The mechanism of dynamic steady states in lamellipodia.

Lamellipodia are quasi-two-dimensional actin projections formed on the leading edge of the cell, playing an important role in sensing surrounding mechanical environments by forming focal adhesions. A branched actin network in the lamellipodia exhibits a stable, yet dynamic steady state characterized by a retrograde flow, which is attributed to a balance between network assembly at the leading edge and disassembly at the rear. Although the molecular players and architecture of the lamellipodia have been investigated extensively during recent decades, it still remains elusive how the dynamic steady state with continuous retrograde flow is achieved and robustly maintained. Using an agent-based computational model, we probed how physical interactions between subcellular components in the lamellipodia mediate and sustain the dynamic steady state. We simulated the branched network found in the lamellipodia, consisting of F-actin, myosin motor, Arp2/3 complex, and actin cross-linking protein, on an elastic substrate. We reproduced a steady retrograde flow induced by myosin activity and balanced by the interplay between network assembly and disassembly, but hindered by resistances from adhesions formed on the underlying substrate. We found that F-actin severing is crucial for maintaining a continuous, uniform retrograde flow because it enhances the disassembly of actin bundle/arc formed due to network contraction at the rear. In addition, we demonstrated that different modes of dynamic steady states are possible, and that a network which failed to show the retrograde flow due to perturbations can be rescued by altering other factors. Our study provides insights into understanding how cells maintain the dynamic steady state of the lamellipodia in highly varying microenvironments.