Phases of Collective Cellular Behavior: Rheology, Order & Feedback

We will discuss some recent or ongoing works around cell monolayer migration. It will be a journey from developmental biology to mechanics, from discrete description of cellular material to continuum mechanics quantification, from experiments to modeling, from sub-cell scale to multi-cell scale, from two dimensions to three dimensions.

Organism development occurs through sequences of astonishingly precise spatiotemporal changes, along which embryonic tissues switch between fluid- and solid-like states, arising from non-linear interactions among cellular constituents. In this context, tissue fluidization observed in vivo in zebrafish embryos was interpreted, within the framework of rigidity percolation, as a rigid-to-floppy transition occurring at a critical point in cell connectivity. The microscopic parameters triggering these changes in cell connectivity, and whether they are interdependent, remain unclear. A density-driven rigidity transition is observed in wildtype embryos at a critical cell fraction, $\phi_c$, marked by the emergence of a Giant Rigid Cluster (GRC), in which cell movements are hindered. Using genetic manipulations, we uncoupled the tissue material response from the jamming behaviour, generating living tissues displaying solid-like or fluid-like properties, although being unjammed or jammed, respectively. We explain this apparently paradoxical behaviour by analytically deriving a critical point in the relative surface tension, $\alpha_c$, beyond which a floppy motif of soft, adhesive spheres spontaneously rigidifies. Simulations of arbitrary arrays of cells, whose energy is described by a soap-bubble-like Hamiltonian, show a sharp transition in the GRC size at the predicted $\alpha_c$; a transition also observed in real embryonic tissues with cell fraction below the critical jamming fraction $\phi<\phi_c$. Embryonic tissues are thus characterized by a phase diagram organized around a double critical point ($\phi_c,\alpha_c$): when uncoupled from changes in cell fraction $\phi$, the relative surface tension $\alpha$ is the main control parameter of the tissue material properties. Furthermore, at the critical point $\alpha_c$ at which adhesion-driven rigidification takes place, a sudden formation of tricellular contacts is observed, dictating an abrupt tissue reorganization and defining a transition from a non-confluent to a fully confluent regime. Our theoretical and experimental results show how basic physical parameters have far-reaching roles in tissue architecture, properties, and functions.

Cell monolayers exhibit both short- and long-range orientational order, which can be spontaneously created or disrupted through continuous cell rearrangements. These rearrangements originate from local mechanical stresses and can also actively generate mechanical stresses. Such active stresses are believed to play a crucial role in tissue reorganization and developmental processes. Despite this, it remains unclear how cells spontaneously modify their collective order and generate dynamic patterns in densely packed environments. In this work, we introduce an active deformable cell model that represents cells with arbitrary shapes, going beyond conventional polygon-based Voronoi or vertex models. Each cell is modelled as a ring of beads with conserved area and perimeter. Cell–cell interactions are mediated by apolar active forces that depend exclusively on the deformation of neighbouring cells and are regulated by an activity parameter. These forces act along the local contact normal and vanish in the absence of cell–cell contact. The activity parameter controls both the magnitude and direction of the contact-induced forces while ensuring that the net active force in the system remains zero. In addition, the strength of cell–cell adhesion can be independently tuned. We study the collective dynamics of cell monolayers by systematically varying the activity level and the degree of confluency. Our simulations reveal the emergence of local, dynamically evolving nematic-like order and an activity-driven unjamming transition. Furthermore, we observe a non-monotonic dependence of local orientational order on activity. We characterize the evolving tissue organization by analyzing correlation times and spatial correlation lengths. Together, these results underscore the fundamental role of activity-dependent collective dynamics in maintaining tissue integrity and shaping multicellular organization.

Embryonic development relies on the ability of tissues to self-organize through a complex interplay of biochemical and mechanical processes. One mechanism known to contribute to morphogenesis is the tendency of distinct cell populations—for example, exhibiting differential cell–cell adhesion to phase separate. While the equilibrium morphologies resulting from such phase separation are well understood, developmental systems rarely reach mechanical equilibrium. Instead, morphogenesis likely relies on transient, nonequilibrium dynamics that can strongly influence tissue organization and cell fate. It is thus crucial to understand unmixing as a dynamical process, especially when it is coupled to cell differentiation (Gsell & Merkel, 2022). To investigate these processes, we employ a two-dimensional ternary Cahn–Hilliard model in which a droplet composed of two phase-separating fluid phases is suspended in a third phase representing the surrounding medium. Hydrodynamic interactions are incorporated by treating all phases as incompressible Newtonian fluids governed by the Stokes equations. We further introduce a minimal cell-differentiation model to account for changes in cell identity during development (Anlaş et al., 2024; Gsell & Tlili et al., 2025). Our simulations reveal a rich diversity of transient morphologies, including croissant-like states, dipolar structures, rings, and multi-cluster configurations. We show that these patterns are controlled by the competition between the timescales of cellular unmixing and differentiation. Small variations in their relative magnitude can redirect the developmental trajectory toward qualitatively different intermediate states, even when the final equilibrium configuration remains unchanged. Finally, we compare our results with recent experiments on embryonic organoids and find qualitative agreement with the diversity of patterns observed during development. These findings highlight the possibly critical role of unmixing dynamics in shaping tissues and provide a minimal framework for understanding how mechanical and developmental timescales interact to generate patterns.

