Coordination of cell migration mediated by site-dependent cell-cell contact

Contact inhibition of locomotion (CIL), the repulsive response of cells upon cell-cell contact, has been the predominant paradigm for contact-mediated responses. However, it is difficult for CIL alone to account for the complex behavior of cells within a multicellular environment, where cells often migrate in cohorts such as sheets, clusters, and streams. Although cell-cell adhesion and mechanical interactions play a role, how individual cells coordinate their migration within a multicellular environment remains unclear. Using micropatterned substrates to guide cell migration and manipulate cell-cell contact, we show that contacts between different regions of cells elicit different responses. Repulsive responses were limited to interaction with the head of a migrating cell, while contact with the tail of a neighboring cell promoted migration toward the tail. The latter behavior, termed contact following of locomotion (CFL), required the Wnt signaling pathway. Inhibition of the Wnt pathway disrupted not only CFL but also collective migration of epithelial cells, without affecting the migration of individual cells. In contrast, inhibition of myosin II with blebbistatin disrupted the migration of both individual epithelial cells and collectives. We propose that CFL, in conjunction with CIL, plays a major role in guiding and coordinating cell migration within a multicellular environment.