Purse-string contraction guides mechanical gradient-dictated heterogeneous migration of epithelial monolayer

Mechanical heterogeneity has been recognized as an important role in mediating collective cell migration, yet the related mechanism has not been elucidated. Herein, we fabricate heterogeneous stiffness gradients by leveraging microelastically-patterned hydrogels with varying periodic distance. We observe that a decrease in the periodic distance of the mechanical heterogeneity is accompanied by an overall increase in the velocity and directionality of the migrating monolayer. Moreover, inhibition of ROCK- and myosin ⅡA- but not Rac1-mediated contraction reduces monolayer migration on the mechanically heterogeneous substrates. Furthermore, we find that F-actin and myosin ⅡA form purse-string at the leading edge on the mechanically heterogeneous substrates. Together, these findings not only show that the orientational cell–cell contraction promotes collective cell migration under the mechanical heterogeneity, but also demonstrate that the mechanosensation arising from large-scale cell–cell interactions through purse-string formation mediated cell–cell orientational contraction can feed back to regulate the reorganization of epithelial tissues.