Cell shapes in confluent tissues range from nearly isotropic epithelial morphologies to highly elongated endothelial ones. In standard vertex models, tissue rigidity is controlled by a target shape index; increasing this index drives cell elongation and ultimate tissue fluidization. Here, we consider the case where cell elongation emerges autonomously by assigning an intrinsic, passive elastic preference for anisotropic shape. This distinction reverses the usual expectation: cell elongation does not fluidize the tissue, but drives a solid-to-solid transition from an ordered isotropic solid to a disordered anisotropic solid, with finite yield stress and shear rigidity on either side of the transition. These results decouple cell shape from tissue rheology and caution against inferring fluid-like mechanics from elongated cell morphologies alone.

A fundamental question in biology is to understand how patterns and shapes emerge from the collective interplay of large numbers of cells. Cells forming two-dimensional epithelial tissues behave as active materials that undergo remodeling and spontaneous shape changes. Focusing on the fly wing as a model system, we find that the cellular packing in the wing epithelium transitions from a disordered packing to an ordered, crystalline packing. While previous studies propose a role of tissue shear flow in establishing the ordered cell packing in the fly wing, we reveal a role of cell size heterogeneity. Indeed, we find that even if tissue shear have been inhibited, cell packings in the fruit fly wing epithelium transition from disordered to an ordered packing. We propose that the transition is controlled by the cell size heterogeneity, which is quantified by the cell size polydispersity. To explore the role of cell size polydispersity in controlling cellular packings, we implement the polydispersity in the vertex model of the epithelial tissues. Through numerical simulations of this model, we show that there is a critical value of cell size polydispersity above which cellular packings are disordered and below which they form a crystalline packing. By analyzing experimental data, we find that cell size polydispersity decreases during fly wing development. The observed dynamics of tissue crystallisation is consistent with the slow ordering kinetics we observe in the vertex model. Therefore, although tissue shear does not control the transition, it significantly enhances the rate of tissue-scale ordering by facilitating alignment of locally ordered crystallites. Our results identify cell size heterogeneity as a control parameter, in both the vertex model and the fruit fly wing epithelium, controlling the transition between ordered and disordered cellular packings.

Living tissues are active materials that continuously generate, transmit, and dissipate mechanical stresses across scales. Yet how these stresses give rise to robust three-dimensional shapes remains incompletely understood. In this talk, I will present recent work exploring two complementary physical mechanisms by which cellular monolayers undergo shape transformations: active viscoelastic buckling and nematic-guided morphogenesis. In the first part, I will delineate the mechanical rules governing epithelial buckling by combining an experimental system that allows us to sculpt epithelial shells and subject them to controlled deflation with a 3D computational model linking cytoskeletal dynamics to tissue mechanics. We show that epithelial buckling emerges from the interplay between the applied loading rate, the viscoelasticity of the actin cortex, and active contractility. We find that epithelial buckling is a multiscale phenomenon involving long-lived supracellular folds as well as short-lived subcellular wrinkles in the actin cortex. By forming epithelial shells with anisotropic curvature, we explore symmetry breaking and direct buckling into predictable wrinkle patterns. In the second part, I will present a strategy to program tissue shape transformations through the nematic organization of cellular forces. By controlling nematic order and topological defects, we generate tissues programmed with specific stress fields. Using a theoretical framework coupling contractile nematics with thin-sheet mechanics, we show that nematically guided active stresses can drive morphogenesis through Gaussian morphing. Experimentally, detachment of nematic tissues triggers out-of-plane deformations, generating reproducible three-dimensional shapes. Together, these studies establish a unifying physical framework in which tissue shape emerges from active stresses, viscoelasticity, nematicity, and geometric frustration. Beyond advancing our understanding of morphogenesis, this framework enables the design of synthetic shape-programmable living surfaces.

How cellular activity is coordinated over long spatial and temporal timescales to robustly build complex 3D tissue morphologies remains a fascinating open topic in biology and biophysics. In my group, we study this question using the Drosophila wing and human organoid model systems, striving to uncover fundamental mechanisms for collective cell organization that are relevant for both development and disease. In this talk, I will discuss our recent work examining how the primordial wing epithelium in the fruit fly larvae undergoes dramatic 3D tissue shape changes during its development. We use multi-angle light sheet microscopy to image and analyze the 3D morphology of the apical surface of the imaginal wing disc tissue at timepoints during its development. In early stages, the tissue folds in a characteristic and robust way. We show, using high resolution electron microscopy and genetic perturbations, that apical extracellular matrix is critical to maintain the correct folded architecture and that its removal is required for unfolding at the next stage of development. Further, we show how the future blade region of the wing disc tissue reshapes itself through active rearrangements in a manner analogous to shape-programmable materials. Our work gives new insight into the physical and genetic mechanisms guiding 3D tissue morphogenesis during animal development.

