Elasticity tunes mechanical stress localization around active topological defects.

Mechanical stresses are increasingly found to be associated with various biological functionalities. At the same time, topological defects are being identified across a diverse range of biological systems and are points of localized mechanical stress. It is therefore important to ask how mechanical stress localization around topological defects is controlled. Here, we use continuum simulations of nonequilibrium, fluctuating and active nematics to explore the patterns of stress localization, as well as their extent and intensity around topological defects. We find that by increasing the orientational elasticity of the material, the isotropic stress pattern around topological defects is changed substantially, from a stress dipole characterized by symmetric compression-tension regions around the core of the defect, to a localized stress monopole at the defect position. Moreover, we show that elastic anisotropy alters the extent and intensity of the stresses, and can result in the dominance of tension or compression around defects. Finally, including both nonequilibrium fluctuations and active stress generation, we find that the elastic constant tunes the relative effect of each, leading to the flipping of tension and compression regions around topological defects. This flipping of the tension-compression regions only by changing the elastic constant presents an interesting, simple, way of switching the dynamic behavior in active matter by changing a passive material property. We expect these findings to motivate further exploration tuning stresses in active biological materials by varying material properties of the constituent units.

Spontaneous flows and dynamics of full-integer topological defects in polar active matter.

Polar active matter of self-propelled particles sustain spontaneous flows through the full-integer topological defects. We study theoretically the incompressible flow profiles around ±1 defects induced by polar and dipolar active forces. We show that dipolar forces induce vortical flows around the +1 defect, while the flow around the -1 defect has an 8-fold rotational symmetry. The vortical flow changes its chirality near the +1 defect core in the absence of the friction with a substrate. We show analytically that the flow induced by polar active forces is vortical near the +1 defect and is 4-fold symmetric near the -1 defect, while it becomes uniform in the far-field. For a pair of oppositely charged defects, this polar flow contributes to a mutual interaction force that depends only on the orientation of the defect pair relative to the background polarization, and that enhances defect pair annihilation. This is in contradiction with the effect of dipolar active forces which decay inversely proportional with the defect separation distance. As such, our analyses reveals a long-ranged mechanism for the pairwise interaction between topological defects in polar active matter.

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.

Investigating the nature of active forces in tissues reveals how contractile cells can form extensile monolayers.

Actomyosin machinery endows cells with contractility at a single-cell level. However, within a monolayer, cells can be contractile or extensile based on the direction of pushing or pulling forces exerted by their neighbours or on the substrate. It has been shown that a monolayer of fibroblasts behaves as a contractile system while epithelial or neural progentior monolayers behave as an extensile system. Through a combination of cell culture experiments and in silico modelling, we reveal the mechanism behind this switch in extensile to contractile as the weakening of intercellular contacts. This switch promotes the build-up of tension at the cell-substrate interface through an increase in actin stress fibres and traction forces. This is accompanied by mechanotransductive changes in vinculin and YAP activation. We further show that contractile and extensile differences in cell activity sort cells in mixtures, uncovering a generic mechanism for pattern formation during cell competition, and morphogenesis.

Quadrupolar active stress induces exotic patterns of defect motion in compressible active nematics.

A wide range of living and artificial active matter exists in close contact with substrates and under strong confinement, where in addition to dipolar active stresses, quadrupolar active stresses can become important. Here, we numerically investigate the impact of quadrupolar non-equilibrium stresses on the emergent patterns of self-organisation in non-momentum conserving active nematics. Our results reveal that beyond having stabilising effects, the quadrupolar active forces can induce various modes of topological defect motion in active nematics. In particular, we find the emergence of both polar and nematic ordering of the defects, as well as new patterns of self-organisation that comprise topological defect chains and transient topological defect asters. The results contribute to further understanding of emergent patterns of collective motion and non-equilibrium self-organisation in active matter.

Bridging microscopic cell dynamics to nematohydrodynamics of cell monolayers.

It is increasingly being realized that liquid-crystalline features can play an important role in the properties and dynamics of cell monolayers. Here, we present a cell-based model of cell layers, based on the phase-field formulation, that connects cell-cell interactions specified at the single cell level to large-scale nematic and hydrodynamic properties of the tissue. In particular, we present a minimal formulation that reproduces the well-known bend and splay hydrodynamic instabilities of the continuum nemato-hydrodynamic formulation of active matter, together with an analytical description of the instability threshold in terms of activity and elasticity of the cells. Furthermore, we provide a quantitative characterisation and comparison of flows and topological defects for extensile and contractile stress generation mechanisms, and demonstrate activity-induced heterogeneity and spontaneous formation of gaps within a confluent monolayer. Together, these results contribute to bridging the gap between cell-scale dynamics and tissue-scale collective cellular organisation.

