Active nematics is an emerging paradigm for characterising biological systems. One aspect of particularly intense focus is the role active nematic defects play in these systems, as they have been found to mediate a growing number of biological processes. Accurately detecting and classifying these defects in biological systems is, therefore, of vital importance to improving our understanding of such processes. While robust methods for defect detection exist for systems of elongated constituents, other systems, such as epithelial layers, are not well suited to such methods. Here, we address this problem by developing a convolutional neural network to detect and classify nematic defects in confluent cell layers. Crucially, our method is readily implementable on experimental images of cell layers and is specifically designed to be suitable for cells that are not rod-shaped. We demonstrate that our machine learning model outperforms current defect detection techniques and that this manifests itself in our method requiring less data to accurately capture defect properties. This could drastically improve the accuracy of experimental data interpretation whilst also reducing costs, advancing the study of nematic defects in biological systems.
The Voronoi-based cellular model is highly successful in describing the motion of two-dimensional confluent cell tissues. In the homogeneous version of this model, the energy of each cell is determined solely by its geometric shape and size, and the interaction between adjacent cells is a byproduct of this additive energy. We generalize this model so as to allow zero or partial contact between cells. We identify several phases, two of which (solid confluent and liquid confluent) were found in previous studies that imposed confluency but others that are novel. Transitions in this model may be r…
In dense biological tissues, cell types performing different roles remain segregated by maintaining sharp interfaces. To better understand the mechanisms for such sharp compartmentalization, we study the effect of an imposed heterotypic tension at the interface between two distinct cell types in a fully 3D model for confluent tissues. We find that cells rapidly sort and self-organize to generate a tissue-scale interface between cell types, and cells adjacent to this interface exhibit signature geometric features including nematic-like ordering, bimodal facet areas, and registration, or alignme…
How can a collection of motile cells, each generating contractile nematic stresses in isolation, become an extensile nematic at the tissue-level? Understanding this seemingly contradictory experimental observation, which occurs irrespective of whether the tissue is in the liquid or solid states, is not only crucial to our understanding of diverse biological processes, but is also of fundamental interest to soft matter and many-body physics. Here, we resolve this cellular to tissue level disconnect in the small fluctuation regime by using analytical theories based on hydrodynamic descriptions o…
We investigate the effects of cell division and apopotosis on collective dynamics in two-dimensional epithelial tissues. Our model includes three key ingredients observed across many epithelia, namely cell-cell adhesion, cell death and a cell division process that depends on the surrounding environment. We show a rich non-equilibrium phase diagram depending on the ratio of cell death to cell division and on the adhesion strength. For large apopotosis rates, cells die out and the tissue disintegrates. As the death rate decreases, however, we show, consecutively, the existence of a gas-like phas…
How can dense biological tissue maintain sharp boundaries between coexisting cell populations? We explore this question within a simple vertex model for cells, focusing on the role of topology and tissue surface tension. We show that the ability of cells to independently regulate adhesivity and tension, together with neighbor-based interaction rules, lets them support strikingly unusual interfaces. In particular, we show that mechanical- and fluctuation-based measurements of the effective surface tension of a cellular aggregate yield different results, leading to mechanically soft interfaces t…
In vivo and in vitro cells rely on the support of an underlying biocompatible substrate, such as the extracellular matrix or a culture substrate, to spread and proliferate. The mechanical and chemical properties of such structures play a central role in the dynamical and statistical properties of the tissue. At the cell scale, these substrates are highly disordered. Here, we investigate how spatial heterogeneities of the cell-substrate interaction influence the motility of the cells in a model confluent tissue. We use the Self-Propelled Voronoi model and describe the disorder as a spatially de…
Recent work on particle-based models of tissues has suggested that any finite rate of cell division and cell death is sufficient to fluidize an epithelial tissue. At the same time, experimental evidence has indicated the existence of glassy dynamics in some epithelial layers despite continued cell cycling. To address this discrepancy, we quantify the role of cell birth and death on glassy states in confluent tissues using simulations of an active vertex model that includes cell motility, cell division, and cell death. Our simulation data is consistent with a simple ansatz in which the rate of …
Rigidity transitions in simple models of confluent cells have been a powerful organizing principle in understanding the dynamics and mechanics of dense biological tissue. In this work we explore the interplay between geometry and rigidity in two-dimensional vertex models confined to the surface of a sphere. By considering shapes of cells defined by perimeters whose magnitude depends on geodesic distances and areas determined by spherical polygons, the critical shape index in such models is affected by the size of the cell relative to the radius of the sphere on which it is embedded. This impli…
