Coherent Motions in Confluent Cell Monolayer Sheets

Cell migration plays a pivotal role in many physiologically important processes such as embryogenesis, wound-healing, immune defense, and cancer metastasis. Although much effort has been directed toward motility of individual cells, the mechanisms underpinning collective cell migration remain poorly understood. Here we develop a collective motility model that incorporates cell mechanics and persistent random motions of individual cells to study coherent migratory motions in epithelial-like monolayers. This model, in absence of any external chemical signals, is able to explain coordinate rotational motion seen in systems ranging from two adherent cells to multicellular assemblies. We show that the competition between the active persistent force and random polarization fluctuation is responsible for the robust rotation. Passive mechanical coupling between cells is necessary but active chemical signaling between cells is not. The predicted angular motions also depend on the geometrical shape of the underlying substrate: cells exhibit collective rotation on circular substrates, but display linear back-and-forth motion on long and narrow substrates.     

Coherent Motions in Confluent Cell Monolayer Sheets

Cell migration plays a pivotal role in many physiologically important processes such as embryogenesis, wound-healing, immune defense, and cancer metastasis. Although much effort has been directed toward motility of individual cells, the mechanisms underpinning collective cell migration remain poorly understood. Here we develop a collective motility model that incorporates cell mechanics and persistent random motions of individual cells to study coherent migratory motions in epithelial-like monolayers. This model, in absence of any external chemical signals, is able to explain coordinate rotational motion seen in systems ranging from two adherent cells to multicellular assemblies. We show that the competition between the active persistent force and random polarization fluctuation is responsible for the robust rotation. Passive mechanical coupling between cells is necessary but active chemical signaling between cells is not. The predicted angular motions also depend on the geometrical shape of the underlying substrate: cells exhibit collective rotation on circular substrates, but display linear back-and-forth motion on long and narrow substrates.     

The planar polarity pathway promotes coordinated cell migration during Drosophila oogenesis

Cell migration is fundamental in both animal morphogenesis and disease. The migration of individual cells is relatively well-studied; however, in vivo, cells often remain joined by cell-cell junctions and migrate in cohesive groups. How such groups of cells coordinate their migration is poorly understood. The planar polarity pathway coordinates the polarity of non-migrating cells in epithelial sheets and is required for cell rearrangements during vertebrate morphogenesis. It is therefore a good candidate to play a role in the collective migration of groups of cells. Drosophila border cell migration is a well-characterised and genetically tractable model of collective cell migration, during which a group of about six to ten epithelial cells detaches from the anterior end of the developing egg chamber and migrates invasively towards the oocyte. We find that the planar polarity pathway promotes this invasive migration, acting both in the migrating cells themselves and in the non-migratory polar follicle cells that they carry along. Disruption of planar polarity signalling causes abnormalities in actin-rich processes on the cell surface and leads to less-efficient migration. This is apparently due, in part, to a loss of regulation of Rho GTPase activity by the planar polarity receptor Frizzled, which itself becomes localised to the migratory edge of the border cells. We conclude that, during collective cell migration, the planar polarity pathway can mediate communication between motile and non-motile cells, which enhances the efficiency of migration via the modulation of actin dynamics.     

Substrate stiffness regulates cadherin-dependent collective migration through myosin-II contractility

The mechanical microenvironment is known to influence single-cell migration; however, the extent to which mechanical cues affect collective migration of adherent cells is not well understood. We measured the effects of varying substrate compliance on individual cell migratory properties in an epithelial wound-healing assay. Increasing substrate stiffness increased collective cell migration speed, persistence, and directionality as well as the coordination of cell movements. Dynamic analysis revealed that wounding initiated a wave of motion coordination from the wound edge into the sheet. This was accompanied by a front-to-back gradient of myosin-II activation and establishment of cell polarity. The propagation was faster and farther reaching on stiff substrates, indicating that substrate stiffness affects the transmission of directional cues. Manipulation of myosin-II activity and cadherin–catenin complexes revealed that this transmission is mediated by coupling of contractile forces between neighboring cells. Thus, our findings suggest that the mechanical environment integrates in a feedback with cell contractility and cell–cell adhesion to regulate collective migration.     

