Cell monolayers provide an interesting example of active matter, exhibiting a phase transition from a flowing to jammed state as they age. Here we report experiments and numerical simulations illustrating how a jammed cellular layer rapidly reverts to a flowing state after a wound. Quantitative comparison between experiments and simulations shows that cells change their self-propulsion and alignement strength so that the system crosses a phase transition line, which we characterize by finite-size scaling in an active particle model. This wound-induced unjamming transition is found to occur generically in epithelial, endothelial and cancer cells.
Collective cell migration plays a central role in tissue development, morphogenesis, wound repair and cancer progression. With the growing realization that physical forces mediate cell motility in development and physiology, a key biological question is how cells integrate molecular activities for force generation on multicellular scales. In this review we discuss recent advances in modeling collective cell migration using quantitative tools and approaches rooted in soft matter physics. We focus on theoretical models of cell aggregates as continuous active media, where the feedback between mec…
Substrate-based cell motility is essential for fundamental biological processes, such as tissue growth, wound healing and immune response. Even if a comprehensive understanding of this motility mode remains elusive, progress has been achieved in its modeling using a whole cell physical model. The model takes into account the main mechanisms of cell motility - actin polymerization, substrate mediated adhesion and actin-myosin dynamics and combines it with steric cell-cell and hydrodynamic interactions. The model predicts the onset of collective cell migration, which emerges spontaneously as a r…
Cell migration is essential for regulating many biological processes in physiological or pathological conditions, including embryonic development and cancer invasion. In vitro and in silico studies suggest that collective cell migration is associated with some biomechanical particularities, such as restructuring of extracellular matrix, stress and force distribution profiles, and reorganization of cytoskeleton. Therefore, the phenomenon could be understood by an in-depth study of cells' behavior determinants, including but not limited to mechanical cues from the environment and from fellow tra…
Tumor cells invade individually or in groups, mediated by mechanical interactions between cells and their surrounding matrix. These multicellular dynamics are reminiscent of leader-follower coordination and epithelial-mesenchymal transitions (EMT) in tissue development, which may occur via dysregulation of associated molecular or physical mechanisms. However, it remains challenging to elucidate such phenotypic heterogeneity and plasticity without precision measurements of single cell behavior. The convergence of technological developments in live cell imaging, biophysical measurements, and 3D …
Collective cell motility is crucial to many biological processes including morphogenesis, wound healing, and cancer invasion. Recently, the biology and biophysics communities have begun to use the term cell jamming to describe the collective arrest of cell motion in tissues. Although this term is widely used, the underlying mechanisms are varied. In this review, we highlight three independent mechanisms that can potentially drive arrest of cell motion -- crowding, tension-driven rigidity, and reduction of fluctuations -- and propose a speculative phase diagram that includes all three. Since mu…
Cells collectively migrate as a cluster in three-dimensional (3D) tissues, such as in embryogenesis and cancer invasion. Here, numerical simulations using a 3D vertex model show that polarized interfacial tension, expressing cell adhesion and cortex contractility, induces the cluster migration in the 3D space. The mechanism is that polarized interfacial tension induced a directional flow of cell-cell interfaces from the front to rear within the whole cluster, producing a driving force, i.e., cells move forward as a cluster by simply expanding and contracting cell-cell boundaries.
Metastasis is a process of cell migration that can be collective and guided by chemical cues. Viewing metastasis in this way, as a physical phenomenon, allows one to draw upon insights from other studies of collective sensing and migration in cell biology. Here we review recent progress in the study of cell sensing and migration as collective phenomena, including in the context of metastatic cells. We describe simple physical models that yield the limits to the precision of cell sensing, and we review experimental evidence that cells operate near these limits. Models of collective migration ar…
Multicellular collective migration is a ubiquitous strategy of cells to translocate spatially in diverse tissue environments to accomplish a wide variety of biological phenomena, viz. embryonic development, wound healing, and tumor progression. Diverse cellular functions and behaviors, for instance, cell protrusions, active contractions, cell-cell adhesion, biochemical signaling, remodeling of tissue micro-environment, etc., play their own role concomitantly to have a single concerted consequence of multicellular migration. Thus unveiling the driving principles, both biochemical and biophysica…
The spontaneous formation of vortices is a hallmark of collective cellular activity. Here, we study the onset and persistence of coherent angular motion (CAMo) as a function of the number of cells $N$ confined in circular micropatterns. We find that the persistence of CAMo increases with $N$ but exhibits a pronounced discontinuity accompanied by a geometric rearrangement of cells to a configuration containing a central cell. Computer simulations based on a generalized Potts model reproduce the emergence of vortex states and show in agreement with experiment that their stability depends on the …
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.
