Insight to motor clutch model for sensing of ECM residual strain

The mechanical microenvironment strongly affects cell state and decisions. Cell mechanosensing has been described by a molecular clutch which gets progressively engaged depending upon the stiffness of the extracellular material. Through the actuation of pulling forces exerted by actin fibres on the mechanosensitive talin-integrin molecular complex, cells sense and react to the stiffness of their surroundings. However, whether the truly cell mechanosensing is regulated by the pure elastic stiffness or by the strain energy density of the ECM is still debated. Here we report that the cell response to change of strain energy density out of loading induced deformation (purely elastic) can be accounted for by including, within the same frame of the molecular clutch model, the residual strain/stress to which the ECM could be subjected before establishing any interaction with the molecular clutches. To include the contribution of residual stresses, an additional spring orthogonal to the ones already present in the original clutch model has been introduced; this spring takes memory of the ECM strain energy when axially deformed before any interaction with cell molecular clutches can occur. To evaluate the influence of strain on the optimum number of clutches, the model has been implemented with different levels of strain. Results suggest that cells undergo a reinforcement process, stiffening the cytoskeleton in response to the ECM stress/strain energy.