Abstract
Cell migration is a fundamental behavior involved in multicellular development, tissue regeneration and homeostasis, which is deregulated in cancer. Epithelial cells migrate individually when isolated and collectively in a tissue, and may be exposed to external guidance cues. How interactions between neighbors affect the efficiency of cell spatial exploration the distance cells can reach in a given time - and sensitivity to external guidance cues is, however, poorly understood. We found that while isolated cells are persistent random walkers, they adopt a super-diffusive behavior within a confluent epithelium that dominates the efficiency of spatial exploration relative to guidance cues, and virtually allows cells to reach greater distances when surrounded by neighbors than when alone. This confluence-induced transition in directional memory emerges from a fractional Brownian motion that results from velocity coordination between neighboring cells and requires intact cytoskeletal connections to intercellular adhesion complexes. Furthermore, we show how the stability and mechanosensitivity of cell-matrix and cell-cell adhesions ultimately regulate the speed of collective migration and sensitivity to guidance cues in a noncell-autonomous manner through their differential dependence on the dimerization of the adhesion protein vinculin. Overall, our results reveal how individual cell speed, tissue-dependent persistence, and guidance by the environment can limit the efficiency of cell spatial exploration at short, intermediate, and long time scales, respectively.
Publisher
Cold Spring Harbor Laboratory