Polarized interfacial tension induces collective migration of cells,as a cluster,in a 3D tissue

In embryogenesis and cancer invasion, cells collectively migrate as a cluster in 3D tissues. Many studies have elucidated mechanisms of either individual or collective cell migration on 2D substrates; however, it remains unclear how cells collectively migrate as a cluster through 3D tissues. To address this issue, we considered the interfacial tension at cell-cell boundaries expressing cortical actomyosin contractions and cell-cell adhesive interactions. The strength of this tension is polarized; i.e., spatially biased within each cell according to a chemoattractant gradient. Using a 3D vertex model, we performed numerical simulations of multicellular dynamics in 3D space. The simulations revealed that the polarized interfacial tension enables cells to migrate collectively as a cluster through a 3D tissue. In this mechanism, interfacial tension induces unidirectional flow of each cell surface from the front to the rear along the cluster surface. Importantly, this mechanism does not necessarily require convection of cells, i.e., cell rearrangement, within the cluster. Moreover, several migratory modes were induced, depending on the strengths of polarity, adhesion, and noise; i.e., cells migrate either as single cells, as a cluster, or aligned like beads on a string, as occurs in embryogenesis and cancer invasion. These results indicate that the simple expansion and contraction of cell-cell boundaries enables cells to move directionally forward and to produce the variety of collective migratory movements observed in living systems.     

A model for cell migration in non-isotropic fibrin networks with an application to pancreatic tumor islets

Cell migration, known as an orchestrated movement of cells, is crucially important for wound healing, tumor growth, immune response as well as other biomedical processes. This paper presents a cell-based model to describe cell migration in non-isotropic fibrin networks around pancreatic tumor islets. This migration is determined by the mechanical strain energy density as well as cytokines-driven chemotaxis. Cell displacement is modeled by solving a large system of ordinary stochastic differential equations where the stochastic parts result from random walk. The stochastic differential equations are solved by the use of the classical Euler–Maruyama method. In this paper, the influence of anisotropic stromal extracellular matrix in pancreatic tumor islets on T-lymphocytes migration in different immune systems is investigated. As a result, tumor peripheral stromal extracellular matrix impedes the immune response of T-lymphocytes through changing direction of their migration.     

Epithelial-to-mesenchymal transition and different migration strategies as viewed from the neural crest

Epithelial-to-mesenchymal transition (EMT) is a dynamic process that produces migratory cells from epithelial precursors. However, EMT is not binary; rather it results in migratory cells which adopt diverse strategies including collective and individual cell migration to arrive at target destinations. Of the many embryonic cells that undergo EMT, the vertebrate neural crest is a particularly good example which has provided valuable insight into these processes. Neural crest cells from different species often adopt different migratory strategies with collective migration predominating in anamniotes, whereas individual cell migration is more prevalent in amniotes. Here, we will provide a perspective on recent work toward understanding the process of neural crest EMT focusing on how these cells undergo collective and individual cell migration.     

Design principles of tissue organisation: How single cells coordinate across scales

Cells act as building blocks of multicellular organisms, forming higher-order structures at different biological scales. Niches, tissues and, ultimately, entire organisms consist of single cells that remain in constant communication. Emergence of developmental patterns and tissue architecture thus relies on single cells acting as a collective, coordinating growth, migration, cell fate transitions and cell type sorting. For this, information has to be transmitted forward from cells to tissues and fed back to the individual cell to allow dynamic and robust coordination. Here, we define the design principles of tissue organisation integrating chemical, genetic and mechanical cues. We also review the state-of-the-art technologies used for dissecting collective cellular behaviours at single cell– and tissue-level resolution. We finally outline future challenges that lie in a comprehensive understanding of how single cells coordinate across biological scales to insure robust development, homoeostasis and regeneration of tissues.     