Collective cell migration underlies important biological processes, such as embryonic development, wound healing and cancer invasion. While many aspects of single cell movements are now well established, the mechanisms leading to displacements of cohesive cell groups are still poorly understood. To elucidate the emergence of collective migration in mechanosensitive cells, we examine a self-propelled Voronoi (SPV) model of confluent tissues with an orientational feedback that aligns a cell's polarization with its local migration velocity. While shape and motility are known to regulate a density…
In development and homeostasis, multi-cellular systems exhibit spatial and temporal heterogeneity in their biochemical and mechanical properties. Nevertheless, it remains unclear how spatiotemporally heterogeneous forces affect the dynamical and mechanical properties of confluent tissue. To address this question, we study the dynamical behavior of the two-dimensional cellular vertex model for epithelial monolayers in the presence of fluctuating cell-cell interfacial tensions, which is a biologically relevant source of mechanical spatiotemporal heterogeneity. In particular, we investigate the e…
Cell migration is important in many biological processes, including embryonic development, cancer metastasis, and wound healing. In these tissues, a cell's motion is often strongly constrained by its neighbors, leading to glassy dynamics. While self-propelled particle models exhibit a density-driven glass transition, this does not explain liquid-to-solid transitions in confluent tissues, where there are no gaps between cells and therefore the density is constant. Here we demonstrate the existence of a new type of rigidity transition that occurs in the well-studied vertex model for confluent ti…
Collective cell migration is a highly regulated process involved in wound healing, cancer metastasis and morphogenesis. Mechanical interactions among cells provide an important regulatory mechanism to coordinate such collective motion. Using a Self-Propelled Voronoi (SPV) model that links cell mechanics to cell shape and cell motility, we formulate a generalized mechanical inference method to obtain the spatio-temporal distribution of cellular stresses from measured traction forces in motile tissues and show that such traction-based stresses match those calculated from instantaneous cell shape…
Large-scale tissue deformation during biological processes such as morphogenesis requires cellular rearrangements. The simplest rearrangement in confluent cellular monolayers involves neighbor exchanges among four cells, called a T1 transition, in analogy to foams. But unlike foams, cells must execute a sequence of molecular processes, such as endocytosis of adhesion molecules, to complete a T1 transition. Such processes could take a long time compared to other timescales in the tissue. In this work, we incorporate this idea by augmenting vertex models to require a fixed, finite time for T1 tr…
Glassy dynamics in a confluent monolayer is indispensable in morphogenesis, wound healing, bronchial asthma, and many others; a detailed theoretical framework for such a system is, therefore, important. Vertex model (VM) simulations have provided crucial insights into the dynamics of such systems, but their nonequilibrium nature makes it difficult for theoretical development. Cellular Potts model (CPM) of confluent monolayer provides an alternative model for such systems with a well-defined equilibrium limit. We combine numerical simulations of CPM and an analytical study based on one of the m…
Surface tension governed by differential adhesion can drive fluid particle mixtures to sort into separate regions, i.e., demix. Does the same phenomenon occur in confluent biological tissues? We begin to answer this question for epithelial monolayers with a combination of theory via a vertex model and experiments on keratinocyte monolayers. Vertex models are distinct from particle models in that the interactions between the cells are shape-based, as opposed to distance-dependent. We investigate whether a disparity in cell shape or size alone is sufficient to drive demixing in bidisperse vertex…
Macroscopic properties and shapes of biological tissues depend on the remodelling of cell-cell junctions at the microscopic scale. We propose a theoretical framework that couples a vertex model of solid confluent tissues with the dynamics describing generation of local force dipoles in the junctional actomyosin. Depending on the myosin-turnover rate, junctions either preserve stable length or collapse to initiate cell rearrangements. We find that noise can amplify and sustain transient oscillations to the fixed point, giving rise to quasi-periodic junctional dynamics. We also discover that jun…
The origin of rigidity in disordered materials is an outstanding open problem in statistical physics. Previously, a class of 2D cellular models has been shown to undergo a rigidity transition controlled by a mechanical parameter that specifies cell shapes. Here, we generalize this model to 3D and find a rigidity transition that is similarly controlled by the preferred surface area: the model is solid-like below a dimensionless surface area of $s_0^\ast\approx5.413$, and fluid-like above this value. We demonstrate that, unlike jamming in soft spheres, residual stresses are necessary to create r…
Various multicellular tissues show chiral morphology. Experimental studies have shown this can originate from cell chirality. However, no theory has been proposed to connect the cellular chiral torque and multicellular chiral morphogenesis. We propose a model of confluent tissue dynamics with cellular chiral torque. We found that cells migrate unidirectionally under a gradient of cellular chiral torque. While the migration speed varies depending on the tissue's mechanical parameters, it is scaled solely by a structural order parameter for liquid-to-solid transition in confluent tissues.