The organisation and phase behaviour of multicellular systems fundamentally determine their function. Tissue mechanics has emerged as a key regulator of physiology and homeostasis, arising from cellular architecture, collective order, and interactions with the extracellular matrix. Mechanical homeostasis describes how tissues maintain their mechanical properties within an optimal range through feedback loops that couple cellular contractility, adhesion and matrix remodelling. Across the lifespan, this balance is challenged by extracellular matrix reorganisation and shifts in cell death and proliferation, driving changes in tissue rheology and structure. Post-mitotic tissues such as the retina provide a powerful model to interrogate how collective cellular mechanics shape physiological function, ageing and disease. We combine stem-cell-derived models with quantitative mechanobiological approaches to reconstruct and analyse the outer retina from the bottom up. Our work shows that the mechanical state of the retinal pigment epithelium (RPE) varies across visual angles due to regional differences in basement membrane composition, integrin engagement and cellular workload, and that these adhesion-dependent traction forces directly regulate the RPE’s capacity to support photoreceptors. By modelling local matrix deformations and progressive RPE cell loss in vitro, we find that adaptation to time-related tissue remodelling alters stress distributions and effective viscoelastic properties, challenging mechanical homeostasis and promoting functional decline. These results position the outer retina as a tractable, post-mitotic model for probing how feedback-controlled phases of collective cellular behaviour emerge, adapt and fail in living tissues.

The collective dynamics of cells show a wide range of emergent behaviors, from flocking or active turbulent motion to jamming. We use optogenetics to intervene into cell motility on demand, by activation of Rho-GTPases such as Rac1, CDC42, and RhoA. Using traction force microscopy, we can record the force response of cells to activation of either pathway. Here, I give an overview of how we have used these optogenetic tools to control cells and their collective dynamics. Using Rac1, we can control polarity, changing traction asymmetry but not magnitude, in order to guide cells. Alternatively, using RhoA or CDC42, we can control traction magnitude and cause collective contraction in monolayers. We use these tools to intervene into monolayer density and cell shapes to explore the phase diagram of collective motion.

What is common between an assembly of motile cells whose movement is fueled by ATP and active colloids able to move using some chemical reactions? This is the question we are addressing using a rheological setup that allows us to probe the mechanical properties of these systems. We have designed a stokes experiment on both cells and colloids, and by analyzing the highly heterogeneous flow that is triggered, we hope to better understand the analogies between these systems and especially the role of activity, which can be easily controlled in case of the colloidal system

\begin{abstract} Density-based phase defects provide a direct bridge between continuum theories of pulsating active matter and experimentally accessible tissue observables. Here we combine quantitative phase imaging (QPI) based density measurements of confluent MDCK epithelial monolayers~\cite{Lastad2026A,Lastad2026B} with a topological analysis inspired by recent theories of pulsating active liquids and active solids~\cite{ZhangFodor2023,Banerjee2025,Gray1998,Li2025,Tang2025} to characterize the regimes of synchronized pulsation, wave propagation, and defect-mediated transitions in dense epithelia. We first construct a complex analytic signal from the demeaned density field using a temporal Hilbert transform, $ Z(x,y,t) = \tilde{\rho}(x,y,t) + i\,H_t[\tilde{\rho}](x,y,t), $ which yields a density-based phase $\psi(x,y,t)$ and amplitude $A(x,y,t)$ for local pulsations. This reveals robust oscillations with spatially heterogeneous amplitudes and instantaneous frequencies, including slowly evolving domains and intermittent fast phase slips along propagating fronts. To access the underlying topology, we introduce a phase-gradient orientation field $ \chi(x,y,t) = \arctan\!\bigl(\partial_y \psi / \partial_x \psi\bigr) $ and its associated topological charge density $ \rho_\chi = \epsilon_{\alpha\beta} (\partial_\alpha \cos\chi)(\partial_\beta \sin\chi), $ following the pulsating-active-matter framework of Banerjee \textit{et al.}\cite{Banerjee2025}. Defects are identified both by plaquette winding of $\psi$ and by peaks in $\rho_\chi$, and the two constructions are shown to share the same spatial cores. A quantitative comparison between the integrated continuous charge and discrete winding counts demonstrates excellent agreement, with the mean ratio of positive integrated charge to $+1$-defect count $\langle Q_+\rangle/\langle N_+\rangle \approx 1.14$, indicating that density-based topological observables are robust to experimental noise. Our data show that the monolayer resides beyond the single diffusive-phase regime of the Tang density--phase--amplitude model, with strongly space--time varying amplitudes, multiple characteristic periods, and well-developed defect--front networks. These results establish QPI-derived density-based phase defects as a powerful, experimentally grounded diagnostic of pulsating-active-matter topology in epithelial tissues, and they open a path to testing theoretical predictions of density fluctuations in living monolayers. \end{abstract} \bibliographystyle{plain} \begin{thebibliography}{9} \bibitem{Lastad2026A} L{\aa}stad, S. B., Abbasova, N., Combriat, T. \& Dysthe, D.K., Quantitative phase imaging of the dynamics of epithelial monolayers, SPIE Proceedings 138610A, (2026) \bibitem{Lastad2026B} L{\aa}stad, S. B., Abbasova, N., Combriat, T. \& Dysthe, D.K., Three Dimensional Dynamics of Epithelial Monolayers, bioRxiv 2026.03.10.710903 (2026). \bibitem{ZhangFodor2023} Zhang, Y., \& Fodor, É. (2023). Pulsating Active Matter. \textit{Phys. Rev. Lett.}, 131, 238302. \bibitem{Banerjee2025} Banerjee, T., et al. (2025). Hydrodynamics of pulsating active liquids. \textit{arXiv:2407.19955}. \bibitem{Gray1998} Gray, R. A., Pertsov, A. M., \& Jalife, J. (1998). Spatial and temporal organization during cardiac fibrillation. \textit{Nature}, 392, 75-78. \bibitem{Li2025} Z. Li, Q. Lei, Y. Ma, Fluidization and anomalous density fluctuations in 2D Voronoi cell tissues with pulsating activity, PNAS. 122 (10) e2421518122, (2025). \bibitem{Tang2025} W. Tang, M. R. Nejad, A. F. Pegoraro, L. Mahadevan, and M. Guo, Collective synchrony in confluent, pulsatile epithelia, arXiv:2507.16772 (2025) \end{thebibliography}{9}

