Regulation of Substrate Dissipation via Tunable Linear Elasticity Controls Cell Activity

Natural tissues and extracellular matrices (ECMs) are not purely elastic materials but exhibit dissipative properties. Although it has recently emerged as a novel regulator of cellular responses, the contribution of material dissipation to guiding cell-fate decisions is still in its infancy. Here, a strategy for tuning the dissipation rate of viscoplastic substrates while precisely regulating linear elasticity is reported. Semi-interpenetrating substrates consisting of a rigid hydrogel network intertwined with a branched biopolymer are described. The release of these weak physical entanglements under loading dissipates the applied stress and leads to the extension of the linear elasticity. These results reveal a crucial link between this material property and cell response in 2D cultures, impacting cell migration mode and speed, vinculin-dependent focal adhesion geometry and size, F-actin organization, the transmission of forces, and Yes-associated protein nuclear translocation. It is shown that cells require joint actomyosin contractility and microtubule tension to probe the substrate and decide whether or not to adhere, revealing a clear correlation between force transmission, substrate dissipation rate, and amount of anchoring points. Overall, these findings introduce linear elasticity as a novel design parameter for assembling tunable dissipative materials to study cell mechanosensing in 2D and possibly also in 3D cultures.