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 develop both a minimal description based on the lattice gas model of statistical physics, and a more realistic framework based on the cellular Potts model which captures cell shape changes and cluster rearrangement. In both cases, we find that cells have an optimal adhesion strength that maximizes cluster migration speed. The optimum negotiates a tradeoff between maintaining cell-cell contact and maintaining cluster fluidity, and we identify maximal variability in the cluster aspect ratio as a revealing signature. Our results suggest a collective benefit for intermediate cell-cell adhesion.
We formulate an active-gel theory for multicellular migration in the extra-cellular matrix (ECM). The cells are modeled as an active, polar solvent, and the ECM as a viscoelastic solid. Our theory enables to analyze the dynamic reciprocity between the migrating cells and their environment in terms of distinct relative forces and alignment mechanisms. We analyze the linear stability of polar cells migrating homogeneously in the ECM. Our theory predicts that, as a consequence of cell-matrix alignment, contractile cells migrate homogeneously for small wave vectors, while sufficiently extensile ce…
Modes of Mechanical Guidance of Adhesion-Independent Cell Migration
TU Bergakademie Freiberg（弗莱贝格工业大学）；Max Planck Institute for the Physics of Complex Systems（马克斯·普朗克复杂系统物理研究所）；Center for Systems Biology Dresden（德累斯顿系统生物学中心）；Cluster of Excellence Physics of Life, TU Dresden（德累斯顿工业大学生命物理学卓越集群）；Universitat de Barcelona（巴塞罗那大学）；Universitat de Barcelona Institute of Complex Systems (UBICS)（巴塞罗那大学复杂系统研究所）；Institució Catalana de Recerca i Estudis Avançats (ICREA)（加泰罗尼亚研究高级学院）；HTW Dresden（德累斯顿应用技术大学）
Cell cell and cell matrix adhesions are fundamental in all multicellular organisms. They play a key role in cellular growth, differentiation, pattern formation and migration. Cell-cell adhesion is substantial in the immune response, pathogen host interactions, and tumor development. The success of tissue engineering and stem cell implantations strongly depends on the fine control of live cell adhesion on the surface of natural or biomimetic scaffolds. Therefore, the quantitative and precise measurement of the adhesion strength of living cells is critical, not only in basic research but in mode…
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…
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.
Cellular decision making allows cells to assume functionally different phenotypes in response to microenvironmental cues, without genetic change. It is an open question, how individual cell decisions influence the dynamics at the tissue level. Here, we study spatio-temporal pattern formation in a population of cells exhibiting phenotypic plasticity, which is a paradigm of cell decision making. We focus on the migration/resting and the migration/proliferation plasticity which underly the epithelial-mesenchymal transition (EMT) and the go or grow dichotomy. We assume that cells change their phen…
Kinetic Monte Carlo and Cellular Particle Dynamics Simulations of Multicellular Systems
多细胞系统的计算机建模已经成为解释和指导与胚胎形态发生、肿瘤生长、血管生成以及最近将细胞聚集体打印为生物墨水颗粒后的结构形成相关的体外实验的有价值的工具。基于Metropolis Monte Carlo（MMC）算法的计算机模拟成功地解释和预测了所得的固定结构（对应于最低的粘附能态）。在这里，我们提出了两种替代MMC方法来模拟细胞运动和自组装：（1）动力学蒙特卡罗（KMC），（2）细胞粒子动力学（CPD）方法。与MMC不同，KMC和CPD方法都能够实时模拟细胞系统的动力学。在KMC方法中，转换速率与蜂窝系统的可能重排相关联，并且相应的时间演化用这些速率来表示。在CPD方法中，细胞被建模为相互作用的细胞粒子（CP）和多细胞系统的时间演化是通过整合所有CP的运动方程来确定的。KMC和CPD方法通过模拟两种实验上熟知的现象进行测试和比较：（1）在由具有不同粘附性的两种类型的细胞形成的聚集体内的细胞分选，以及（2）活细胞的两个球形聚集体的融合。
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…
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…
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.