Models of 3D confluent tissue as under-constrained glasses
Department of Physics, Emory University（埃默里大学物理系）；Aix Marseille Univ, Université de Toulon, CNRS, CPT (UMR 7332), Turing Centre for Living systems（艾克斯马赛大学、土伦大学、法国国家科学研究中心、CPT（UMR 7332）、图灵生命系统中心）
We introduce an Active Vertex Model (AVM) for cell-resolution studies of the mechanics of confluent epithelial tissues consisting of tens of thousands of cells, with a level of detail inaccessible to similar methods. The AVM combines the Vertex Model for confluent epithelial tissues with active matter dynamics. This introduces a natural description of the cell motion and accounts for motion patterns observed on multiple scales. Furthermore, cell contacts are generated dynamically from positions of cell centres. This not only enables efficient numerical implementation, but provides a natural de…
We use a computational phase-field model together with analytical analysis to study how inter-cellular active forces can mediate individual cell morphology and collective motion in a confluent cell monolayer. Contractile inter-cellular interactions lead to cell elongation, nematic ordering and active turbulence, characterised by motile topological defects. Extensile interactions result in frustration, and perpendicular cell orientations become more prevalent. Furthermore, we show that contractile behaviour can change to extensile behaviour if anisotropic fluctuations in cell shape are consider…
Models for confluent biological tissues often describe the network formed by cells as a triple-junction network, similar to foams. However, higher order vertices or multicellular rosettes are prevalent in developmental and {\it in vitro} processes and have been recognized as crucial in many important aspects of morphogenesis, disease, and physiology. In this work, we study the influence of rosettes on the mechanics of a confluent tissue. We find that the existence of rosettes in a tissue can greatly influence its rigidity. Using a generalized vertex model and effective medium theory we find a …
The spongy mesophyll is a complex, porous tissue found in plant leaves that enables carbon capture and provides mechanical stability. Unlike many other biological tissues, which remain confluent throughout development, the spongy mesophyll must develop from an initially confluent tissue into a tortuous network of cells with a large proportion of intercellular airspace. How the airspace in the spongy mesophyll develops while the cells remain mechanically stable remains unknown. Here, we used computer simulations of deformable particles to develop a purely mechanical model for the development of…
The mechanical properties of cells, which influence the properties of the tissue they belong to, are controlled by various mechanisms. Bi et al. theoretically demonstrated that density-independent rigidity transition occurs in two-dimensional confluent tissues that consist of mechanically uniform cells. They also analyzed the dynamical behavior of tissues near the critical point, which is geometrically controlled by `shape parameter'. To investigate whether the behavior of three-dimensional tissues is similar to that of two-dimensional ones, we extend the model proposed by Bi et al. to a three…
Epithelial cell monolayers show remarkable displacement and velocity correlations over distances of ten or more cell sizes that are reminiscent of supercooled liquids and active nematics. We show that many observed features can be described within the framework of dense active matter, and argue that persistent uncoordinated cell motility coupled to the collective elastic modes of the cell sheet is sufficient to produce swirl-like correlations. We obtain this result using both continuum active linear elasticity and a normal modes formalism, and validate analytical predictions with numerical sim…
Cell motion inside dense tissues governs many biological processes, including embryonic development and cancer metastasis, and recent experiments suggest that these tissues exhibit collective glassy behavior. To make quantitative predictions about glass transitions in tissues, we study a self-propelled Voronoi (SPV) model that simultaneously captures polarized cell motility and multi-body cell-cell interactions in a confluent tissue, where there are no gaps between cells. We demonstrate that the model exhibits a jamming transition from a solid-like state to a fluid-like state that is controlle…
In biological tissues, it is now well-understood that mechanical cues are a powerful mechanism for pattern regulation. While much work has focused on interactions between cells and external substrates, recent experiments suggest that cell polarization and motility might be governed by the internal shear stiffness of nearby tissue, deemed "plithotaxis". Meanwhile, other work has demonstrated that there is a direct relationship between cell shapes and tissue shear modulus in confluent tissues. Joining these two ideas, we develop a hydrodynamic model that couples cell shape, and therefore tissue …
Biological cells can actively tune their intracellular architecture according to their overall shape. Here we explore the rheological implication of such coupling in a minimal model of a dense cellular material where each cell exerts an active mechanical stress along its axis of elongation. Increasing the active stress amplitude leads to several transitions. An initially hexagonal crystal motif is first destabilized into a solid with anisotropic cells. Increasing activity further, we find a re-entrant transition to a regime with finite hexatic order and finite shear modulus, in which cells arr…