Epithelial cell layers are an active material that plays a crucial role in development, wound healing and tissue homeostasis. The spreading of epithelial layers is driven by active traction forces generated by polarized, motile cells. But how do cells polarize? Inspired by experimental findings, we propose that cells in a tissue polarize away from tension, and we formulate a continuum model that accounts for force-induced cell polarization. We show that supracellular contractile tension allows cells at the edge of a cell layer to ‘feel’ free space and polarize outwards to drive spreading. Additionally, force-induced polarization gives rise to patterns of high and low cell density regions through an instability of the uniform unpolarized state. This instability can even lead to the self-rupture of a confluent cell layer, which breaks up into cell aggregates. Our work predicts the collective behaviors arising from the feedback between cell polarity and endogenous mechanical cues.

Collective motion in confluent epithelial cell sheets is remarkably varied, and includes swirl-like correlations over multiple cell diameters. Remarkably, it depends on boundary conditions: when surrounded by free space, as in wound healing, cells collectively invade the free space in the form of multicellular fingers. On the other hand, cell sheets in confinement shows striking system-scale oscillations. Here, I will present an active solid framework that explains how these active correlations emerge from the interplay of cell motility and viscoelastic interactions. First, we combine this theory with in vitro experiments on freely expanding MDCK monolayers and simulations of the self-propelled Voronoi model, to show that finger formation emerges naturally from correlated cell movements. This robust finger formation, without the need for any feedback mechanism, suggests that leader cells, cell-cell signalling, and division modulate an intrinsic process instead of causing it. Second, we focus on system scale oscillations in confinement. They can be attributed to a local feedback mechanism, self-alignment, where cells align their polarity to the total force vector (plithotaxis and CIL). We develop a linearized theory for the normal modes of such an active solid that explains the oscillations as arising from differential damping, by selecting the lowest available elastic modes of the cell sheet in the confined geometry.

There is now increasing evidence that epithelial tissues, at least sometimes, resemble active nematics. To better understand the role of nematic activity in tissues, we study a vertex model extended to include active nematic stresses [1] under channel confinement [2]. Channel-confined active nematics are well known to be able to produce spontaneous flows along the channel. However, under the substrate friction dissipation dynamics commonly used in vertex models, flows in the channel are always chaotic and organised channel flows do not develop. However, if dissipation is instead internal, modelled as vertex-vertex friction, channel-wide sustained unidirectional flows emerge. The transition from chaotic to unidirectional flows takes place because internal dissipation allows the model to develop long-range velocity-velocity and director-director correlations. Based on these findings, we turn to understanding the physical underpinnings of gastrulation in avian embryos. Using a vertex model extended with nematic active stresses and internal dissipation, we develop a mechanical model for the formation of the primitive streak. We then compare two possible mechanisms for orienting the activity axis in the tissue: chemical signalling and mechanical feedback. References: 1. S.-Z. Lin, M. Merkel, and J.-F. Rupprecht, Phys. Rev. Lett. 130, 058202 (2023). 2. J. Rozman, Chaithanya K. V. S., J. M. Yeomans, and R. Sknepnek, Nat. Commun. 16, 530 (2025).

Cell migration emerges from the interplay between intracellular processes that establish polarity and generate forces and interactions with the cell’s physical and biochemical environment. Together, these govern how cells polarize, change shape, move, and respond to their surroundings and other cells. While experiments increasingly capture these behaviors in quantitative detail, understanding the dynamical rules that couple them remains a major challenge. Here, we present a data-driven framework for learning and disentangling stochastic dynamics directly from experimental observations, from single-cell migration to multicellular collective behavior. Using experiments with a molecular polarity marker, we infer the coupled dynamics of cell motion, morphology, and polarity. We identify dynamical states associated with persistent migration in small cells that disappear in larger cells, revealing how cell size modulates polarity-driven migration. Extending this approach to cell–cell interactions, we uncover distinct interaction rules across cell types. Non-cancerous epithelial cells exhibit reciprocal repulsion and velocity alignment, whereas cancerous mesenchymal cells additionally display nonreciprocal interactions that modulate self-propulsion. These interactions alter the onset and speed of collective migration, directly linking microscopic interaction rules to emergent multicellular dynamics. Together, our results establish a principled route from quantitative observations to interpretable stochastic laws of cell migration, connecting cell-intrinsic dynamics and cell–cell interactions to emergent behavior across scales.

