Mechanical competition promotes selective listening to receptor inputs to resolve directional dilemmas in neutrophil migration

Abstract

As neutrophils navigate complex environments to reach sites of infection, they may encounter obstacles that force them to split their front into multiple leading edges, raising the question of how the cell selects which front to maintain and which front(s) to abandon. Here we challenge chemotaxing HL60 neutrophil-like cells with symmetric bifurcating microfluidic channels, enabling us to probe the cell-intrinsic properties of their decision-making process. Using supervised statistical learning, we demonstrate that cells commit to one leading edge late in the decision-making process, rather than amplifying early pre-existing asymmetries. Furthermore, we use optogenetic tools to show that receptor inputs only bias the decision similarly late, once mechanical stretching begins to weaken each front. Finally, optogenetic attempts to reverse cell decisions reveal that, once an edge begins retracting, it commits to this fate, with the kinase ROCK limiting its sensitivity to inputs until the retraction is complete. Collectively our results suggest a "selective listening" model in which both actively protruding cell fronts and actively retracting cell rears have strong commitment to their current migratory program.

Emergent oscillations during cellular directional decision-making on junctions

“…In this model the decision is performed due to spontaneous symmetry breaking, involving deterministic oscillations. The model explains how the duration of the directional decision making depends on the internal motility parameters of the cell, offering a natural explanation for the puzzling slowness of this process in many cells [18].…”

Quantifying the Probing and Selection of Microenvironmental Pores by Motile Immune Cells

“…Whereas we here describe detailed protocols to investigate the probing and selection of microenvironmental pores by immune cells, these assays can also be performed with other cell types like cancer cells (Denais et al, 2016;Sabeh, Shimizu-Hirota, & Weiss, 2009;Wolf et al, 2013). Moreover, these assays can be modified to symmetric path junctions composed of micro-channels of the same diameter, enabling the investigation of directional decisions independent of pore decisions (Hadjitheodorou et al, 2022;Hadjitheodorou et al, 2021;Tweedy et al, 2020;Wang, Hossain, Bogoslowski, Kubes, & Irimia, 2020). research question aims to investigate how cells navigate through microenvironments of heterogeneous porosity, we recommend careful selection of the most suitable experimental approach for the individual cellular model (Fig.…”

Emergent oscillations during cellular directional decision-making on junctions

“…In order to decipher how motile cells pass through complex paths, several in-vitro studies constrained cells to migrate along networks of confining one-dimensional channels or adhesive stripes [5][6][7][14][15][16][17][18]. When moving through such a network, the cells encounter junctions, and are often observed to form multiple protrusions along the alternative paths that leave the junction.…”