Physical forces and mechanical waves during tissue growth

Abstract

Fundamental biological processes such as morphogenesis, tissue regeneration, and cancer invasion, depend on the collective migration of cell groups. The mechanisms that result in collective migration are not well understood, partially because the physical forces that initiate and maintain collective cell migration remain largely unknown. These forces include the traction forces, exerted by the cells on the extracellular matrix, and the cell-cell forces, transmitted between adjacent cells through cell-cell junctions. While the former have been studied, the latter have never been measured in the context of collective cell migration. The objective of this thesis has been to study these forces and integrate them in order to define the biomechanical mechanisms involved in the expansion of an epithelial monolayer. The thesis is presented as a compilation of two articles. In the first article, a new method for measuring intra-and intercellular forces in a cell monolayer was reported. It was shown that cells tend to align and migrate in the direction of maximal principal stress, demonstrating that intercellular forces act as a guidance mechanism during collective cell migration. In the second article, the expansion of an epithelial monolayer was studied. A new experimental model based on a barrier migration assay using polydimethylsiloxane membranes was implemented, allowing the study of epithelial expansion in a controlled and systematic manner. Structural and morphological changes at the cell level were observed during the expansion of the cellular monolayer. Furthermore, a mechanical wave propagates slowly spanning the entire monolayer, traversing intercellular junctions in a cooperative manner and building up differentials of mechanical stress. A minimal model based on sequential fronts of cytoskeletal reinforcement and fluidization captured essential features of this wave generation and propagation. These findings established a mechanism of long-range cell guidance, symmetry breaking and pattern formation during monolayer expansion.