focal adhesions in the direction of the force and predicts that focal adhesions only grow within a range of force that is determined by the composition and matrix properties. This prediction is consistent with the observations of a force threshold for the appearance of elongated focal adhesions and the disruption of adhesions into fibrils on a mobile extracellular matrix. The growth dynamics is calculated and the predicted sliding of focal adhesions is consistent with several experiments

The minimal structural unit that defines living organisms is a single cell. By proliferating and mechanically interacting with each other, cells can build complex organization such as tissues that ultimately organize into even more complex multicellular living organisms, such as mammals, composed of billions of single cells interacting with each other. As opposed to passive materials, living cells actively respond to the mechanical perturbations occurring in their environment. Tissue cell adhesion to its surrounding extracellular matrix or to neighbors is an example of a biological process that adapts to physical cues. The adhesion of tissue cells to their surrounding medium induces the generation of intracellular contraction forces whose amplitude adapts to the mechanical properties of the environment. In turn, solicitation of adhering cells with physical forces, such as blood flow shearing the layer of endothelial cells in the lumen of arteries, reinforces cell adhesion and impacts cell contractility. In biological terms, the sensing of physical signals is transduced into biochemical signaling events that guide cellular responses such as cell differentiation, cell growth and cell death. Regarding the biological and developmental consequences of cell adaptation to mechanical perturbations, understanding mechanotransduction in tissue cell adhesion appears as an important step in numerous fields of biology, such as cancer, regenerative medicine or tissue bioengineering for instance. Physicists were first tempted to view cell adhesion as the wetting transition of a soft bag having a complex, adhesive interaction with the surface. But surprising responses of tissue cell adhesion to mechanical cues challenged this view. This, however, did not exclude that cell adhesion could be understood in physical terms. It meant that new models and descriptions had to be created specifically for these biological issues, and could not straightforwardly be adapted from dead matter. In this review, we present physical concepts of tissue cell adhesion and the unexpected cellular responses to mechanical cues such as external forces and stiffness sensing. We show how biophysical approaches, both experimentally and theoretically, have contributed to our understanding of the regulation of cellular functions through physical force sensing mechanisms. Finally, we discuss the different physical models that could explain how tissue cell adhesion and force sensing can be coupled to internal mechanosensitive processes within the cell body.

Cell/matrix adhesions are modulated by cytoskeletal or external stresses and adapt to the mechanical properties of the extracellular matrix. We propose that this mechanosensitivity arises from the activation of a mechanosensor located within the adhesion itself. We show that this mechanism accounts for the observed directional growth of focal adhesions and the reduction or even cessation of their growth when cells adhere to a soft extracellular matrix. We predict quantitatively that both the elasticity and the thickness of the matrix play a key role in the dynamics of focal adhesions. Two different types of dynamics are expected depending on whether the thickness of the matrix is of order of or much larger than the adhesion size. In the latter situation, we predict that the adhesion region reaches a saturation size that can be tuned by the mechanical properties of the matrix.

Neurons are sensitive to topographical cues provided either by in vivo or in vitro environments on the micrometric scale. We have explored the role of randomly distributed silicon nano-pillars on primary hippocampal neurite elongation and axonal differentiation. We observed that neurons adhere on the upper part of nano-pillars with a typical distance between adhesion points of about 500nm. These neurons produce less neurites, elongate faster, and differentiate an axon earlier than those grown on flat silicon surfaces. Moreover, when confronted to a differential surface topography, neurons specify an axon preferentially onto nano-pillars. As a whole, these results highlight the influence of the physical environment in many aspects of neuronal growth.

Background: Cohesion of interendothelial junctions is maintained by the connections existing between the VE-cadherin⅐catenin complex and the actin cytoskeleton. Results: By interacting with ␣-catenin, the actin-binding protein EPLIN (epithelial protein lost in neoplasm) facilitates the recruitment of vinculin. Conclusion:The EPLIN␣-catenin link provides a mechanosensory machinery by acting as a tension transmitter. Significance: By anchoring the VE-cadherin⅐catenin complex to F-actin, EPLIN strengthens interendothelial junctions.

Clusters, rafts, nanodomains, and patches are names frequently used to depict cell membranes. This wide vocabulary emphasizes the heterogeneous organization of membrane constituents, which is essential for cellular functions such as signalling, trafficking and adhesion. Despite their diversity, cell membrane domains might share similar physical grounds. In an attempt to integrate them in a general framework, we review here recent studies on domains in adhering and non-adhering membranes. We show that a broad range of biological studies challenged the concepts of membrane physics at thermodynamic equilibrium and enriched the classical physical-chemistry approaches on model systems.

It is now well established that the mechanical environment of the cells in tissues deeply impacts cellular fate, including life cycle, differentiation and tumor progression. Designs of biomaterials already include the control of mechanical parameters, and in general, their main focus is to control the rheological properties of the biomaterials at a macroscopic scale. However, recent studies have demonstrated that cells can stress their environment below the micron scale, and therefore could possibly respond to the rheological properties of their environment at this micron scale. In this context, probing the mechanical properties of physiological cellular environments at subcellular scales is becoming critical. To this aim, we performed in vitro indentation measurements using AFM on sliced human pituitary gland tissues. A robust methodology was implemented using elasto-adhesive models, which shows that accounting for the adhesion of the probe on the tissue is critical for the reliability of the measurement. In addition to quantifying for the first time the rigidity of normal pituitary gland tissue, with a geometric mean of 9.5 kPa, our measurements demonstrated that the mechanical properties of this tissue are far from uniform at subcellular scales. Gradients of rigidity as large as 12 kPa μm(-1) were observed. This observation suggests that physiological rigidity can be highly non-uniform at the micron-scale.

Cell focal adhesions are micrometer-sized aggregates of proteins that anchor the cell to the extracellular matrix. Within the cell, these adhesions are connected to the contractile, actin cytoskeleton; this allows the adhesions to transmit forces to the surrounding matrix and makes the adhesion assembly sensitive to the rigidity of their environment. In this article, we predict the dynamics of focal adhesions as a function of the rigidity of the substrate. We generalize previous theories and include the fact that the dynamics of proteins that adsorb to adhesions are also driven by their coupling to cell contractility and the deformation of the matrix. We predict that adhesions reach a finite size that is proportional to the elastic compliance of the substrate, on a timescale that also scales with the compliance: focal adhesions quickly reach a relatively small, steady-state size on soft materials. However, their apparent sliding is not sensitive to the rigidity of the substrate. We also suggest some experimental probes of these ideas and discuss the nature of information that can be extracted from cell force microscopy on deformable substrates.