The importance of collective cellular migration during embryogenesis and tissue repair asks for a sound understanding of underlying principles and mechanisms. Here, we address recent in vitro experiments on cell monolayers which show that the advancement of the leading edge relies on cell proliferation and protrusive activity at the tissue margin. Within a simple viscoelastic mechanical model amenable to detailed analysis, we identify a key parameter responsible for tissue expansion, and we determine the dependence of the monolayer velocity as a function of measurable rheological parameters. O…
The multicellular organization of diverse systems, such as embryos, intestines and tumours, relies on the coordinated migration of cells in 3D curved environments. In these settings, cells establish supracellular patterns of motion, including collective rotation and invasion. While such collective modes are increasingly well understood in 2D flat systems, the consequences of geometrical and topological constraints on collective cell migration in 3D curved tissues are largely unknown. Here, we study 3D collective migration in mammary cell spheroids, which represent a common and conceptually sim…
Collective cell migration is a key driver of embryonic development, wound healing, and some types of cancer invasion. Here we provide a physical perspective of the mechanisms underlying collective cell migration. We begin with a catalogue of the cell-cell and cell-substrate interactions that govern cell migration, which we classify into positional and orientational interactions. We then review the physical models that have been developed to explain how these interactions give rise to collective cellular movement. These models span the sub-cellular to the supracellular scales, and they include …
Collective migration -- the directed, coordinated motion of many self-propelled agents -- is a fascinating emergent behavior exhibited by active matter that has key functional implications for biological systems. Extensive studies have elucidated the different ways in which this phenomenon may arise. Nevertheless, how collective migration can persist when a population is confronted with perturbations, which inevitably arise in complex settings, is poorly understood. Here, by combining experiments and simulations, we describe a mechanism by which collectively migrating populations smooth out la…
Dense monolayers of living cells display intriguing relaxation dynamics, reminiscent of soft and glassy materials close to the jamming transition, and migrate collectively when space is available, as in wound healing or in cancer invasion. Here we show that collective cell migration occurs in bursts that are similar to those recorded in the propagation of cracks, fluid fronts in porous media and ferromagnetic domain walls. In analogy with these systems, the distribution of activity bursts displays scaling laws that are universal in different cell types and for cells moving on different substra…
Key to collective cell migration is the ability of cells to rearrange their position with respect to their neighbors. Recent theory and experiments demonstrated that cellular rearrangements are facilitated by cell shape, with cells having more elongated shapes and greater perimeters more easily sliding past their neighbors within the cell layer. Though it is thought that cell perimeter is controlled primarily by cortical tension and adhesion at each cell's periphery, experimental testing of this hypothesis has produced conflicting results. Here we studied collective cell migration in an epithe…
The migration of cells is relevant for processes such as morphogenesis, wound healing, and invasion of cancer cells. In order to move, single cells deform cyclically. However, it is not understood how these shape oscillations influence collective properties. Here we demonstrate, using numerical simulations, that the interplay of directed motion, shape oscillations, and excluded volume enables cells to locally "synchronize" their motion and thus enhance collective migration. Our model captures elongation and contraction of crawling ameboid cells controlled by an internal clock with a fixed peri…
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…
Collective cell migration contributes to embryogenesis, wound healing and tumor metastasis. Cell monolayer migration experiments help understanding what determines the movement of cells far from the leading edge. Inhibiting cell proliferation limits cell density increase and prevents jamming; we observe long-duration migration and quantify space-time characteristics of the velocity profile over large length- and time-scales. Velocity waves propagate backwards and their frequency depends only on cell density at the moving front. Both cell average velocity and wave velocity increase linearly wit…
We investigate morphologies of proliferating cellular tissues using a newly developed numerical simulation model for mechanical cell division and migration in 2D. The model is applied to a bimodal mixture consisting of stiff cells with a low growth potential and soft cells with a high growth potential; cancer cells are typically considered to be softer than healthy cells. In an even mixture, the soft cells develop into a tissue matrix and the stiff cells into a dendrite-like network structure. When soft cells are placed inside a tissue consisting of stiff cells (to model cancer growth), the so…
Collective cell migration in response to a chemical cue occurs in many biological processes such as morphogenesis and cancer metastasis. Clusters of migratory cells in these systems are capable of responding to gradients of less than 1% difference in chemical concentration across a cell length. Multicellular systems are extremely sensitive to their environment and while the limits to multicellular sensing are becoming known, how this information leads to coherent migration remains poorly understood. We develop a computational model of multicellular sensing and migration in which groups of cell…
