Collective motion of cells crawling on a substrate: roles of cell shape and contact inhibition

Abstract

Contact inhibition plays a crucial role in cell motility, wound healing, and tumour formation. By mimicking the mechanical motion of cells crawling on a substrate, we constructed a minimal model of migrating cells that naturally gives rise to contact inhibition of locomotion (CIL). The model cell consists of two disks, a front disk (a pseudopod) and a back disk (cell body), which are connected by a finite extensible spring. Despite the simplicity of the model, the collective behaviour of the cells is highly non-trivial and depends on both the shape of the cells and whether CIL is enabled. Cells with a small front disk (i.e., a narrow pseudopod) form immobile colonies. In contrast, cells with a large front disk (e.g., a lamellipodium) exhibit coherent migration without any explicit alignment mechanism in the model. This result suggests that crawling cells often exhibit broad fronts because this helps facilitate alignment. After increasing the density, the cells develop density waves that propagate against the direction of cell migration and finally stop at higher densities.Directional collective motion of cells is fundamentally important for embryogenesis, wound healing and tumour invasion [1][2][3][4][5] . Cells move in clusters, strands or sheets to cover empty areas 6 , grow or invade tissues. The manner in which the cells coordinate and control their motion is the subject of ongoing research. At the level of a single cell, it is well-established that a cell's motion is intricately linked to its shape. The shape of crawling cells is highly variable and depends on the type of cell, the substrate and aspects of the migration process itself [7][8][9][10] . To move, a cell needs to break symmetry 8 , as a circular cell does not move. While there is evidence that shape has a strong influence on scattering and can lead to clustering and collective directed motion in the case of active swimming particles 11,12 , less is known regarding the role of cell shape in the organization of collective crawling. It has been shown in simulations that inelastic collisions between crawling cells, e.g., due to deformation, can lead to coherent migration [13][14][15][16][17] , which suggests that deformation is important for collective cell behaviour. When crawling cells come into contact, their protrusions are inhibited, which tends to change their shape and orientation 18,19 . It was shown that this effect, which is called contact inhibition of locomotion (CIL), enables cells to follow chemical gradients more effectively by aligning them 20,21 . In growing colonies, CIL leads to a slowdown of the motility of individual cells when the density of their environment crosses a certain threshold 22 . Thus, CIL is believed to play a crucial role in the control of collective tissue migration 15,20,[23][24][25][26] , tissue growth 22,27 , morphogenesis, wound healing and tumour development 28 . The behaviour of cells undergoing CIL depends on many factors, such as the presence of cell adhesion molecules and receptors, and different types o...

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

“…This strategy was followed earlier for self-propulsion, but experiments are instead often modelled by complex models with many competing processes [18,29,30]. We argue that it is relevant to introduce a simplified model to analyse the effect of active particle deformation in a dense assembly of nonpropelled soft objects.…”

“…Such tissues display a surprisingly fast and collective dynamics, which would not take place under equilibrium conditions [10]. This dynamics has been ascribed to at least three distinct active processes [13]: (i) self-propulsion through cell motility such as crawling [15], (ii) self-deformation through protrusion and contraction [16][17][18], and (iii) cell division and apoptosis [14]. The vertex model for tissues [12,19,20] includes the first two of these active processes and predicts a continuous static transition from an arrested to a flowing state [21].…”

Dexamethasone-Mediated Upregulation of Calreticulin Inhibits Primary Human Glioblastoma Dispersal Ex Vivo

“…Single cell locomotion is largely dependent on cell shape. If by activating a5 integrin CALR also indirectly changes cell shape to inhibit scattering [ 40 ], it is possible that a reduction in capacity for dispersal could further inhibit cell migration through a mechanism of contact inhibition of locomotion (CIL) [ 41 ]. In growing colonies, CIL leads to a slowdown of the motility of individual cells when the density of their environment crosses a certain threshold [ 42 ].…”

Bridging from single to collective cell migration: A review of models and links to experiments

“…Yet another modification of particle-based models is [153], where a cell is represented by a spring linking 2 discs, to depict the "cell body" and the "pseudopod." The model demonstrates various outcomes of binary collisions in a 2D domain, as well as order-disorder transitions and velocity waves in large 2D cell groups with and without CIL.…”

“…A recent work, [168], describes fingering at the front of an epithelial sheet using several of the above approaches. Cells are represented by pairs of points, as in [153], and also by Voronoi polygons for computations corresponding to experiments in [131]. The authors develop an active fluid model for the epithelium.…”