Physical biology of cell–substrate interactions under cyclic stretch

Mechanosensitive focal adhesion (FA) complexes mediate dynamic interactions between cells and substrates and regulate cellular function. Integrins in FA complexes link substrate ligands to stress fibers (SFs) and aid load transfer and traction generation. We developed a one-dimensional, multi-scale, stochastic finite element model of a fibroblast on a substrate that includes calcium signaling, SF remodeling, and FA dynamics. We linked stochastic dynamics, describing the formation and clustering of integrins to substrate ligands via motor-clutches, to a continuum level SF contractility model at various locations along the cell length. We quantified changes in cellular responses with substrate stiffness, ligand density, and cyclic stretch. Results show that tractions and integrin recruitments varied along the cell length; tractions were maximum at lamellar regions and reduced to zero at the cell center. Optimal substrate stiffness, based on maximum tractions exerted by the cell, shifted toward stiffer substrates at high ligand densities. Mean tractions varied biphasically with substrate stiffness and peaked at the optimal substrate stiffness. Cytosolic calcium increased monotonically with substrate stiffness and accumulated near lamellipodial regions. Cyclic stretch increased the cytosolic calcium, integrin concentrations, and tractions at lamellipodial and intermediate regions on compliant substrates. The optimal substrate stiffness under stretch shifted toward compliant substrates for a given ligand density. Stretch also caused cell deadhesions beyond a critical substrate stiffness. FA’s destabilized on stiff substrates under cyclic stretch. An increase in substrate stiffness and cyclic stretch resulted in higher fibroblast contractility. These results show that chemomechanical coupling is essential in mechanosensing responses underlying cell–substrate interactions.