How systems are endowed with migration capacity is a fascinating question with implications ranging from the design of novel active systems to the control of microbial populations. Bacteria, which can be found in a variety of environments, have developed among the richest set of locomotion mechanisms both at the microscopic and collective levels. Here, we uncover experimentally a new mode of collective bacterial motility in humid environment through the depinning of bacterial droplets. While capillary forces are notoriously enormous at the bacterial scale, even capable of pinning water droplet…
Collections of cells exhibit coherent migration during morphogenesis, cancer metastasis, and wound healing. In many cases, bigger clusters split, smaller sub-clusters collide and reassemble, and gaps continually emerge. The connections between cell-level adhesion and cluster-level dynamics, as well as the resulting consequences for cluster properties such as migration velocity, remain poorly understood. Here we investigate collective migration of one- and two-dimensional cell clusters that collectively track chemical gradients using a mechanism based on contact inhibition of locomotion. We dev…
Cell migration in fibreous extracellular matrix (ECM) is crucial to many physiological and pathological processes such as tissue regeneration, immune response and cancer progression. During migration, individual cells can generate active pulling forces via actin filament contraction, which are transmitted to the ECM fibers through focal adhesion complexes, remodel the ECM, and eventually propagate to and can be sensed by other cells in the system. The microstructure and physical properties of the ECM can also significantly influence cell migration, e.g., via durotaxis and contact guidance. Her…
Most cells possess the capacity to locomote. Alone or collectively, this allows them to adapt, to rearrange, and to explore their surroundings. The biophysical characterization of such motile processes, in health and disease, has so far focused mostly on two limiting cases: single-cell motility on the one hand, and the dynamics of confluent tissues such as the epithelium on the other. The in-between regime of clusters, composed of relatively few cells, moving as a coherent unit has received less attention. Such small clusters are, however, deeply relevant in development but also in cancer meta…
Contact inhibition plays a crucial role in the motility of cells, the process of wound healing, and the formation of tumors. By mimicking the mechanical motion of calls crawling on a substrate using a pseudopod, we constructed a minimal model for migrating cells which gives rise to contact inhibition of locomotion (CIL) naturally. The model cell consists of two disks, one in the front (a pseudopod) and the other one in the back (cell body), connected by a finitely extensible spring. Despite the simplicity of the model, the cells' collective behavior is highly nontrivial, depending on the shape…
In response to natural or anthropocentric pollutions coupled to global climate changes, microorganisms from aquatic environments can suddenly accumulate on water surface. These dense suspensions, known as blooms, are harmful to ecosystems and significantly degrade the quality of water resources. In order to determine the physico-chemical parameters involved in their formation and quantitatively predict their appearance, we successfully reproduced irreversible cyanobacterial blooms in vitro. By combining chemical, biochemical and hydrodynamic evidences, we identify a mechanism, unrelated to the…
Epithelial cell monolayers expand on substrates by forming finger-like protrusions, created by leader cells, in the monolayer boundary. Information transmission and communication between individual entities in the cohesive collective lead to long-range order, vortical structures, and disorder to ordered phase transitions. We ask the following questions: what makes a leader? What is the role of followers in leader cell formation? We used a particle-based model to simulate epithelial cell migrations on substrates of 9.4 kPa, 21 kPa and 33 kPa stiffness. The dynamics of cellular motion in the ens…
Migration of cells can be characterized by two, prototypical types of motion: individual and collective migration. We propose a statistical-inference approach designed to detect the presence of cell-cell interactions that give rise to collective behaviors in cell-motility experiments. Such inference method has been first successfully tested on synthetic motional data, and then applied to two experiments. In the first experiment, cell migrate in a wound-healing model: when applied to this experiment, the inference method predicts the existence of cell-cell interactions, correctly mirroring the …
During metastatic dissemination, streams of cells collectively migrate through a network of narrow channels within the extracellular matrix, before entering into the blood stream. This strategy is believed to outperform other migration modes, based on the observation that individual cancer cells can take advantage of confinement to switch to an adhesion-independent form of locomotion. Yet, the physical origin of this behaviour has remained elusive and the mechanisms behind the emergence of coherent flows in populations of invading cells under confinement are presently unknown. Here we demonstr…
Collective cell migration in cohesive units is vital for tissue morphogenesis, wound repair, and immune response. While the fundamental driving forces for collective cell motion stem from contractile and protrusive activities of individual cells, it remains unknown how their balance is optimized to maintain tissue cohesiveness and the fluidity for motion. Here we present a cell-based computational model for collective cell migration during wound healing that incorporates mechanochemical coupling of cell motion and adhesion kinetics with stochastic transformation of active motility forces. We s…
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…
We present a model of soft active particles that leads to a rich array of collective behavior found also in dense biological swarms of bacteria and other unicellular organisms. Our model uses only local interactions, such as Vicsek-type nearest neighbor alignment, short-range repulsion, and a local boundary term. Changing the relative strength of these interactions leads to migrating swarms, rotating swarms and jammed swarms, as well as swarms that exhibit run-and-tumble motion, alternating between migration and either rotating or jammed states. Interestingly, although a migrating swarm moves …
