The effect of substrate stiffness on tensile force transduction in the epithelial monolayers.
Abstract:
In recent years, the importance of mechanical signaling and the cellular mechanical microenvironment in affecting cellular behavior has been widely accepted. Cells in epithelial monolayers are mechanically connected to each other and the underlying extracellular matrix (ECM), forming a highly connected mechanical system subjected to various mechanical cues from their environment, such as the ECM stiffness. Changes in the ECM stiffness have been linked to many pathologies, including tumor formation. However, our understanding of how ECM stiffness and its heterogeneities affect the transduction of mechanical forces in epithelial monolayers is lacking. To investigate this, we used a combination of experimental and computational methods. The experiments were conducted using epithelial cells cultured on an elastic substrate and applying a mechanical stimulus by moving a single cell by micromanipulation. To replicate our experiments computationally and quantify the forces transduced in the epithelium, we developed a new model that described the mechanics of both the cells and the substrate. Our model further enabled the simulations with local stiffness heterogeneities. We found the substrate stiffness to distinctly affect the force transduction as well as the cellular movement and deformation following an external force. Also, we found that local changes in the stiffness can alter the cells’ response to external forces over long distances. Our results suggest that this long-range signaling of the substrate stiffness depends on the cells’ ability to resist deformation. Furthermore, we found that the cell’s elasticity in the apico-basal direction provides a level of detachment between the apical cell-cell junctions and the basal focal adhesions. Our simulation results show potential for increased ECM stiffness, e.g. due to a tumor, to modulate mechanical signaling between cells also outside the stiff region. Furthermore, the developed model provides a good platform for future studies on the interactions between epithelial monolayers and elastic substrates.
