Leading Edge Maintenance in Migrating Neutrophil-Like HL-60 Cells is an Emergent Property of Branched Actin Growth

Abstract

Listen

Translate article

Actin-driven, directional cell motility is one of the most fundamental behaviors in animal cell biology. To maintain polarized migration, cells must coordinate the stochastic growth of tens of thousands of nanometer-sized actin filaments over micron-scale distances along their leading edge. We employed high speed, high resolution microscopy of migrating neutrophil-like HL-60 cells to directly observe leading edge maintenance evolving over time. To our surprise, we discovered that cells’ leading edge shape continuously undergoes dynamic sub-micron, sub-second undulations, all while maintaining nearly constant overall cell shape. Under the assumption that these shape fluctuations reflect the underlying actin dynamics driving migration, we set out to quantitatively characterize and then perturb shape dynamics in order to develop a deeper understanding of the mechanisms cells use to maintain leading edge shape, and thus polarized migration. Adapting well-established methods from polymer physics, we used Fourier mode time-autocorrelation analysis to investigate the relaxation of shape fluctuations over time. Surprisingly, we found that shape fluctuations at all wavelengths undergo oscillations as they decay, implying some memory exists in the system that causes fluctuations to “overshoot” as they relax, much like a Hookean spring. The rich behavior and quantitative nature of this dataset made it primed for physical modeling. We thus employed a swath of simple “toy” models to explore potential molecular mechanisms that could explain leading edge oscillations. Remarkably, we found that a simple evolutionary filament orientation model (Maly and Borisy 2001) is sufficient to explain the oscillations. Excitingly, these results suggest that branched actin growth against a membrane is inherently self-correcting and thus sufficient for maintaining leading edge shape without requiring higher-level regulation.