Modeling of Mechanosensing Mechanisms Reveals Distinct Cell Migration Modes to Emerge From Combinations of Substrate Stiffness and Adhesion Receptor–Ligand Affinity

Mesenchymal cell migration is an integral process in development and healing. The process is regulated by both mechanical and biochemical properties. Mechanical properties of the environment are sensed through mechanosensing, which consists of molecular responses mediated by mechanical signals. We developed a computational model of a deformable 3D cell on a flat substrate using discrete element modeling. The cell is polarized in a single direction and thus moves along the long axis of the substrate. By modeling discrete focal adhesions and stress fibers, we implement two mechanosensing mechanisms: focal adhesion stabilization by force and stress fiber strengthening upon contraction stalling. Two substrate-associated properties, substrate (ligand) stiffness and adhesion receptor–ligand affinity (in the form of focal adhesion disassembly rate), were varied for different model setups in which the mechanosensing mechanisms are set as active or inactive. Cell displacement, focal adhesion number, and cellular traction were quantified and tracked in time. We found that varying substrate stiffness (a mechanical property) and adhesion receptor–ligand affinity (a biochemical property) simultaneously dictate the mode in which cells migrate; cells either move in a smooth manner reminiscent of keratocytes or in a cyclical manner reminiscent of epithelial cells. Mechanosensing mechanisms are responsible for the range of conditions in which a cell adopts a particular migration mode. Stress fiber strengthening, specifically, is responsible for cyclical migration due to build-up of enough force to elicit rupture of focal adhesions and retraction of the cellular rear. Together, both mechanisms explain bimodal dependence of cell migration on substrate stiffness observed in the literature.