Leading edge stability in motile cells is an emergent property of branched actin network growth

Animal cell migration is predominantly driven by the coordinated, yet stochastic, polymerization of thousands of nanometer-scale actin filaments across micron-scale cell leading edges. It remains unclear how such inherently noisy processes generate robust cellular behavior. We employed high-speed imaging of migrating neutrophil-like HL-60 cells to explore the fine-scale shape fluctuations that emerge and relax throughout the process of leading edge maintenance. We then developed a minimal stochastic model of the leading edge that reproduces this stable relaxation behavior. Remarkably, we find lamellipodial stability naturally emerges from the interplay between branched actin network growth and leading edge shape - with no additional feedback required - based on a synergy between membrane-proximal branching and lateral spreading of filaments. These results thus demonstrate a novel biological noise-suppression mechanism based entirely on system geometry. Furthermore, our model suggests that the Arp2/3-mediated ~70-80{degrees} branching angle optimally smooths lamellipodial shape, addressing its long-mysterious conservation from protists to mammals. Significance StatementAll cellular functions are driven by the stochastic dynamics of macromolecules, and thus are subject to biological noise. Here, as a model system for noise-suppression in the context of cell migration, we investigate lamellipodial maintenance - where thousands of stochastically polymerizing filaments self-organize into a highly-stable, micron-scale leading edge. Combining experiment and computational modeling, we (1) establish lamellipodial stability is an emergent property of dendritically-branched actin network growth, (2) outline a noise-suppression mechanism based on the geometry of lamellipodial actin, and (3) determine the evolutionarily-conserved Arp2/3-mediated ~70-80{degrees} branching angle optimally suppresses stochastic fluctuations. Our results not only explain the essential role of Arp2/3-mediated branching in lamellipodial formation, but also address the decades-old question of why this specific geometry is so well-conserved.