Cell mechanosensing is regulated by substrate strain energy rather than stiffness

Significance In the long-lasting debate about the duality of the force/deformation cell sensing mechanism we focused attention on the question of whether the cell is sensitive to the stiffness or to the energy required to deform the surrounding material. To address the role of strain energy as a regulator of cell mechanosensing we investigated the cytoskeleton mechanics of cells seeded on linearly elastic substrates, applying several levels of deformation before and after cell seeding. The results indicated that cells recognize the prestrain, exhibiting a stiffer cytoskeleton on stretched material compared to cells seeded on unstretched substrate. This observation clearly suggests that cell mechanosensing is not mediated only by the stiffness but also by the deformation energy of the substrate.