Force loading on molecular clutches governs the stability of cell lamellipodia

Cells can utilize the lamellipodia, a thin actin-rich membrane protrusion, to probe the mechanical properties of microenvironments. During the mechanosensing process, the lamellipodium usually exhibits instability in dynamics, i.e., protrusion-retraction cycles. However, how mechanical instability arises in lamellipodia, along with the functional role of dynamic instability in mechanosensing, is poorly understood. Here, we develop a minimal mechanochemical model for lamellipodia dynamics that integrates membrane deformation, myosin contractility, and binding kinetics of adhesion molecules (molecular clutches). Through stochastic simulations and analytical mean-field analysis, we demonstrate that both force-loading rate and magnitude applied by myosin-driven retrograde flow mediate the clutch binding kinetics, governing lamellipodial stability and hence the mechanosensing. Specifically, a slow force loading rate allows the clutches to bind and traction to accumulate, while a high loading magnitude collapses the bound clutches, causing protrusion-retraction cycles (instability) in lamellipodia. Our model predicts that a stiffer substrate stabilizes the lamellipodia by increasing the force loading rate, consistence with previous experiments. Furthermore, our model predictions on the biphasic regulation effect of myosin perturbations have been quantitatively validated by experimental results. Overall, the theoretical framework highlights the force loading as the key mechanical input driving lamellipodial instability and cell mechanosensing, advancing our understanding of mechanotransduction's role in cell behaviors.