Fig. 6.

Proposed model of compression-modulated leader-cell formation and coordinated migration. (A) Cells seeded at the corners and edges of square islands have different extents of free perimeter, which affects actomyosin-driven intracellular stress. (B) In uncompressed cultures, free perimeter affects leader-cell formation. On average, the corner cells in the square islands have more free-cell perimeter than the edge cells and are therefore able to extend more protrusions than the edge cells, resulting in higher intracellular stress. (C) The resulting change in force balance within the cell likely causes their phenotypic change into “leader” cells. In our system, cell–cell adhesion is maintained, so cells adjacent to the leader cells (either behind or on the sides) appear to be pulled in the coordinated migration. As a result, the sheet preferentially extends from the corners of the square pattern. (D) In contrast, when the culture is compressed, all cells around the periphery of the island are deformed, or extruded, against the substrate, into the empty space. Similar to the case of the active extension of the uncompressed corner cells, cell extrusion has the effect of increasing cell-substrate contact (and also intracellular stress). (E) Hence, all cells around the periphery of the square pattern can become leader cells. The leader cells then continue to secrete and deposit fibronectin during cell spreading and movement, thereby forming new adhesion contacts with the substrate and resulting in enhanced coordinated migration.