Morphogenesis by coupled regulatory networks: Reliable control of positional information and proportion regulation

Based on a non-equilibrium mechanism for spatial pattern formation we study how position information can be controlled by locally coupled discrete dynamical networks, similar to gene regulation networks of cells in a developing multicellular organism. As an example we study the developmental problems of domain formation and proportion regulation in the presence of noise, as well as in the presence of cell flow. We find that networks that solve this task exhibit a hierarchical structure of information processing and are of similar complexity as developmental circuits of living cells. Proportion regulation is scalable with system size and leads to sharp, precisely localized boundaries of gene expression domains, even for large numbers of cells. A detailed analysis of noise-induced dynamics, using a mean-field approximation, shows that noise in gene expression states stabilizes (rather than disrupts) the spatial pattern in the presence of cell movements, both for stationary as well as growing systems. Finally, we discuss how this mechanism could be realized in the highly dynamic environment of growing tissues in multicellular organisms.     

种群统计随机性和环境随机性对种群绝灭的影响

影响种群绝灭的随机干扰可分为种群统计随机性、环境随机性和随机灾害三大类。在相对稳定的环境条件下和相对较短的时间内,以前两类随机干扰对种群绝灭的影响为生态学家关注的焦点。但是,由于自然种群动态及其影响因子的复杂特征,进一步深入研究随机干扰对种群绝灭的作用在理论上和实践上都必须发展新的技术手段。本文回顾了种群统计随机性与环境随机性的概念起源与发展,系统阐述了其分析方法。归纳了两类随机性在种群绝灭研究中的应用范围、作用方式和特点的异同和区别方法。各类随机作用与种群动态之间关系的理论研究与对种群绝灭机理的实践研究紧密相关。根据理论模型模拟和自然种群实际分析两方面的研究现状,作者提出了进一步深入研究随机作用与种群非线性动态方法的策略。指出了随机干扰影响种群绝灭过程的研究的方向：更多的研究将从单纯的定性分析随机干扰对种群动力学简单性质的作用,转向结合特定的种群非线性动态特征和各类随机力作用特点具体分析绝灭极端动态的成因,以期做出精确的预测。     

Mechanobiology of leader–follower dynamics in epithelial cell migration

Collective cell migration is fundamental to biological form and function. It is also relevant to the formation and repair of organs and to various pathological situations, including metastatic propagation of cancer. Technological, experimental, and computational advancements have allowed the researchers to explore various aspects of collective migration, spanning from biochemical signalling to inter-cellular force transduction. Here, we summarize our current understanding of the mechanobiology of collective cell migration, limiting to epithelial tissues. On the basis of recent studies, we describe how cells sense and respond to guidance signals to orchestrate various modes of migration and identify the determining factors dictating leader–follower interactions. We highlight how the inherent mechanics of dense epithelial monolayers at multicellular length scale might instruct individual cells to behave collectively. On the basis of these findings, we propose that mechanical resilience, obtained by a certain extent of cell jamming, allows the epithelium to perform efficient collective migration during wound healing.     

BIO-LGCA: A cellular automaton modelling class for analysing collective cell migration

Collective dynamics in multicellular systems such as biological organs and tissues plays a key role in biological development, regeneration, and pathological conditions. Collective tissue dynamics—understood as population behaviour arising from the interplay of the constituting discrete cells—can be studied with on- and off-lattice agent-based models. However, classical on-lattice agent-based models, also known as cellular automata, fail to replicate key aspects of collective migration, which is a central instance of collective behaviour in multicellular systems. To overcome drawbacks of classical on-lattice models, we introduce an on-lattice, agent-based modelling class for collective cell migration, which we call biological lattice-gas cellular automaton (BIO-LGCA). The BIO-LGCA is characterised by synchronous time updates, and the explicit consideration of individual cell velocities. While rules in classical cellular automata are typically chosen ad hoc, rules for cell-cell and cell-environment interactions in the BIO-LGCA can also be derived from experimental cell migration data or biophysical laws for individual cell migration. We introduce elementary BIO-LGCA models of fundamental cell interactions, which may be combined in a modular fashion to model complex multicellular phenomena. We exemplify the mathematical mean-field analysis of specific BIO-LGCA models, which allows to explain collective behaviour. The first example predicts the formation of clusters in adhesively interacting cells. The second example is based on a novel BIO-LGCA combining adhesive interactions and alignment. For this model, our analysis clarifies the nature of the recently discovered invasion plasticity of breast cancer cells in heterogeneous environments.     

