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Cell Migration under Mechanical Constraints

Final Report Summary - DURACELL (Cell Migration under Mechanical Constraints)

Mechanical constraints and force transmission play an essential role in multicellular living organisms, regulating basic biological processes such as morphogenesis, tumor metastasis and tissue repair. Cell adhesion, coupled to the contractile cytoskeleton, is a major site of force transmission in cells. This mechanical coupling, which enables cells to sense, signal, and respond to physical changes in the environment, has however been largely understudied. In this project, we studied cellular responses to physical environmental cues.
A first axis aimed at understanding how single cells interact with their environment (cell to substratum interactions), and to use this knowledge to control cell functions. In particular, we studied the cooperation between adhesive, mechanical and biochemical signaling in the regulation of cell adhesion and migration. To address these questions, we developed a repertoire of micro- and nanofabrication and micro-manipulation tools to control and measure the adhesive and mechanical environment of cells. Using these tools in combination with classical molecular and cellular approaches and optical techniques, we showed that the actin cytoskeleton acted as a large-scale mechanical sensor of substrate rigidity and thus fostered cell polarity and migration.
A second axis aimed at studying collective cell migration and the role of cell-cell contacts during such processes. Epithelia have important roles in shaping tissues and organs during embryogenesis, as well as in protecting tissues from loss of homeostasis during wound healing. Many physiological and pathological processes involve the (re-)sealing of epithelial gaps. From single cell apoptosis to macroscopic wounds, discontinuities of the epithelial barrier occur continuously throughout the lifetime of organisms and in various scales and geometries.We analysed the influence of mechanical constraints such as geometry, topography, stiffness; as well as the contribution of cadherin-mediated intercellular adhesion. We investigated epithelial sheet integrity in various contexts that include epithelial gap closure and epithelial monolayer homeostasis. In particular, we showed that biological tissues behave like active liquid crystals in which epithelial cells are somewhat elongated and closely packed, and thus spontaneously align in a similar way to the molecules in nematic liquid crystals. Even more, the analogy we made opens new routes in the understanding of tissue homeostasis and cell extrusion and death. Second, we discovered a new mode of cell migration triggered cellular physical environment. Changes in curvature of the cell front that can be induced by the local environment lead to either the well-described lamellipodium or more surprisingly assembles a so far unreported inverted structure, reminiscent of a reverse lamellipodium. The striking reverse organization between actin structures at negative and positive curvatures demonstrates for the first time that similar functional cytoskeletal components can give rise to completely opposite migration mechanisms.
The third axis led us to develop new substrates that could better mimic cellular behaviors in in vivo environments. We thus studied single cell migration along suspended nanofibers and described new modes of migration that rely on a balance between cell contractility and cell body extension through cytoskeleton polymerisation. Second, we used microfabricated environments to study epithelial cell behaviors in microtubes and on micro-vili structures to mimic morphogenetic processes and intestinal epithelium regulation. We discovered that substrate topography can promote the emergence of various modes of collective cell migration and better reproduce intestinal diseases found in vivo.
Overall, our research work opens new routes at the interface between physics and biology in the emergent area of cell and molecular mechanics and mechanobiology.