Mechanical pre-stretch of extracellular matrix regulates podosome dynamics via contact stiffness

Podosomes are actin-rich protrusions in immune cells that function as mechanosensors, helping cells to probe the extracellular matrix (ECM). These structures exhibit spontaneous oscillations, driven by a balance between actin-driven protrusion and myosin-mediated contraction. While podosome responses to matrix stiffness are well studied, their behavior in mechanically pre-stretched ECMs-common in both physiological and pathological contexts-remains unclear. In this study, we developed a chemo-mechanical model that integrates intracellular force generation with contact mechanics at the podosome-ECM interface. This model introduces ECM pre-stretch as a global deformation, altering the local stress field and modulating the contact response at the interface. Our model captures podosome oscillations and stiffness-dependent changes in protrusion depth, as reported in previous studies. Our model shows that pre-stretch reduces protrusion depth and enhances oscillations, driven by increased contact stiffness at the podosome-ECM interface. This work establishes a theoretical framework for understanding how ECM pre-stretch regulates podosome mechanosensing, identifying contact stiffness as a key link between interfacial mechanics and podosome dynamics.