Directional Dependence of Cyclic Stretch-induced Cell Migration in Wound Healing Process of Monolayer Cells

Cells sense the mechanical properties of their surrounding environment and activate intracellular signaling pathways that play important roles in cell survival, proliferation, differentiation, and migration. Migration of cells into an injury site is crucial for repair after injury and requires cytoskeletal reorganization and remodeling of focal adhesions that connect the cytoskeleton to the extracellular matrix. Thus, it is possible that a directional cyclic stretch stimulation of cells may facilitate the wound healing process and establish ordered tissue formation. Here, we investigated the effects of directional cyclic uniaxial stretch on wound repair processes of monolayer epithelial-like cells that was scratch wounded. We controlled the direction of scratched wound in cell tissue to be i) perpendicular to the stretch direction (perpendicular stretch), ii) parallel to the direction of the zero normal strain in the substrate theta(0) (similar to 60 degrees) (oblique stretch), and iii) parallel to stretch direction (parallel stretch). We found that cyclic stretching perpendicular to the scratched wound direction did not improve cell migration, whereas oblique stretching, by which cells were induced to align in the zero normal strain direction theta(0), significantly facilitated cell migration for wound closure even though the migration direction was varied. We further found that cell migration for wound closure was improved most efficiently by cyclic stretching parallel to the wound direction, which facilitated polymerization of actin cytoskeleton aligning in the migration direction and vinculin-actin interactions. These results indicate that cell migration for wound healing is significantly influenced not only by the normal strain applied to cells but also by shear strain under cyclic strain fields, and cells for wound healing preferentially migrate to the direction in which both the normal and shear strains applied to them become smaller.