Distinct impacts of polar and nematic self-propulsion on active unjamming.

Though jamming transitions are long studied in condensed matter physics and granular systems, much less is known about active jamming (or unjamming), which commonly takes place in living materials. In this paper, we explore, by molecular dynamic simulations, the jamming-unjamming transition in a dense system of active semiflexible filaments. In particular, we characterize the distinct impact of polar vs nematic driving for different filament rigidities and at varying densities. Our results show that high densities of dynamic active filaments can be achieved by only changing the nature of the active force, nematic or polar. Interestingly, while polar driving is more effective at unjamming the system at high densities below confluency, we find that at even higher densities, nematic driving enhances unjamming compared to its polar counterpart. The effect of varying the rigidity of filaments is also significantly different in the two cases: While for nematic driving, lowering the bending rigidity unjams the system, we find an intriguing reentrant jamming-unjamming-jamming transition for polar driving as the filament rigidity is lowered. While the first transition (unjamming) is driven by softening due to reduced rigidity, the second transition (jamming) is a cooperative effect of ordering and coincides with the emergence of nematic order in the system. Together, through a generic model of self-propelled flexible filaments, our results demonstrate how tuning the nature of self-propulsion and flexibility can be employed by active materials to achieve high densities without getting jammed.

Memory effects, arches and polar defect ordering at the cross-over from wet to dry active nematics.

We use analytic arguments and numerical solutions of the continuum, active nematohydrodynamic equations to study how friction alters the behaviour of active nematics. Concentrating on the case where there is nematic ordering in the passive limit, we show that, as the friction is increased, memory effects become more prominent and +1/2 topological defects leave increasingly persistent trails in the director field as they pass. The trails are preferential sites for defect formation and they tend to impose polar order on any new +1/2 defects. In the absence of noise and for high friction, it becomes very difficult to create defects, but trails formed by any defects present at the beginning of the simulations persist and organise into parallel arch-like patterns in the director field. We show aligned arches of equal width are approximate steady state solutions of the equations of motion which co-exist with the nematic state. We compare our results to other models in the literature, in particular dry systems with no hydrodynamics, where trails, arches and polar defect ordering have also been observed.

Activity-induced instabilities of brain organoids.

We present an analytical and numerical investigation of the activity-induced hydrodynamic instabilities in model brain organoids. While several mechanisms have been introduced to explain the experimental observation of surface instabilities in brain organoids, the role of activity has been largely overlooked. Our results show that the active stress generated by the cells can be a, previously overlooked, contributor to the emergence of surface deformations in brain organoids.

Flow States and Transitions of an Active Nematic in a Three-Dimensional Channel.

We use active nematohydrodynamics to study the flow of an active fluid in a 3D microchannel, finding a transition between active turbulence and regimes where there is a net flow along the channel. We show that the net flow is only possible if the active nematic is flow aligning and that, in agreement with experiments, the appearance of the net flow depends on the aspect ratio of the channel cross section. We explain our results in terms of when the hydrodynamic screening due to the channel walls allows the emergence of vortex rolls across the channel.

Active nematics with anisotropic friction: the decisive role of the flow aligning parameter.

We use continuum simulations to study the impact of anisotropic hydrodynamic friction on the emergent flows of active nematics. We show that, depending on whether the active particles align with or tumble in their collectively self-induced flows, anisotropic friction can result in markedly different patterns of motion. In a flow-aligning regime and at high anisotropic friction, the otherwise chaotic flows are streamlined into flow lanes with alternating directions, reproducing the experimental laning state that has been obtained by interfacing microtubule-motor protein mixtures with smectic liquid crystals. Within a flow-tumbling regime, however, we find that no such laning state is possible. Instead, the synergistic effects of friction anisotropy and flow tumbling can lead to the emergence of bound pairs of topological defects that align at an angle to the easy flow direction and navigate together throughout the domain. In addition to confirming the mechanism behind the laning states observed in experiments, our findings emphasise the role of the flow aligning parameter in the dynamics of active nematics.

Sustained Oscillations of Epithelial Cell Sheets.

Morphological changes during development, tissue repair, and disease largely rely on coordinated cell movements and are controlled by the tissue environment. Epithelial cell sheets are often subjected to large-scale deformation during tissue formation. The active mechanical environment in which epithelial cells operate have the ability to promote collective oscillations, but how these cellular movements are generated and relate to collective migration remains unclear. Here, combining in vitro experiments and computational modeling, we describe a form of collective oscillations in confined epithelial tissues in which the oscillatory motion is the dominant contribution to the cellular movements. We show that epithelial cells exhibit large-scale coherent oscillations when constrained within micropatterns of varying shapes and sizes and that their period and amplitude are set by the smallest confinement dimension. Using molecular perturbations, we then demonstrate that force transmission at cell-cell junctions and its coupling to cell polarity are pivotal for the generation of these collective movements. We find that the resulting tissue deformations are sufficient to trigger osillatory mechanotransduction of YAP within cells, potentially affecting a wide range of cellular processes.

