Emerging modes of collective cell migration induced by geometrical constraints

Abstract

The role of geometrical confinement on collective cell migration has been recognized but has not been elucidated yet. Here, we show that the geometrical properties of the environment regulate the formation of collective cell migration patterns through cell-cell interactions. Using microfabrication techniques to allow epithelial cell sheets to migrate into strips whose width was varied from one up to several cell diameters, we identified the modes of collective migration in response to geometrical constraints. We observed that a decrease in the width of the strips is accompanied by an overall increase in the speed of the migrating cell sheet. Moreover, largescale vortices over tens of cell lengths appeared in the wide strips whereas a contraction-elongation type of motion is observed in the narrow strips. Velocity fields and traction force signatures within the cellular population revealed migration modes with alternative pulling and/or pushing mechanisms that depend on extrinsic constraints. Force transmission through intercellular contacts plays a key role in this process because the disruption of cell-cell junctions abolishes directed collective migration and passive cell-cell adhesions tend to move the cells uniformly together independent of the geometry. Altogether, these findings not only demonstrate the existence of patterns of collective cell migration depending on external constraints but also provide a mechanical explanation for how large-scale interactions through cell-cell junctions can feed back to regulate the organization of migrating tissues.cell traction forces | collective dynamics | madin darby canine kidney epithelial cells | particle image velocimetry C ollective behavior is a fundamental phenomenon exhibited by a wide variety of systems such as flows in granular matter (1), collective movements of animals (2), self-organization of bacteria (3), and morphogenesis of biological tissues (4). Although collective behaviors have been observed across diverse physical and biological systems, it is increasingly clear that there are broad unifying and common parameters that govern the emergence of this phenomenon such as the density of the constituent particles, the boundary conditions within which the movements occur, and the nature of coupling between the individual particles. In this context, collective behavior in migrating cells is of particular interest as a highly out-of-equilibrium process where cells passively interact with each other and exert active forces in response to their mechanical environment (4). Such collective behavior drives many biological processes such as embryonic development (5), tissue morphogenesis (6), wound healing (7), and tumor metastasis (8, 9). Although single cell dynamics has been extensively studied (10-12), the movement of multicellular structures could not be simply explained by cell autonomous behaviors (13-16). Instead, intercellular interactions and large-scale propagation of mechanical signals (over several cell sizes) are necessary to understand the emergen...

Collective cell traction force analysis on aligned smooth muscle cell sheet between three-dimensional microwalls

“…For instance, E-cadherin, which is essential for collective directional migration [33], is connected to integrin-based focal adhesions [34] and conducts the loading forces exerted by the actomyosin cytoskeleton at the cell-cell adherent junctions in an epithelial cell sheet [35]. Interestingly, collective cells grown under two-dimensional geometrical constraints can form different modes of collective migration under cell-cell interactions [36]. Elucidation of the mechanisms of three-dimensional collective mechanotransduction remains a tremendous challenge, because the mechanical stresses of a cell sheet are difficult to quantify with existing physical models.…”

Discontinuous fluidization transition in time-correlated assemblies of actively deforming particles

“…Another theoretical line of research is based on self-propelled particles [22] which display at high density a nonequilibrium glass transition [23,24] accompanied by a continuous increase of space and time correlations which diverge on approaching the arrested phase [25][26][27]. However, typical correlation lengthscales in tissues do not seem to diverge [9,11,28,29].…”

“…Another theoretical line of research is based on self-propelled particles [22] which display at high density a nonequilibrium glass transition [23,24] accompanied by a continuous increase of space and time correlations which diverge on approaching the arrested phase [25][26][27]. However, typical correlation lengthscales in tissues do not seem to diverge [9,11,28,29].To disentangle the dynamic consequences of the various sources of activity in tissues at large scale, we suggest to decompose the original complex problem into simpler ones, and to study particle-based models which only include a specific source of activity. This strategy was followed earlier for self-propulsion, but experiments are instead often modelled by complex models with many competing processes [18,29,30].…”

Viscoelastic and elastomeric active matter: Linear instability and nonlinear dynamics

“…The symmetry breaking characterized by net throughputs, which we observe at moderate polymer relaxation times (τ C /τ Q ≈ 10), could have particular relevance for studies of cytoplasmic streaming, where coherent flow is crucial for material transport within the cell. The same physics may also apply, albeit at larger scales, to cell migration in confined geometries [29]. Our results with explicit coupling that show oscillatory shuffling states may also be relevant in describing the cell shape oscillations of Ref.…”

“…Indeed, it has been argued that the confinement of subcellular active matter may in part be responsible for cytoplasmic streaming [26,27], an important process whereby coherent fluid flows facilitate the circulation of nutrients and organelles within the cell [28]. At a larger scale, a recent study of cell migration in artificial channels observed increases in mean cell velocity and flow coherence as the channel was narrowed [29]. Also, suspensions of B. subtilis were observed to form stable spiral structures when confined in a droplet [30].…”