Acto-myosin based response to stiffness and rigidity sensing

Abstract

Cells sense the rigidity of their environment and respond to it. Most studies have been focused on the role of adhesion complexes in rigidity sensing. In particular, it has been clearly shown that proteins of the adhesion complexes were stretch-sensitive, and could thus trigger mechano-chemical signaling in response to applied forces. In order to understand how this local mechano-sensitivity could be coordinated at the cell scale, we have recently carried out single cell traction force measurements on springs of varying stiffness. We found that contractility at the cell scale (force, speed of contraction, mechanical power) was indeed adapted to external stiffness, and reflected ATPase activity of non-muscle myosin II and acto-myosin response to load. Here we suggest a scenario of rigidity sensing where local adhesions sensitivity to force could be coordinated by adaptation of the acto-myosin dependent cortical tension at the global cell scale. Such a scenario could explain how spreading and migration are oriented by the rigidity of the cell environment.

Figure 1

Acto-myosin contractility, adhesion complexes and rigidity. An adherent cell applies traction forces that are generated by the contractile acto-myosin machinery (green) and are transmitted to the substrate through integrin-based adhesion complexes (red). The resultant dipole forces, F, are resisted by the elasticity of the substrate which acts basically as a spring. Current models of rigidity sensing are mainly based on (local) stretching of sensory molecules of the adhesion complexes (zoom). On rigid-weakly deformable-substrates local force components, f, induce stretching and phosphorylation of specific molecules, thus triggering mechano-chemical signaling cascades that enhance in turn contractility.

Figure 2

Principle of a single cell traction force assay. A single cell spreads between and pull on two parallel glass microplates coated with fibronectin. Cell traction force is measured through the deflection d of a flexible plate of calibrated stiffness k; F = kd. The setup is equivalent to one where the cell would be compressing a spring of stiffness k. By using plates of different stiffness, we have recently investigated the effect of rigidity on the contractile activity at the cell scale, i.e., on the overall force F.

Figure 3

Force generation is dependent on stiffness. The rate of force build-up (dF/dt, slope of the force curves) increased with stiffness. This implies that, after a given time t, cells apply higher forces FH on stiff plates than on soft ones Fl. This phenomenon could explain why cells migrating on anisotropic substrates orient along the stiffest axis.

Figure 4

A model of initial cell “polarization” on a substrate with anisotropic rigidity. (1) When cell is non-adherent, acto-myosin based cortical tension is isotropic and the cell is rounded. (2) When cell reaches the substrate and begins to spread, tension in the free part of the cortex is transferred to the substrate through adhesions situated at the cell periphery. Since the rate of force build-up increases with stiffness, cortical tension will become anisotropic. This will result in higher forces applied on the cell poles situated along the stiffest axis of the substrate. Following adhesions sensitivity to force, these poles will concentrate adhesion complexes and their related mechano-chemical signaling processes.