Sumesh P. Thampi

Topological defects in epithelia govern cell death and extrusion

Epithelial tissues (epithelia) remove excess cells through extrusion, preventing the accumulation of unnecessary or pathological cells. The extrusion process can be triggered by apoptotic signalling, oncogenic transformation and overcrowding of cells. Despite the important linkage of cell extrusion to developmental, homeostatic and pathological processes such as cancer metastasis, its underlying mechanism and connections to the intrinsic mechanics of the epithelium are largely unexplored. We approach this problem by modelling the epithelium as an active nematic liquid crystal (that has a long range directional order), and comparing numerical simulations to strain rate and stress measurements within monolayers of MDCK (Madin Darby canine kidney) cells. Here we show that apoptotic cell extrusion is provoked by singularities in cell alignments in the form of comet-shaped topological defects. We find a universal correlation between extrusion sites and positions of nematic defects in the cell orientation field in different epithelium types. The results confirm the active nematic nature of epithelia, and demonstrate that defect-induced isotropic stresses are the primary precursors of mechanotransductive responses in cells, including YAP (Yes-associated protein) transcription factor activity, caspase-3-mediated cell death, and extrusions. Importantly, the defect-driven extrusion mechanism depends on intercellular junctions, because the weakening of cell–cell interactions in an α-catenin knockdown monolayer reduces the defect size and increases both the number of defects and extrusion rates, as is also predicted by our model. We further demonstrate the ability to control extrusion hotspots by geometrically inducing defects through microcontact printing of patterned monolayers. On the basis of these results, we propose a mechanism for apoptotic cell extrusion: spontaneously formed topological defects in epithelia govern cell fate. This will be important in predicting extrusion hotspots and dynamics in vivo, with potential applications to tissue regeneration and the suppression of metastasis. Moreover, we anticipate that the analogy between the epithelium and active nematic liquid crystals will trigger further investigations of the link between cellular processes and the material properties of epithelia.

Velocity correlations in an active nematic.

The flow properties of a continuum model for an active nematic are studied and compared with recent experiments on suspensions of microtubule bundles and molecular motors. The velocity correlation length is found to be independent of the strength of the activity while the characteristic velocity scale increases monotonically as the activity is increased, both in agreement with the experimental observations. We interpret our results in terms of the creation and annihilation dynamics of a gas of topological defects.

Instabilities and topological defects in active nematics

We study a continuum model of an extensile active nematic to show that mesoscale turbulence develops in two stages: i) ordered regions undergo an intrinsic hydrodynamic instability generating walls, lines of strong bend deformations; ii) the walls relax by forming oppositely charged pairs of defects. Both creation and annihilation of defect pairs reinstate nematic regions which undergo further instabilities, leading to a dynamic steady state. We compare this with the development of active turbulence in a contractile active nematic.

Stabilization of active matter by flow-vortex lattices and defect ordering.

Active systems, from bacterial suspensions to cellular monolayers, are continuously driven out of equilibrium by local injection of energy from their constituent elements and exhibit turbulent-like and chaotic patterns. Here we demonstrate both theoretically and through numerical simulations, that the crossover between wet active systems, whose behaviour is dominated by hydrodynamics, and dry active matter where any flow is screened, can be achieved by using friction as a control parameter. Moreover, we discover unexpected vortex ordering at this wet–dry crossover. We show that the self organization of vortices into lattices is accompanied by the spatial ordering of topological defects leading to active crystal-like structures. The emergence of vortex lattices, which leads to the positional ordering of topological defects, suggests potential applications in the design and control of active materials.

Vorticity, defects and correlations in active turbulence

We describe a numerical investigation of a continuum model of an active nematic, concentrating on the regime of active turbulence. Results are presented for the effect of three parameters, activity, elastic constant and rotational diffusion constant, on the order parameter and flow fields. Defects and distortions in the director field act as sources of vorticity, and thus vorticity is strongly correlated to the director field. In particular, the characteristic length of decay of vorticity and order parameter correlations is controlled by the defect density. By contrast, the decay of velocity correlations is determined by a balance between activity and dissipation. We highlight the role of microscopic flow generation mechanisms in determining the flow patterns and characteristic scales of active turbulence and contrast the behaviour of extensile and contractile active nematics.