The ability of epithelial tissues to sustain mechanical stress and avoid rupture is a fundamental pillar of their function. During developmental morphogenesis, epithelia undergo dramatic deformation as they are shaped into organs in a process often driven by forces exerted by cells within the tissue. In post-natal animals, epithelia are continuously subjected to forces as part of normal physiological function and mutations in single genes can render tissues more prone to rupture, leading to disease. Yet, our understanding of the forces exerted between cells and their propagation within tissues remains in its infancy because of the lack of experimental tools that allow a direct measurement of intercellular forces. We have developed a new experimental approach to characterise absolute forces within tissues based on DNA nanotechnology and microscopy. We engineer model living tissues in which cell-cell junctions feature DNA-based molecular force sensors that provide local molecular scale force readout based on fluorescence with picoNewton precision and second resolution. This approach paves the way for illuminating how forces propagate in living tissues in vitro, in development and in normal physiological function.

During embryonic development, wound healing, and other collective cellular processes, tissues continuously reorganize and reshape by transitioning between solid-like and fluid-like states. These emergent mechanical behaviors arise from the interplay between cell deformations and cellular rearrangements, giving rise to visco-plasto-elastic properties at the tissue scale. A central challenge is therefore to bridge the microscopic dynamics of individual cells with coarse-grained descriptions of tissue mechanics. To address this challenge, we first introduce RheoLearn, a machine-learning framework based on physics-informed neural networks that infers mechanical properties directly from coarse-grained flow fields. Applied to vertex-model simulations, RheoLearn reconstructs the underlying stress field and estimates rheological parameters, including the effective viscosity and viscoelastic relaxation time, using flow velocity data alone. Beyond parameter estimation, the framework also tackles the more demanding task of constitutive-model identification. We then turn to oil--water emulsions as a controlled model system that captures key rheological features of living tissues. Using pressure-controlled rheometry, we show that the emulsion viscosity is primarily governed by droplet pressure and can be described by a unified constitutive law spanning the dilute regime to jamming. This experimentally grounded rheology provides a benchmark for RheoLearn, which we subsequently apply to microfluidic experiments in which emulsions flow through complex geometries. Finally, combining vertex-model simulations with experiments on flowing emulsions, we investigate how local deformations and cellular rearrangements cooperate to accommodate deformation in dense cellular materials. We propose a mesoscopic model describing the dynamics of droplet anisotropy under shear, thereby linking microscopic structure to macroscopic response. By integrating data-driven inference, controlled experiments, and mesoscopic modeling, our long-term goal is to establish a unified framework for the rheology of cellular materials that connects single-cell dynamics to coarse-grained tissue mechanics.

During early embryonic development, pluripotent cells differentiate, change shape, and rearrange spatially to establish the body plan. While the molecular pathways governing developmental morphogenesis have been studied extensively, the role of biophysical properties of cells and tissues in regulating this inherently mechanical process has only recently come into focus. Here, we use gastruloids—three-dimensional aggregates of mouse embryonic stem cells that spontaneously break symmetry and extend along an axis—to investigate how cell surface mechanics contribute to morphogenetic movements reminiscent of early post-implantation embryo. We have shown that gastruloid elongation is inhibited by maintaining high plasma membrane tension through expression of constitutively active ezrin (ezrinCA), an actin–membrane linker protein. Importantly, ezrinCA does not prevent mesodermal commitment, indicating that the observed morphogenetic defect is not primarily a result of impaired developmental progression. Using spheroid fusion as an assay that probes tissue mechanics, we observe that ezrinCA impairs the merging of gastruloids at the onset of elongation, suggesting reduced tissue fluidity. We are currently investigating associated changes in tissue rheology and cell motility. Our work reveals how cell surface mechanics impacts morphogenetic movements in gastruloids and, more broadly, how single-cell mechanical properties shape collective tissue behaviours.

Gastrulation, the early stage of embryonic development, is an essential, highly conserved process in the development of all vertebrate embryos, including humans. During gastrulation, the embryo transforms from a single layer of epithelial cells into a three-layered structure of three major embryonic cell types, the ectoderm, the mesoderm and the endoderm, in a process involving large-scale cell and tissue movements. When not executed properly, it causes abortion of development and, in milder cases, leads to a wide range of congenital defects. The cellular mechanisms controlling gastrulation, when activated in the wrong place or at the wrong time, result in severe disease in adult life, such as cancer and malfunctioning of the immune system. Gastrulation requires the integration of critical cell behaviours, such as cell differentiation, division, and movement, through chemical and mechanical cell-cell signalling to achieve the morphogenesis essential for proper function. These interactions between signalling and cell behaviours create complex feedback loops between tissue, cell, and molecular length- and timescales that have evolved to enable the robust formation of complex multicellular structures. In this talk, using the vertex model for cell-level description of epithelial tissues, we will discuss how various forms of active processes, such as mechano-chemical feedback, cell growth, division, ingression, etc., couple to cell mechanics and lead to pattern formation and flows in model tissues. We will also make qualitative comparisons with primitive streak formation (i.e., gastrulation) in chick embryos.

In the avian embryo, the primitive streak organizes large-scale flows in the surrounding homogeneous epithelium during the process of gastrulation. This narrow streak of mechanically active material first extends and then regresses as gastrulation comes to a close. Here, we investigate the transition between streak extension and streak regression in terms of the underlying mechanical forces. We develop the hydrodynamic theory of an active crack embedded in a viscous material. This allows us to infer active tensions and torques acting at the streak from experimental flow measurements. In our model, the streak acts as a localized sink of material, introducing discontinuities in the hydrodynamic stress and velocity fields. We show that away from the crack tip the flow field surrounding an active crack can be captured by an expansion in terms of the complex logarithm, which captures key features in experimental data. This allows us to quantitatively account for the measured embryo-scale flow field in terms of just two parameters, yielding a mechanical model of the streak as a one-dimensional active material embedded in a homogenous fluid. We find that the flux into such an active crack generally yields viscous forces that are pulling at the crack tip. These forces balance the line tension of the crack to drive its elongation. In contrast, we find that streak regression results from mechanical activity external to the streak, driving the convergent extension of the neural furrow. Finally, we discuss how the concept of an active crack allows us to understand the mechanics and stability of other lines of mechanically active materials such as the cytokinetic ring.