Zugunruhe of migratory and non-migratory birds in a circannual context

Recent findings in non-migratory birds have reopened questions about the interpretation and seasonal organization of Zugunruhe . I address the relationship between Zugunruhe and migration by comparing underlying circannual patterns in captive populations of migratory and non-migratory stonechats. Zugunruhe was highly variable and lacked clear periodicity, indicating its sensitivity to external cues. Patterns of Zugunruhe were similar in African residents, European short-distance migrants, and Siberian long-distance migrants, revealing no major difference in circannual organization. Moult was regulated independently of Zugunruhe and timed more rigidly, particularly in stonechats from equatorial Africa. The persistent and variable circannual patterns of Zugunruhe suggest that non-migratory and migratory stonechats have similar underlying programs but have modified the expression of actual migration. The findings, together with published observations from other species, emphasize the importance of considering programs for migration in a wide range of species, without losing sight of its environmental context.     

Heterogeneous CD8+ T Cell Migration in the Lymph Node in the Absence of Inflammation Revealed by Quantitative Migration Analysis

The three-dimensional positions of immune cells can be tracked in live tissues precisely as a function of time using two-photon microscopy. However, standard methods of analysis used in the field and experimental artifacts can bias interpretations and obscure important aspects of cell migration such as directional migration and non-Brownian walk statistics. Therefore, methods were developed for minimizing drift artifacts, identifying directional and anisotropic (asymmetric) migration, and classifying cell migration statistics. These methods were applied to describe the migration statistics of CD8+ T cells in uninflamed lymph nodes. Contrary to current models, CD8+ T cell statistics are not well described by a straightforward persistent random walk model. Instead, a model in which one population of cells moves via Brownian-like motion and another population follows variable persistent random walks with noise reproduces multiple statistical measures of CD8+ T cell migration in the lymph node in the absence of inflammation.     

The relationship between migratory behaviour, memory and the hippocampus: an intraspecific comparison

It has been hypothesized that memory-demanding ecological conditions might result in enhanced memory and an enlarged hippocampus, an area of the brain involved in memory processing, either via extensive memory experience or through evolutionary changes. Avian migration appears to represent one of such memory-demanding ecological conditions. We compared two subspecies of the white-crowned sparrow: migratory Zonotrichia leucophrys gambelii and non-migratory Z. l. nuttalli. Compared to non-migratory Z. l. nuttalli, migratory Z. l. gambelii showed better memory performance on spatial one-trial associative learning tasks and had more hippocampal neurons. Migratory subspecies also had larger hippocampi relative to the remainder of the telencephalon but not relative to body mass. In adults, the differences between migratory and non-migratory sparrows were especially pronounced in the right hippocampus. Juvenile migratory Z. l. gambelii had relatively larger hippocampal volume compared to juvenile non-migratory Z. l. nuttalli. Adult migratory Z. l. gambelii had more neurons in their right hippocampus compared to juveniles but such differences were not found in non-migratory Z. l. nuttalli. Our results suggest that migratory behaviour might be related to enhanced spatial memory and an enlarged hippocampus with more neurons, and that differences in the hippocampus between migratory and non-migratory sparrows might be experience-dependent. Furthermore, for the first time our results suggest that the right hippocampus, which encodes global spatial information, might be involved in migratory behaviour.     

