Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound . Cell migration is a broad term that we use to refer to those processes that involve the translation of cells from one location to another. This may occur in non-live. Cell migration is a fundamental process, from simple, uni-cellular organisms such as amoeba, to complex multi-cellular organisms such as mammals. Whereas.
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The switchable integrin adhesome. Functional atlas of the integrin adhesome. A paxillin tyrosine phosphorylation switch regulates the assembly and form of cell-matrix adhesions. Tissue formation during embryonic development , wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations. Cells often migrate in response to specific external signals, including chemical signals and mechanical signals.
An understanding of the mechanism by which cells migrate may lead to the development of novel therapeutic strategies for controlling, for example, invasive tumour cells. Due to the highly viscous environment low Reynolds number , cells need to permanently produce forces in order to move. Cells achieve active movement by very different mechanisms. Many less complex prokaryotic organisms and sperm cells use flagella or cilia to propel themselves.
Eukaryotic cell migration typically is far more complex and can consist of combinations of different migration mechanisms. It generally involves drastic changes in cell shape which are driven by the cytoskeleton. Two very distinct migration scenarios are crawling motion most commonly studied and blebbing motility.
The migration of cultured cells attached to a surface is commonly studied using microscopy. Such videos Figure 1 reveal that the leading cell front is very active, with a characteristic behavior of successive contractions and expansions. It is generally accepted that the leading front is the main motor that pulls the cell forward. The processes underlying mammalian cell migration are believed to be consistent with those of non- spermatozooic locomotion.
The latter feature is most easily observed when aggregates of a surface molecule are cross-linked with a fluorescent antibody or when small beads become artificially bound to the front of the cell. Other eukaryotic cells are observed to migrate similarly. The amoeba Dictyostelium discoideum is useful to researchers because they consistently exhibit chemotaxis in response to cyclic AMP ; they move more quickly than cultured mammalian cells; and they have a haploid genome that simplifies the process of connecting a particular gene product with its effect on cellular behaviour.
There are two main theories for how the cell advances its front edge: It is possible that both underlying processes contribute to cell extension. Experimentation has shown that there is rapid actin polymerisation at the cell's front edge.
Other cytoskeletal components like microtubules have important functions in cell migration. When microtubules in the trailing edge of cell are dynamic, they are able to remodel to allow retraction.
When dynamics are suppressed, microtubules cannot remodel and, therefore, oppose the contractile forces. It can be concluded that microtubules act both to restrain cell movement and to establish directionality.
Studies have also shown that the front of the migration is the site at which the membrane is returned to the cell surface from internal membrane pools at the end of the endocytic cycle. In addition, the damaged airway epithelium prevents key metabolic functions of the airways including fluid and ion transport to the lumen and mucociliary clearance.
The ability of the epithelium to rapidly self-repair is thus critical to restore pulmonary function and to prevent further damage. Wound repair is particularly well understood in the skin but increasing evidence supports that the main stages of the process are conserved across organs The initial physiological response to wounding is the activation of circulating platelets at the site of vascular injury. Such activation is initiated by direct contact between the platelet surface and proteins located at the basement membrane of the endothelium such as collagen, fibronectin, laminin, and von Willebrand factor Activated platelets rapidly aggregate to form stable clots that prevent hemorrhage until the healing process is completed.
Platelet aggregates are initially stabilized by a fibrin network that will later serve as a provisional scaffold rich in growth factors on which cells may crawl In parallel with fibrin clotting, damaged cells initiate a stress response that includes the activation of MAPK pathways, the secretion of chemotactic factors, and the recruitment of circulating neutrophils and monocytes to clear pathogens from the injured area This initial inflammatory response is followed by reepithelialization.
During this process, cells surrounding the wound migrate collectively across a provisional matrix rich in fibrin and fibronectin To migrate onto and through this provisional matrix, cells at the first few rows behind the wound margin alter their expression of cell-cell and cell-matrix adhesion proteins Fibrinolytic enzymes such as plasmin and MMPs degrade the matrix to enable rapid cell migration , In addition, cells undergo structural changes of their cytoskeleton characterized by the synthesis of transverse stress fibers and by the extension of filopodia and lamellipo-dia into the wound area , In striking analogy with development, epithelial cells use two main modes of collective migration during reepithelialization The first mode involves the assembly of a supracellular actin cable at the wound perimeter.
