Binding cooperativity of membrane adhesion receptors

The adhesion of cells is mediated by receptors and ligands anchored in apposing membranes. A central question is how to characterize the binding affinity of these membrane-anchored molecules. For soluble molecules, the binding affinity is typically quantified by the binding equilibrium constant K3D in the linear relation [RL] = K3D [R][L] between the volume concentration [RL] of bound complexes and the volume concentrations [R] and [L] of unbound molecules. For membrane-anchored molecules, it is often assumed by analogy that the area concentration of bound complexes [RL] is proportional to the product [R][L] of the area concentrations for the unbound receptor and ligand molecules. We show here (i) that this analogy is only valid for two planar membranes immobilized on rigid surfaces, and (ii) that the thermal roughness of flexible membranes leads to cooperative binding of receptors and ligands. In the case of flexible membranes, the area concentration [RL] of receptor-ligand bonds is proportional to the square of [R][L] for typical lengths and concentrations of receptors and ligands in cell adhesion zones. The cooperative binding helps to understand why different experimental methods for measuring the binding affinity of membrane-anchored molecules have led to values differing by several orders of magnitude.Comment: 9 pages, 4 figures; to appear in Soft Matte

Adhesion of membranes via receptor-ligand complexes: Domain formation, binding cooperativity, and active processes

Cell membranes interact via anchored receptor and ligand molecules. Central questions on cell adhesion concern the binding affinity of these membrane-anchored molecules, the mechanisms leading to the receptor-ligand domains observed during adhesion, and the role of cytoskeletal and other active processes. In this review, these questions are addressed from a theoretical perspective. We focus on models in which the membranes are described as elastic sheets, and the receptors and ligands as anchored molecules. In these models, the thermal membrane roughness on the nanometer scale leads to a cooperative binding of anchored receptor and ligand molecules, since the receptor-ligand binding smoothens out the membranes and facilitates the formation of additional bonds. Patterns of receptor domains observed in Monte Carlo simulations point towards a joint role of spontaneous and active processes in cell adhesion. The interactions mediated by the receptors and ligand molecules can be characterized by effective membrane adhesion potentials that depend on the concentrations and binding energies of the molecules.Comment: Review article, 13 pages, 9 figures, to appear in Soft Matte

Quantification of cellular forces on rigidity patterned substrates evidences distinct length scales in rigidity sensing

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Data from: Collective cell migration without proliferation: density determines cell velocity and wave velocity

Collective cell migration contributes to embryogenesis, wound healing and tumor metastasis. Cell monolayer migration experiments help understanding what determines the movement of cells far from the leading edge. Inhibiting cell proliferation limits cell density increase and prevents jamming; we observe long-duration migration and quantify space-time characteristics of the velocity profile over large length- and time-scales. Velocity waves propagate backwards and their frequency depends only on cell density at the moving front. Both cell average velocity and wave velocity increase linearly with the cell effective radius regardless of the distance to the front. Inhibiting lamellipodia decreases cell velocity while waves either disappear or have a lower frequency. Our model combines conservation laws, monolayer mechanical properties and a phenomenological coupling between strain and polarity: advancing cells pull on their followers which then become polarized. With reasonable values of parameters, this model agrees with several of our experimental observations. Together, our experiments and model disantangle the respective contributions of active velocity and of proliferation in monolayer migration, explain how cells maintain their polarity far from the moving front, and highlight the importance of strain-polarity coupling and density in long-range information propagation

Collective cell migration without proliferation: density determines cell velocity and wave velocity

International audienceCollective cell migration contributes to embryogenesis, wound healing and tumour metastasis. Cell monolayer migration experiments help in understanding what determines the movement of cells far from the leading edge. Inhibiting cell proliferation limits cell density increase and prevents jamming; we observe long-duration migration and quantify space–time characteristics of the velocity profile over large length scales and time scales. Velocity waves propagate backwards and their frequency depends only on cell density at the moving front. Both cell average velocity and wave velocity increase linearly with the cell effective radius regardless of the distance to the front. Inhibiting lamellipodia decreases cell velocity while waves either disappear or have a lower frequency. Our model combines conservation laws, monolayer mechanical properties and a phenomenological coupling between strain and polarity: advancing cells pull on their followers, which then become polarized. With reasonable values of parameters, this model agrees with several of our experimental observations. Together, our experiments and model disantangle the respective contributions of active velocity and of proliferation in monolayer migration, explain how cells maintain their polarity far from the moving front, and highlight the importance of strain–polarity coupling and density in long-range information propagation

Intracellular stresses in patterned cell assemblies

International audienceConfining cells on adhesive patterns allows performing robust, weakly dispersed, statistical analysis. A priori, adhesive patterns could be efficient tools to analyze intracellular cell stress fields, in particular when patterns are used to force the geometry of the cytoskeleton. This tool could then be very helpful in deciphering the relationship between the internal architecture of the cells and the mechanical, intracellular stresses. However, the quantification of the intracellular stresses is still something delicate to perform. Here we first propose a new, very simple and original method to quantify the intracellular stresses, which directly relates the strain the cells impose on the extracellular matrix to the intracellular stress field. This method is used to analyze how confinement influences the intracellular stress field. As a result, we show that the more confined the cells are, the more stressed they will be. The influence of the geometry of the adhesive patterns on the stress patterns is also discussed

Supporting Movie S1.

Monolayer of MDCK cells migrating within a straight strip with mitomycin C to prevent divisions. Phase contrast image showing cell contours. Strip total length 4 mm, width 1 mm. The first image, noted t = 0, is taken after around 5 h of migration. Duration of the movie: 26 h. Because of file size constraints, the movie resolution has been decreased, and the time interval between frame has been doubled (10 min instead of 5 min in the original)