The role of SF/HGF and c-Met in the development of skeletal muscle

Hypaxial skeletal muscles develop from migratory and non-migratory precursor cells that are generated by the lateral lip of the dermomyotome. Previous work shows that the formation of migratory precursors requires the c-Met and SF/HGF genes. We show here that in mice lacking c-Met or SF/HGF, the initial development of the dermomyotome proceeds appropriately and growth and survival of cells in the dermomyotome are not affected. Migratory precursors are also correctly specified, as monitored by the expression of Lbx1. However, these cells remain aggregated and fail to take up long range migration. We conclude that parallel but independent cues converge on the migratory hypaxial precursors in the dermomyotomal lip after they are laid down: a signal given by SF/HGF that controls the emigration of the precursors, and an as yet unidentified signal that controls Lbx1. SF/HGF and c-Met act in a paracrine manner to control emigration, and migratory cells only dissociate from somites located close to SF/HGF-expressing cells. During long range migration, prolonged receptor-ligand-interaction appears to be required, as SF/HGF is expressed both along the routes and at the target sites of migratory myogenic progenitors. Mice that lack c-Met die during the second part of gestation due to a placental defect. Rescue of the placental defect by aggregation of tetraploid (wild type) and diploid (c-Met-/-) morulae allows development of c-Met mutant animals to term. They lack muscle groups that derive from migratory precursor cells, but display otherwise normal skeletal musculature.     

Hippocampal neurogenesis is associated with migratory behaviour in adult but not juvenile sparrows (Zonotrichia leucophrys ssp.)

It has been hypothesized that individuals who have higher demands for spatially based behaviours should show increases in hippocampal attributes. Some avian species have been shown to use a spatially based representation of their environment during migration. Further, differences in hippocampal attributes have been shown between migratory and non-migratory subspecies as well as between individuals with and without migratory experience (juveniles versus adults). We tested whether migratory behaviour might also be associated with increased hippocampal neurogenesis, and whether potential differences track previously reported differences in hippocampal attributes between a migratory (Zonotrichia leucophrys gambelii) and non-migratory subspecies (Z. l. nuttalli) of white-crowned sparrows. We found that non-migratory adults had relatively fewer numbers of immature hippocampal neurons than adult migratory birds, while adult non-migrants had a lower density of new hippocampal neurons than adult and juvenile migratory birds and juvenile non-migratory birds. Our results suggest that neurogenesis decreases with age, as juveniles, regardless of migratory status, exhibit similar and higher levels of neurogenesis than non-migratory adults. However, our results also suggest that adult migrants may either seasonally increase or maintain neurogenesis levels comparable to those found in juveniles. Our results thus suggest that migratory behaviour in adults is associated with maintained or increased neurogenesis and the differential production of new neurons may be the mechanism underpinning changes in the hippocampal architecture between adult migratory and non-migratory birds.     

Multiscale mechanisms of cell migration during development: theory and experiment

Long-distance cell migration is an important feature of embryonic development, adult morphogenesis and cancer, yet the mechanisms that drive subpopulations of cells to distinct targets are poorly understood. Here, we use the embryonic neural crest (NC) in tandem with theoretical studies to evaluate model mechanisms of long-distance cell migration. We find that a simple chemotaxis model is insufficient to explain our experimental data. Instead, model simulations predict that NC cell migration requires leading cells to respond to long-range guidance signals and trailing cells to short-range cues in order to maintain a directed, multicellular stream. Experiments confirm differences in leading versus trailing NC cell subpopulations, manifested in unique cell orientation and gene expression patterns that respond to non-linear tissue growth of the migratory domain. Ablation experiments that delete the trailing NC cell subpopulation reveal that leading NC cells distribute all along the migratory pathway and develop a leading/trailing cellular orientation and gene expression profile that is predicted by model simulations. Transplantation experiments and model predictions that move trailing NC cells to the migratory front, or vice versa, reveal that cells adopt a gene expression profile and cell behaviors corresponding to the new position within the migratory stream. These results offer a mechanistic model in which leading cells create and respond to a cell-induced chemotactic gradient and transmit guidance information to trailing cells that use short-range signals to move in a directional manner.