During development, groups of cells generate shape by coordinating their mechanical properties through an interplay of self-organization and pre-patterning. However, how mechanics participate in self-organized pattern formation remains unknown. To study this, we use the regenerative abilities of the cnidarian Hydra vulgaris, which displays a striking planar pattern of actin fibers at the organism scale. Cellular aggregates of Hydra cells initially lose all cell actin polarity, yet can regenerate a long-range actin pattern within a week. We use concepts from the physics of liquid crystals to better understand this process. We measure the appearance of the actin pattern over days and show that the actin field evolves from a disordered symmetric state to an ordered state in which rotational symmetry is broken, and translational symmetry is partially broken, with the associated order parameters (respectively nematic and smectic) increasing over days. On shorter time scales, the actin field displays spatial heterogeneity in the nematic order parameter, and ordered domains progressively grow and fuse, suggesting that ordering occurs through local cell-cell interactions. To better understand the mechanisms driving it, we perturb the tissue’s physical constraints and show that, while topology and geometry do not appear to have a direct effect, stretch can strongly bias the actin field pattern within hours. The conserved protein Wnt is expressed in the Hydra head and is involved in body axis formation, and we show that head grafts can align actin. However, Wnt inhibition impairs head formation but not actin alignment, and the bias in our stretch assay occurs without a significant Wnt enrichment. This suggests a direct mechanical role in the alignment of the actin fibers. Overall, we show in vivo the physical properties and constraints of a self-organized supracellular actin pattern.

Growing tumors generate and respond to stress in their local environment. On the one hand, local cell proliferation and apoptosis lead to complex strain patterns in the tissue. On the other hand, tissue re-arrangements can relax the resulting mechanical shear stresses and make the tissue more fluid-like. To predict the outcomes of these nonlinear visco-elastic interactions, we introduce the framework of morphoelasticity to phase field modeling of a growing tumor embedded in a surrounding host tissue. Coupling this continuum system to diffusible growth-promoting nutrient, our simulations identify a symmetry-breaking instability in 2D and 3D, driven by two primary mechanisms: (i) elastic buckling instabiliies due to differential growth induced by the nutrient gradient and (ii) instabilities generated by apoptosis-related volumetric loss. Further, tissue fluidity and compressibility can lead to changes in tumor topologies. Our modeling framework provides a methodology for investigating how tissue mechanics and growth factor signaling influence the progression of solid tumors.

Morphogenesis is driven by the collective motion of cells and growing evidence suggests that many biological processes are governed by cell alignment and self-organization. Topological defects that organize active stresses have been proposed to act as hotspots for differentiation and morphogenesis. As a result, a liquid crystal physics approach provides an insightful framework to describe collective cellular behavior and orientational order in three-dimensional tissues. C2C12 muscle precursor cells have strong shape anisotropy and long-range alignment interactions. This nematic-like behavior allows them to align and fuse to create muscle. In this work, we investigate how mechanical stimulation influences the organization and differentiation of C2C12 myoblasts within 3D purely cellular spherical aggregates. Magnetic nanoparticles are internalized by the cells, which can then be remotely stimulated using an external magnetic field. This approach enables the formation of multicellular aggregates with controlled size and shape, as well as the application of mechanical constraints. We focus on the organization of supracellular actin filaments and the emergence of topological defects depending on the differentiation potential of the cells. Multilayering is observed with crisscrossed, spiral-like structures. In addition, the aggregates can be mechanically confined by compressing them between two glass plates thus altering their defect type. Our results will improve our understanding of the interplay between organization and differentiation and how mechanical forces influence the structure and function of three-dimensional tissues by controlling cell alignment can be an essential contribution to tissue engineering (Nagle et al.2022 and Nagle et al 2025).

Nematic order in a monolayer of the soil bacterium Myxococcus xanthus generates abundant half-integer topological defects whose dynamics govern the sequential formation of cell layers, favoring further development of three-dimensional aggregation structures like starvation-induced fruiting-bodies. Under a variety of environmental conditions, these cells are able to tune their reversal frequency and transition from a predominantly nematic regime to a state of mixed local polar and nematic domains, enriching the phenomenology of the simple active nematic description. We investigate the role of polar order in collective pattern formation and possible functionality of emerging structures. We thank Nanyang Technological University for the Start-Up Grant. The authors thank the Ministry of Education, Singapore, for its support through the Tier 1 (RG154/23) and Tier 2 (MOE-T2EP50124-0010) grants.

