Contact Stiffness Provides a Unified Frame of Reference for Understanding the Effects of Extracellular Matrix Mechanics on Cell Behaviors

Abstract In cell-extracellular matrix (ECM) interactions, contact mechanics theory indicates that local ECM deformation depends on both local and non-local forces imposed by cells. Here, we investigated the use of a comprehensive variable, contact stiffness (CS), to interpret cell-ECM interactions. CS defines the relationship between the local ECM deformation and the total force from a cell, integrating the effects of ECM stiffness, ECM thickness, cell adhesion area, etc. We showed that CS scaled well in the form of a power function with both YAP activity and the extent of differentiation in human mesenchymal stem cells. A CS-based motor clutch model was proposed which reveals the intrinsic cross-scale mechanism underlying ECM mechanosensing and suggests that various physical or chemical stimuli affects the reaction force from the ECM by altering the CS. The CS-based motor clutch model interprets the contributions of cell architecture evolution to stem cell differentiation and predicts the influence of a non-adjacent ECM layer on cell behaviours. These results demonstrate that the use of CS provides a quantitative predictive framework that allows researchers to address longstanding questions about the effects of cell-ECM interactions on cell behaviors.