Guidance of collective cell migration by substrate geometry

Abstract

Collective behavior refers to the emergence of complex migration patterns over scales larger than those of the individual elements constituting a system. It plays a pivotal role in biological systems in regulating various processes such as gastrulation, morphogenesis and tissue organization. Here, by combining experimental approaches and numerical modeling, we explore the role of cell density ('crowding'), strength of intercellular adhesion ('cohesion') and boundary conditions imposed by extracellular matrix (ECM) proteins ('constraints') in regulating the emergence of collective behavior within epithelial cell sheets. Our results show that the geometrical confinement of cells into well-defined circles induces a persistent, coordinated and synchronized rotation of cells that depends on cell density. The speed of such rotating large-scale movements slows down as the density increases. Furthermore, such collective rotation behavior depends on the size of the micropatterned circles: we observe a rotating motion of the overall cell population in the same direction for sizes of up to 200 μm. The rotating cells move as a solid body, with a uniform angular velocity. Interestingly, this upper limit leads to length scales that are similar to the natural correlation length observed for unconfined epithelial cell sheets. This behavior is strongly altered in cells that present a downregulation of adherens junctions and in cancerous cell types. We anticipate that our system provides a simple and easy approach to investigate collective cell behavior in a well-controlled and systematic manner.

Nonautonomous contact guidance signaling during collective cell migration

“…Cell streaming also requires cell-cell coordination and is observed above a threshold cell density (32) and has previously been compared with behavior in crowded particulate systems (26,33). In such systems, cooperative movement arises owing to volume exclusion and forced reorganization of the particles within a confined space.…”

Cytoskeletal Symmetry Breaking and Chirality: From Reconstituted Systems to Animal Development

“…More generally, it has been proposed that rotating movements seems to be a general feature of normal epithelial cells when confined [158,159], however, not in transformed cells [153,158]. This behavior can even be further extended to unicellular organisms (e.g., Dictyostelium discoideum [160]).…”

How cells respond to environmental cues – insights from bio-functionalized substrates

“…This migration assay with controlled boundary conditions results in a large-scale, swirling collective motion within the monolayer, as well as in the appearance of 'leader cells' with distinct migratory characteristics (Poujade et al, 2007). Cell swirls largely depend on the lateral confinement of the monolayer (Deforet et al, 2014;Doxzen et al, 2013;Rørth, 2012;Tanner et al, 2012;Vedula et al, 2013). The emergence of this synchronized collective cell motion can be correlated with contractile waves that involve multiple cells as measured by traction force microscopy (Angelini et al, 2010;Serra-Picamal et al, 2012).…”