HB-EGF enhances collective cell migration via spatial coordination of traction

An important process in wound healing is re-epithelialization, wherein cells collectively migrate to cover the wounded area. Here, we investigate how cellular forces lead to the migration of an epithelial monolayer in a wound healing assay. We report that heparin-bound epidermal growth factor (HB-EGF) increased the rate of collective migration in a phospholipase C-dependent manner through a combination of increased cell speed and straighter, more coordinated motion. Using traction force microscopy, we found that HB-EGF increased the forces within the cell monolayer, producing a competition between elevated traction at the edge of the monolayer and elevated stress within the bulk of the monolayer. To investigate how this interplay led to faster monolayer migration, we used a theoretical model for collective cell migration, which, when compared against the experimental data, suggested faster migration resulted from increased active propulsive forces at both the leading edge and within the bulk of the cell monolayer. Experimental analysis of actin stress fibers and vinculin foci supported inferences made from the model. Combined, our results support that HB-EGF induced a greater magnitude of traction for cells at the edge of the monolayer and aligned the direction of traction for cells within the bulk, thereby leading to faster and more persistent collective migration.