During migration cells exhibit a rich variety of seemingly random migration patterns, which makes unraveling the underlying mechanisms that control cell migration a daunting challenge. For efficient migration cells require a mechanism for polarization, so that traction forces are produced in the direction of motion, while adhesion is released to allow forward migration. To simplify the study of this process cells have been studied when placed along one-dimensional tracks, where single cells exhibit both smooth and stick-slip migration modes. The stick-slip motility mode is characterized by pro…
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 …
The one-dimensional crawling movement of a cell is considered in this theoretical study. Our active gel model shows that for a cell with weakly mechanosensitive adhesion complexes, as myosin contractility increases, a cell starts to move at a constant velocity. As the mechanosensitivity of the adhesion complexes increases, a cell can exhibit stick-slip motion. Finally, a cell with highly mechanosensitive adhesion complexes exhibits periodic back-and-forth migration. A simplified model which assumes that the cell crawling dynamics are controlled by the evolution of the myosin density dipole and…
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…
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…
Functionality of living cells is inherently linked to subunits with dimensions on the nanoscale. In case of osteoblasts the cell surface plays a particularly important role for adhesion and spreading which are crucial properties with regard to bone implants. Here we present a comprehensive characterization of the 3D nanomorphology of living as well as fixed osteoblastic cells using scanning ion conductance microscopy (SICM) which is a nanoprobing method largely avoiding forces. Dynamic ruffles are observed, manifesting themselves in characteristic membrane protrusions. They contribute to the o…
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…
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…
Force fluctuations exhibited in focal adhesions (FAs) that connect a cell to its extracellular environment, point to the complex role of the underlying machinery that controls cell migration. To elucidate the explicit role of myosin motors in the temporal traction force oscillations, we vary the contractility of these motors in a dynamical model based on the molecular clutch hypothesis. As the contractility is lowered, effected both by changing the motor velocity and the rate of attachment/detachment, we show analytically in an experimentally relevant parameter space that the system goes from …
Constructing physical models of living cells and tissues is an extremely challenging task because of the high complexities of both intra- and intercellular processes. In addition, the force that a single cell generates vanishes in total due to the law of action and reaction. The typical mechanics of cell crawling involve periodic changes in the cell shape and in the adhesion characteristics of the cell to the substrate. However, the basic physical mechanisms by which a single cell coordinates these processes cooperatively to achieve autonomous migration are not yet well understood. To obtain a…
Cell migration in confining physiological environments relies on the concerted dynamics of several cellular components, including protrusions, adhesions with the environment, and the cell nucleus. However, it remains poorly understood how the dynamic interplay of these components and the cell polarity determine the emergent migration behavior at the cellular scale. Here, we combine data-driven inference with a mechanistic bottom-up approach to develop a model for protrusion and polarity dynamics in confined cell migration, revealing how the cellular dynamics adapt to confining geometries. Spec…
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…
University of Chicago（芝加哥大学）；Loyola University Chicago（芝加哥洛约拉大学）
Cellular form and function emerge from complex mechanochemical systems within the cytoplasm. No systematic strategy currently exists to infer large-scale physical properties of a cell from its many molecular components. This is a significant obstacle to understanding biophysical processes such as cell adhesion and migration. Here, we develop a data-driven biophysical modeling approach to learn the mechanical behavior of adherent cells. We first train neural networks to predict forces generated by adherent cells from images of cytoskeletal proteins. Strikingly, experimental images of a single f…
Collective cell migration is crucial in many biological processes such as wound healing, tissue morphogenesis, and tumor progression. The leading front of a collective migrating epithelial cell layer often destabilizes into multicellular finger-like protrusions, each of which is guided by a leader cell at the fingertip. Here, we develop a subcellular-element-based model of this fingering instability, which incorporates leader cells and other related properties of a monolayer of epithelial cells. Our model recovers multiple aspects of the dynamics, especially the traction force patterns and vel…