Gravity is a major cue for the proper growth and development of plants. The plant response to gravity involves starch-filled plastids, called statoliths, which sediment to the bottom of specialized gravity-sensing cells known as statocytes. Statoliths are thought to regulate the transport of the growth hormone auxin by acting on specific auxin transporters, the PIN proteins. However, the complete gravitropic signaling pathway, from the intracellular signal associated with statolith sedimentation to plant bending, remains poorly understood. In this talk, I will show that gravisensors in plant cells behave as position sensors–not as gravitational force sensors, as previously believed–whose remarkable sensitivity arises from the agitation of statoliths by cytoskeletal activity. I will then show how this "position sensor" hypothesis can be incorporated into a simple model linking statolith position, PIN reorganization, and auxin transport. This model recapitulates the main features of the plant gravitropic response while raising new questions about the underlying molecular mechanisms.

Proliferation and motility are ubiquitous drivers of activity in biological systems. Here, we study a dense binary mixture of motile and proliferating particles with exclusively repulsive interactions, where homeostasis in the proliferating subpopulation is maintained by pressure-induced removal. Using numerical simulations, we show that this heterogeneous active matter undergoes spontaneous phase separation at high density and weak enough self-propulsion. We map the full two-component system to an effective single-component Active Brownian Particle model that recapitulates this behavior. This allows us to identify the emergent effects of the proliferating matrix on motile particles that interact to produce phase separation: enhanced diffusion, renormalized self-propulsion, reduced persistence, and an effective attraction between motile particles. Our results establish a new type of phase transition and reveal how mechanical activity from growth can mediate non-equilibrium interactions and fluctuations. This mechanism provides a conceptual framework to reinterpret the physics of dense pattern-forming cellular populations, such as bacterial colonies or tumors, as systems of mixed active matter.

Reorganization processes in dense active matter remain a central open question in non-equilibrium physics. In particular, how persistent self- propulsion drives local rearrangements and triggers collective failure events is not well understood. Here, we investigate such activity- induced rearrangements, that sometimes rapidly cascade to avalanches, in a dense assembly of self-propelled particles with extremely persis- tent activity. These systems evolve through abrupt transitions between mechanically stable configurations, giving rise to rich intermittent be- havior. Using large-scale simulations, we systematically characterize avalanche statistics across a range of system sizes and activity proto- cols. We quantify the scaling properties of avalanche-size distributions for two widely studied active matter models: active Brownian particles and active Ornstein-Uhlenbeck particles. By comparing these classes of dynamics, we identify how the nature of the propulsion mechanism influences the exponents associated with the avalanche size distribu- tion. In addition, we report the frequency and temporal organization of avalanches. Our results provide a unified picture of how persistent activity drives rearrangements in dense active systems and highlight the connections between active intermittency, mechanical stability, and avalanche dynamics.

Collective stress generation in cellular monolayers is a key phenomenological process governing coordinated migration and emergent multicellular dynamics. We employ a generic active nematics model to investigate stress generation and its associated properties. By analyzing the maximal principal stress and its correlation with the nematic director across different activity strengths, we find that the principal stress aligns perpendicular (parallel) to the nematic director for extensile (contractile) activity. In the turbulent regime, we identify a distinct isoline derived from anisotropic stress components along which all ±1/2 defects (both nematic and stress) are localized. This feature is robust and remains unchanged with variations in both the magnitude and nature (extensile or contractile) of activity. Our findings provide a new route to probe the mechanical and rheological properties of confluent cell layers, where stress measurements are more accessible than detailed cell shape or size characterization.

Cell segregation is a fundamental process in tissue organization, morphogenesis, and development. While classical explanations often rely on differences in adhesion, several biological systems suggest that mechanical properties of the cell cortex can also play a central role. In this work, we investigate how local contraction can drive demixing in a binary mixture of deformable particles. We model cells as active deformable rings composed of interacting particles connected by elastic springs, with area conservation, repulsion, adhesion, and an explicit local contraction interaction. Starting from initially mixed configurations, we show that differences in local contraction are sufficient to generate spontaneous segregation. Depending on the interaction strength and activity, the system can organize into mixed, checkerboard-like, or fully segregated states. Our results highlight local contraction as a minimal physical mechanism for demixing in deformable active matter and provide a computational framework to study cell sorting, tissue organization, and pattern formation in biological systems

Active forces and fluctuations are fundamental features of living systems, driving morphological and mechanical changes that are directly linked to biological functions. Recent studies have shown that such forces can induce transitions in biological tissues between fluid-like and solid-like states and vice versa. However, how distinct modes of active forces govern non-equilibrium dynamics remains poorly understood. Here, we employ a cell-based computational model, the Active Foam model, to investigate the similarities and differences in fluid tissues driven independently by traction forces or tension fluctuations. We find that cell geometry, cellular rearrangement dynamics, and spatiotemporal correlations depend sensitively on active force modes, indicating that commonly used structural and dynamical measures do not provide robust predictions of tissue fluidity. In contrast, we show that a persistent Brownian motion framework yields a universal description of tissue fluidity, independent of the specific nature of the active forces. Our results establish persistent Brownian motion as a unifying framework for predicting tissue fluidity in active systems, while non-universal correlations between geometry, dynamics, and fluidity provide identifiable signatures that can be used to infer the dominant mode of active forces.