Topology and Morphology of Self-Deforming Active Shells.

We present a generic framework for modeling three-dimensional deformable shells of active matter that captures the orientational dynamics of the active particles and hydrodynamic interactions on the shell and with the surrounding environment. We find that the cross talk between the self-induced flows of active particles and dynamic reshaping of the shell can result in conformations that are tunable by varying the form and magnitude of active stresses. We further demonstrate and explain how self-induced topological defects in the active layer can direct the morphodynamics of the shell. These findings are relevant to understanding morphological changes during organ development and the design of bioinspired materials that are capable of self-organization.

Emergence of Active Nematic Behavior in Monolayers of Isotropic Cells.

There is now growing evidence of the emergence and biological functionality of liquid crystal features, including nematic order and topological defects, in cellular tissues. However, how such features that intrinsically rely on particle elongation emerge in monolayers of cells with isotropic shapes is an outstanding question. In this Letter, we present a minimal model of cellular monolayers based on cell deformation and force transmission at the cell-cell interface that explains the formation of topological defects and captures the flow-field and stress patterns around them. By including mechanical properties at the individual cell level, we further show that the instability that drives the formation of topological defects, and leads to active turbulence, emerges from a feedback between shape deformation and active driving. The model allows us to suggest new explanations for experimental observations in tissue mechanics, and to propose designs for future experiments.

Active matter invasion.

Biologically active materials such as bacterial biofilms and eukaryotic cells thrive in confined micro-spaces. Here, we show through numerical simulations that confinement can serve as a mechanical guidance to achieve distinct modes of collective invasion when combined with growth dynamics and the intrinsic activity of biological materials. We assess the dynamics of the growing interface and classify these collective modes of invasion based on the activity of the constituent particles of the growing matter. While at small and moderate activities the active material grows as a coherent unit, we find that blobs of active material collectively detach from the cohort above a well-defined activity threshold. We further characterise the mechanical mechanisms underlying the crossovers between different modes of invasion and quantify their impact on the overall invasion speed.

Active transport in a channel: stabilisation by flow or thermodynamics.

Recent experiments on active materials, such as dense bacterial suspensions and microtubule-kinesin motor mixtures, show a promising potential for achieving self-sustained flows. However, to develop active microfluidics it is necessary to understand the behaviour of active systems confined to channels. Therefore here we use continuum simulations to investigate the behaviour of active fluids in a two-dimensional channel. Motivated by the fact that most experimental systems show no ordering in the absence of activity, we concentrate on temperatures where there is no nematic order in the passive system, so that any nematic order is induced by the active flow. We systematically analyze the results, identify several different stable flow states, provide a phase diagram and show that the key parameters controlling the flow are the ratio of channel width to the length scale of active flow vortices, and whether the system is flow aligning or flow tumbling.

Topological states in chiral active matter: Dynamic blue phases and active half-skyrmions.

We numerically study the dynamics of two-dimensional blue phases in active chiral liquid crystals. We show that introducing contractile activity results in stabilised blue phases, while small extensile activity generates ordered but dynamic blue phases characterised by coherently moving half-skyrmions and disclinations. Increasing extensile activity above a threshold leads to the dissociation of the half-skyrmions and active turbulence. We further analyse isolated active half-skyrmions in an isotropic background and compare the activity-induced velocity fields in simulations to an analytical prediction of the flow. Finally, we show that confining an active blue phase can give rise to a system-wide circulation, in which half-skyrmions and disclinations rotate together.

Dancing disclinations in confined active nematics.

The spontaneous emergence of collective flows is a generic property of active fluids and often leads to chaotic flow patterns characterised by swirls, jets, and topological disclinations in their orientation field. However, the ability to achieve structured flows and ordered disclinations is of particular importance in the design and control of active systems. By confining an active nematic fluid within a channel, we find a regular motion of disclinations, in conjunction with a well defined and dynamic vortex lattice. As pairs of moving disclinations travel through the channel, they continually exchange partners producing a dynamic ordered state, reminiscent of Ceilidh dancing. We anticipate that this biomimetic ability to self-assemble organised topological disclinations and dynamically structured flow fields in engineered geometries will pave the road towards establishing new active topological microfluidic devices.

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.