Invited Talk

Chemo-mechanical diffusion waves orchestrate collective dynamics of immune cell podosomes

Center for Engineering Mechanobiology and School of Engineering, University of Pennsylvania, 220 South 33rd Street 107 Towne Building, PA 19104-6391, Philadelphia, USA

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Immune cells, such as macrophages and dendritic cells, can utilize podosomes, mechanosensitive actin-rich protrusions, to generate forces, migrate, and patrol for foreign antigens. Individual podosomes probe their microenvironment through periodic protrusion and retraction cycles while oscillations of multiple podosomes in a cluster are coordinated in a wave-like fashion. However, the mechanisms governing both the individual vertical oscillations and the collective spatiotemporal wave-like dynamics remain unclear. Here, 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 the wave-like dynamics in clusters. Our model reveals that podosomes show oscillatory growth when actin polymerization-driven protrusion and signaling-associated myosin contraction occur at similar rates, while the diffusion of actin monomers within the cluster drives wave-like mesoscale coordination of podosome oscillations. Our theoretical predictions are validated by different pharmacological treatments (targeting myosin activity, actin polymerization, and mechanosensitive Rho-ROCK pathway) and the impact of microenvironment stiffness on chemo-mechanical waves. Overall, our integrated theoretical and experimental approach reveals how collective wave dynamics arise from 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.