Hydrogel Elastic Energy: A Stressor Triggering an Adaptive Stress‐Mediated Cell Response

The crosstalk between the cells and the extracellular matrix (ECM) is bidirectional and consists of a pushing/pulling stretch exerted by the cells and a mechanical resistance counteracted by the surrounding microenvironment. It is widely recognized that the stiffness of the ECM, its viscoelasticity, and its overall deformation are the most important traits influencing the response of the cells. Here these three parameters are combined into a concept of elastic energy, which in biological terms represents the mechanical feedback that cells perceive when the ECM is deformed. It is shown that elastic energy is a stress factor that influences the response of cells in three‐dimensional (3D) cultures. Strikingly, the higher the elastic energy of the matrix and thus the mechanical feedback, the higher the stress state of the cells, which correlates with the formation of G3BP‐mediated stress granules. This condition is associated with an increase in alkaline phosphatase (ALP) activity but a decrease in gene expression and is mediated by the nuclear translocation of Yes‐associated protein (YAP). This work supports the importance of considering the elastic energy as mechano‐controller in regulating cellular stress state in 3D cultures. In three‐dimensional (3D) microenvironments, cells deform the surrounding extracellular matrix and experience mechanical feedback that influences their response. The resulting cellular stress state promotes the formation of stress granules, increased alkaline phosphatase activity, and nuclear translocation of Yes‐associated protein. The mechanical feedback, proposed here as elastic energy, can be considered as a mechano‐controller in regulating cellular response in 3D cultures.