The rheology of biological tissues is important for their function, and we would like to better understand how single cells control global tissue properties such as tissue fluidity. A confluent tissue can fluidize when cells diffuse by executing a series of cell rearrangements, or T1 transitions. In a disordered 2D vertex model, the tissue fluidizes when the T1 energy barriers disappear as the target shape index approaches a critical value ($s^*_{0} \sim 3.81$), and the shear modulus describing the linear response also vanishes at this same critical point. However, the ordered ground states of…
Confluent cell monolayers and epithelia tissues show remarkable patterns and correlations in structural arrangements and actively-driven collective flows. We simulate these properties using multiphase field models. The models are based on cell deformations and cell-cell interactions and we investigate the influence of microscopic details to incorporate active forces on emerging phenomena. We compare four different approaches, one in which the activity is determined by a random orientation, one where the activity is related to the deformation of the cells and two models with subcellular details…
Stable array of point defects was generated in nematic liquid crystal. Point defects with topological charge of +1 and -1 (hedgehogs) were generated in vertically aligned liquid crystal cell. The hedgehogs were arranged in square or hexagonal arrays, and the shape of defect, such as radial or circular hedgehogs, were under the control of delicately patterned electrodes. Base on the two-dimensional defect array discovered in experiments, three-dimensional crystals of defects were postulated. The flux of the liquid crystal director field was summarized for each unit cell. The analysis showed tha…
Biological cells in living tissues form dynamic patterns with local orientational order and topological defects. Here we demonstrate an approach to produce cell monolayer with the predesigned orientational patterns using human dermal fibroblast cells (HDF) placed onto a photoaligned liquid crystal elastomer (LCE). The alignment of cells is caused by anisotropic swelling of the substrates in contact with the aqueous cell growth medium. The patterns predesigned in the LCE cause a strong spatial variation of cell phenotype (evidenced by shape variations), their surface density and number density …
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 mechanical properties 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 ins…
Solid-to-solid transition in dense assemblies of elongated cells
Sun Yat-sen University（中山大学）；Guangdong Provincial Key Laboratory of Magnetoelectric Physics and Devices, School of Physics, Sun Yat-sen University（中山大学物理学院磁电物理与器件广东省重点实验室）；Interdisciplinary Research Center for Physical Mechanics in Complex Systems and Its Engineering Applications, School of Physics, Sun Yat-sen University（中山大学物理学院复杂系统力学及其工程应用交叉研究中心）；Aix Marseille Univ, CNRS and Turing Centre for Living Systems, CPT (UMR 7332)（艾克斯-马赛大学、法国国家科学研究中心及图灵生命系统中心，CPT（UMR 7332））；Aix Marseille Univ, Université de Toulon, CNRS, LAI (UMR 7333), Turing Centre for Living Systems（艾克斯-马赛大学、土伦大学、法国国家科学研究中心、LAI（UMR 7333）及图灵生命系统中心）
Cell deformability is an essential determinant for tissue-scale mechanical nature, such as fluidity and rigidity, and is thus crucial for understanding tissue homeostasis and stable developmental processes. However, numerical simulations for the collective dynamics of cells with arbitral cell deformations akin to mesenchymal, ameboid, and epithelial cells in a non-confluent situation need high computational costs and are still challenging. Here we propose a new method that allows us to study significantly larger numbers of cells than existing methods. Using the method, we investigated the dens…
In living matter, shape fluctuations induced by acto-myosin are usually studied in vitro via reconstituted gels, whose properties are controlled by changing the concentrations of actin, myosin and cross-linkers. Such an approach deliberately avoids to consider the complexity of biochemical signaling inherent to living systems. Acto-myosin activity inside living cells is mainly regulated by the Rho signaling pathway which is composed of multiple layers of coupled activators and inhibitors. We investigate how such a pathway controls the dynamics of confluent epithelial tissues by tracking the di…
In developing organisms, internal cellular processes generate mechanical stresses at the tissue scale. The resulting deformations depend on the material properties of the tissue, which can exhibit long-ranged orientational order and topological defects. It remains a challenge to determine these properties on the time scales relevant for developmental processes. Here, we build on the physics of liquid crystals to determine material parameters of cell monolayers. Specifically, we use a hydrodynamic description to characterize the stationary states of compressible active polar fluids around defec…
Growing experimental evidence indicates that topological defects could serve as organizing centers in the morphogenesis of tissues. Here, we provide a quantitative explanation for this phenomenon, rooted in the buckling theory of deformable active polar liquid crystals. Using a combination of linear stability analysis and computational fluid dynamics, we demonstrate that active layers, such as confined cell monolayers, are unstable to the formation of protrusions in the presence of disclinations. The instability originates from an interplay between the focusing of the elastic forces, mediated …