Do liquid drops roll or slide on inclined surfaces

We study the motion of a two-dimensional droplet on an inclined surface, under the action of gravity, using a diffuse interface model which allows for arbitrary equilibrium contact angles. The kinematics of motion is analyzed by decomposing the gradient of the velocity inside the droplet into a shear and a residual flow. This decomposition helps in distinguishing sliding versus rolling motion of the drop. Our detailed study confirms intuition, in that rolling motion dominates as the droplet shape approaches a circle, and the viscosity contrast between the droplet and the ambient fluid becomes large. As a consequence of kinematics, the amount of rotation in a general droplet shape follows a universal curve characterized by geometry, and independent of Bond number, surface inclination and equilibrium contact angle, but determined by the slip length and viscosity contrast. Our results open the way toward a rational design of droplet-surface properties, both when rolling motion is desirable (as in self-cleaning hydrophobic droplets) and when it must be prevented (as in insecticide sprays on leaves).

Lattice-Boltzmann-Langevin simulations of binary mixtures.

We report a hybrid numerical method for the solution of the Model H fluctuating hydrodynamic equations for binary mixtures. The momentum conservation equations with Landau-Lifshitz stresses are solved using the fluctuating lattice Boltzmann equation while the order parameter conservation equation with Langevin fluxes is solved using stochastic method of lines. Two methods, based on finite difference and finite volume, are proposed for spatial discretization of the order parameter equation. Special care is taken to ensure that the fluctuation-dissipation theorem is maintained at the lattice level in both cases. The methods are benchmarked by comparing static and dynamic correlations and excellent agreement is found between analytical and numerical results. The Galilean invariance of the model is tested and found to be satisfactory. Thermally induced capillary fluctuations of the interface are captured accurately, indicating that the model can be used to study nonlinear fluctuations.

Defect-Mediated Morphologies in Growing Cell Colonies.

Morphological trends in growing colonies of living cells are at the core of physiological and evolutionary processes. Using active gel equations, which include cell division, we show that shape changes during the growth can be regulated by the dynamics of topological defects in the orientation of cells. The friction between the dividing cells and underlying substrate drives anisotropic colony shapes toward more isotropic morphologies, by mediating the number density and velocity of topological defects. We show that the defects interact with the interface at a specific interaction range, set by the vorticity length scale of flows within the colony, and that the cells predominantly reorient parallel to the interface due to division-induced active stresses.

Celebrating Soft Matter's 10th Anniversary: Cell division: a source of active stress in cellular monolayers.

We introduce the notion of cell division-induced activity and show that the cell division generates extensile forces and drives dynamical patterns in cell assemblies. Extending the hydrodynamic models of lyotropic active nematics we describe turbulent-like velocity fields that are generated by the cell division in a confluent monolayer of cells. We show that the experimentally measured flow field of dividing Madin-Darby Canine Kidney (MDCK) cells is reproduced by our modeling approach. Division-induced activity acts together with intrinsic activity of the cells in extensile and contractile cell assemblies to change the flow and director patterns and the density of topological defects. Finally we model the evolution of the boundary of a cellular colony and compare the fingering instabilities induced by cell division to experimental observations on the expansion of MDCK cell cultures.

Biphasic, lyotropic, active nematics.

We perform dynamical simulations of a two-dimensional active nematic fluid in coexistence with an isotropic fluid. Drops of active nematic become elongated, and an effective anchoring develops at the nematic-isotropic interface. The activity also causes an undulatory instability of the interface. This results in defects of positive topological charge being ejected into the nematic, leaving the interface with a diffuse negative charge. Quenching the active lyotropic fluid results in a steady state in which phase-separating domains are elongated and then torn apart by active stirring.