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 migra-tion, 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 het-erogeneous 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 ori-entational 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 reorga-nization of epithelial tissues.Statement of significanceBy detecting the links between heterogenous rigidity and collective cell migration behavior at the molecular level, we reveal that collective cell migration in the mechanical heterogeneity is driven by ROCK-and myosin-II A-dependent cytoskeletal tension. We confirm that cytoskeletal tension across the epithelial tissue is holistically linked through F-actin and myosin-II A, which cooperate to form purse-string structures for modulating collective tissue behavior on the exogenous matrix with me-chanical heterogeneity. Mechanical heterogeneity initiates tissue growth, remodelling, and morphogen-esis by orientating cell contractility. Therefore, tensional homeostasis across large-scale cell interac-tions appears to be necessary and sufficient to trigger collective tissue behavior. Overall, these findings shed light on the role of mechanical heterogeneity in tissue microenvironment for reorganization and morphogenesis.(c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

Mechanical heterogeneity plays an important role in mediating collective cell migration. By fabricating microelastically-patterned hydrogels with varying periodic distance, it was observed that a decrease in periodic distance leads to increased velocity and directionality of migrating cells. Inhibition of ROCK and myosin IIA contraction reduces cell migration on mechanically heterogeneous substrates. F-actin and myosin IIA form purse-string structures at the leading edge on mechanically heterogeneous substrates, revealing their involvement in cell-cell interactions and mechanical perception.