Animal tissues acquire their shape through morphogenesis, a process in which cells organize, deform, migrate, and interact to generate complex three-dimensional architectures. To investigate the multiscale mechanics underlying this process, we employ vertex models that represent individual cells as polyhedra defined by the positions of their vertices. Using a 2.5D vertex model of planar epithelia, we study a rigidity transition in which tissues switch between rigid and floppy states. We show that isotropic in-plane strain induces a reentrant columnar-to-squamous rigidity transition, with a critical point near the unit-cell aspect ratio. Beyond the vanishing shear modulus, the phase diagram also exhibits floppy states with zero in-plane bulk modulus, as well as a discontinuous columnar–squamous transition governed by lateral tension. We further extend the model by introducing basal cell self-propulsion and investigate the resulting active solid-to-fluid transition driven by cell motility. Our findings place the rigidity transition of the well-studied 2D Area- and Perimeter-Elasticity (APE) model in a three-dimensional context

Gastruloids are organoids derived from embryonic stem cells, whose gene expression patterns parallel the embryo’s anterior–posterior and dorso–ventral axes in vivo. They also recapitulate aspects of early organogenesis, giving rise to cardiac-, vascular-, somitic-, gut-, and neural tube-like structures. Since their introduction about a decade ago, gastruloids have attracted substantial interest and have been extensively studied and characterized, but almost exclusively from biochemical and genetic perspectives. By contrast, the general biophysical mechanisms driving their early organization remain poorly understood. In this talk, I will present our recent experimental and theoretical work on the biophysical processes underlying early gastruloid self-organization and symmetry breaking. In particular, I will discuss how organoid-scale tissue flows correlate with genetic patterning and differentiation gradients across the tissue. I will then present our ongoing efforts to extend this framework to morphogenesis at single-cell resolution in 3D, and to later stages in which initially continuous tissues diversify into cavities and organ-like structures

As the largest organelle, the cell nucleus can affect the shape, spatial organisation and mechanics of cells in a variety of tissue contexts. Despite extensive studies on the molecular mechanisms underlying nuclear positioning and mechanics, it remains unclear whether the nucleus actively controls tissue architecture. Here, we combine elasticity theory, vertex modelling and the Drosophila blastoderm stage embryo as a generic experimental model to investigate the mechanical role of nuclei on epithelial organisation. By developing a general method that integrates mechanical and geometrical properties extracted from imaging data, we show that from elastic coupling between nuclei and the cell surface, a mechanically driven phase transition emerges between simple columnar and pseudostratified tissue architectures. Genetic and optogenetic experimental perturbations provide evidence supporting such a coupling and confirm the predicted transitions following changes in mechanical and geometric parameters. Our work identifies a novel mechanical role of nuclear elasticity, independent of specialised machineries and may represent a general, generic mechanism controlling emergence of tissue level structures.

In this talk, I will demonstrate that the maturation of a confluent epithelial tissue can be understood from a theoretical perspective through aging dynamics. Aging refers to the slow evolution of physical properties of a system with waiting time after a quench. We investigate the aging dynamics of confluent epithelial tissue within the Voronoi model, following both an instantaneous thermal quench and a quench in the preferred cell shape index, $p_0$. We find that the system exhibits clear signatures of aging, as revealed by two-time correlation functions such as the self-overlap function and self-intermediate scattering function, both of which show a pronounced dependence on the waiting time $t_w$. The associated relaxation time $\tau$ follows a power-law scaling as $\tau \sim t_w^{\delta}$, where the aging exponent $\delta$ lies in the range $0.45 < \delta < 0.7$, depending on $p_0$. For large values of $p_0$, corresponding to an unusual glassy regime, we observe smaller aging exponents, whereas for smaller $p_0$, associated with a super-Arrhenius regime, $\delta$ approaches 0.7. We demonstrate a universal aging behavior with $p_0$ quench. We analyze the static properties of the tissue, including the evolution of the mean and fluctuations of the cell aspect ratio and its distribution with waiting time during aging. Remarkably, the scaled aspect ratio distribution follows a near-universal behavior across waiting times, which we explain using a mean-field cell-shape theory. We rationalize our theoretical understanding with existing experimental data on the maturation of a confluent tissue and provide some new predictions which can be tested experimentally.

The closest living relatives of animals, choanoflagellates, exist in both uni- and multi-cellular forms. The choanoflagellate Choanoeca flexa uniquely forms colonies both clonally (from a single cell) and aggregatively (through the association of many independent cells). How individual cells aggregate to form sheet-like colonies—and how the colony structure controls its function—remains unknown. Here, combining experiments and simulations, we show that C. flexa aggregation is a biphasic process: cells first collide, and then maximize nearest-neighbor contacts. The competition between these timescales, tuned independently by cell concentration and salinity, dictates emergent colony structure, yielding a continuum from compact to fractal geometries. Further, while individual cells within colonies behave identically, only compact colonies achieve full collective functionality: feeding, inverting curvature, and swimming. Altogether, our study establishes that simple physical rules---rather than complex biological signaling---dictate the structure and, consequently, the function of aggregative choanoflagellate colonies, and explains why naturally occurring functional colonies have a stereotypically compact structure.

Growth and division are active mechanical processes: each division breaks orientational symmetry, injects stress into the collective, and contributes to flows and deformations that feed back on cell orientation and the direction of future division. In growing multicellular systems, metabolism spatially patterns this feedback by controlling where proliferation occurs, creating a specific mechanical environment that becomes a driver of cell reorientation and morphogenesis. Using a minimal nutrient-limited particle model of proliferation with tunable lineage memory of the division axis, we ask when such inherited orientation can propagate to collective scales, when it is overwritten by emergent mechanics, and how this balance shapes growth morphology and competition outcomes.