Chemo-mechanical Diffusion Waves Orchestrate Collective Dynamics of Immune Cell Podosomes

Immune cells, such as macrophages and dendritic cells, can utilize podosomes, actin-rich protrusions, to generate forces, migrate, and patrol for foreign antigens. In these cells, individual podosomes exhibit periodic protrusion and retraction cycles (vertical oscillations) to probe their microenvironment, while multiple podosomes arranged in clusters demonstrate coordinated wave-like spatiotemporal dynamics. However, the mechanisms governing both the individual vertical oscillations and the coordinated oscillation waves in clusters remain unclear. By integrating actin polymerization, myosin contractility, actin diffusion, and mechanosensitive signaling, we develop a chemo-mechanical model for both the oscillatory growth of individual podosomes and wave-like dynamics in clusters. Our model reveals that podosomes show oscillatory growth when the actin polymerization-associated protrusion and the signaling-associated myosin contraction occur at similar rates, while the diffusion of actin monomers within the cluster drives mesoscale coordination of individual podosome oscillations in an apparent wave-like fashion. Our model predicts the influence of different pharmacological treatments targeting myosin activity, actin polymerization, and mechanosensitive pathways, as well as the impact of the microenvironment stiffness on the wavelengths, frequencies, and speeds of the chemo-mechanical waves. Overall, our integrated theoretical and experimental approach reveals how collective wave dynamics arise due to the coupling between chemo-mechanical signaling and actin diffusion, shedding light on the role of podosomes in immune cell mechanosensing within the context of wound healing and cancer immunotherapy.