Actin dynamics as a multiscale integrator of cellular guidance cues

Abstract

Cells are able to integrate multiple, and potentially competing, cues to determine a migration direction. For instance, in wound healing, cells follow chemical signals or electric fields to reach the wound edge, regardless of any local guidance cues. To investigate this integration of guidance cues, we monitor the actin-polymerization dynamics of immune cells in response to cues on a subcellular scale (nanotopography) and on the cellular scale (electric fields, EFs). In the fast, amoeboid-type migration, commonly observed in immune cells, actin polymerization at the cells leading edge is the driver of motion. The excitable systems character of actin polymerization leads to self-propagating, two-dimensional wavefronts that enable persistent cell motion. We show that EFs guide these wavefronts, leading to turning of cells when the direction of the EF changes. When nanoridges promote one-dimensional (1D) waves of actin polymerization that move along the ridges (esotaxis), EF guidance along that direction is amplified. 1D actin waves cannot turn or change direction, so cells respond to a change in EF direction by generating new 1D actin waves. At the cellular scale, the emergent response is a turning of the cell. For nanoridges perpendicular to the direction of the EF, the 1D actin waves are guided by the nanotopography, but both the average location of new actin waves and the whole cell motion are guided by the EF. Thus, actin waves respond to each cue on its intrinsic length scale, allowing cells to exhibit versatile responses to the physical microenvironment. Significance StatementEffective cell migration requires the integration of multiple, and sometimes competing, guidance cues. For instance, in wound healing, immune cells are guided towards a wound edge by long-range electrical and chemical cues that may conflict with guidance cues from the local environment. How cells combine and respond to such cues is not well understood. We demonstrate that multiple guidance mechanisms can act simultaneously, but on different scales. Nanotopography, a local mechanical cue, guides individual waves of actin polymerization, thereby biasing the direction cell motion on the time scale of these waves. An external electric field applied at the same time biases the locations of new waves of actin polymerization, leading to overall directed migration over long distance scales.