The second mode of migration involves the extension of dynamic lamellipodia and filopodia into the wound area This mechanism appears to be reminiscent of single cell migration although recent studies proved that it also involves strong cooperativity between cells 12 , In addition to playing a central role in reepithelialization, collective cell migration is also involved in wound healing as a primary mediator of angiogenesis Angiogenesis is fundamental during wound healing to provide oxygen and nutrients to the newly assembled tissues and its inhibition impairs wound healing.
In response to these signaling macromolecules, endothelial cells upregulate integrins at the tips of sprouting capillaries to collectively migrate through the surrounding tissue As in the case of reepithelialization, proteolytic enzymes released into the wound tissue degrade the ECM to favor the advance of endothelial cell sprouts.
While collective cell migration is crucial in development and tissue repair, it also mediates devastating diseases such as cancer 45 , 75 , The traditional view of cancer metastasis is based on the notion that single cells detach from primary tumors, crawl through the stroma, enter the blood and lymphatic vessels, and finally colonize in healthy tissues to form a secondary tumor.
However, increasing evidence indicates that tumor dissemination is driven not only by single cells but also by cohesive cell groups Fig. This notion is supported by the observation that clusters of metastatic cells are often present in the blood and lymphatic vasculature of cancer patients 31 , In addition, histopathological sections of breast, colon, ovarian, lung, and other differentiated carcinomas exhibit clusters, chains, and sheets in the stromal areas surrounding primary tumors , , , Collective cell migration in cancer.
A Different invasion patterns in primary melanoma invading the mid-dermis in vivo. Arrowheads indicate scattered individual cells. Image modified, with permission, from Friedl and Wolf B Invasion modes in a modified skin-fold chamber model of orthotopic invasion of human HT fibrosarcoma cells.
Patterns include lack of invasion top, left , disseminating single cells top, right , and diffuse or compact strand-like collective invasion lower panels. C Frequency of invasion modes displayed in B. Adapted, with permission, from Alexander et al. One successful strategy to study the role of these cohesive cell aggregates in cancer metastasis has been to analyze the dynamics of neoplastic tissue explants or cell line tumor spheroids in vitro 76 , , When embedded in 3D collagen I gels or Matrigel, these cell systems extend multicellular chains or strands into the surrounding matrix.
Collective migration of this kind is initiated either by the polarization of a single cell within the cluster or by the activation of fibroblasts from the tumor stroma These leading cells initiate the formation of a migration track by both cleaving and remodeling the surrounding matrix.
The cooperative proteolytic activity of leading cells and their followers ultimately results in the generation of large invasive paths into the stroma Our mechanistic understanding of collective invasion in cancer is currently undergoing rapid progress thanks to the development of intravital microscopy This technique enables the continuous monitoring of the dynamics of tumor tissue implanted in animal models.
Typically, the implanted cells are fluorescently labeled with indicators of promoter activity, enzyme activity, or gene expression. Intravital microscopy has demonstrated the coexistence of single and collective cell invasion in a variety of organotypic cancer models. Cells forming such invasive sheets or strands display heterogeneous phenotypes. While innermost cells in the clusters retain epithelial polarity and cell junctions, marginal cells display mesenchymal traits such as loss of apical-basalolateral polarity, actin-rich protrusions, and proteolytic activity 83 , Recent studies using an organotypic model of breast mammary tumor metastasis showed that single-cell migration following dissemination from a primary tumor is relatively fast and capable of creating lung metastases via blood vessel circulation By contrast, collective cell invasion is much slower and mainly invades lymph vessels.
To move as cohesive groups, cells require both cell-matrix and cell-cell adhesions. In this section, we will thus focus on the four major types of cell-cell adhesions: Scheme depicting the key molecules that mediate cell-cell adhesion during collective cell migration.
Adherens junctions are responsible for a wide range of cellular functions including assembly and maintenance of cell-cell adhesions, stabilization of the actin cytoskeleton, and transcriptional regulation 34 , Adherens junctions are based on the generally homophilic interaction between transmembrane glycoproteins of the calcium-dependent cadherin family.
Currently more than members of this family have been described in about 30 species, with epithelial E- cadherin being the best characterized , The extracellular domain of classical cadherins is composed of five domain repeats EC1-EC5 , which bind calcium ions to form parallel homodimers Transpairing of the EC1 domains between cadherins from adjacent cells is required for proper conformational organization of adherens junctions , but other EC domains are likely to mediate cell-cell adhesion as well The cytoplasmic domain of cadherins is formed by two subdomains that mediate junctional stabilization and binding to the actin cytoskeleton The subdomain that lies closer to the cell membrane is termed juxtamembrane domain JMD.
This domain contains a highly conserved octopeptide sequence that binds pcatenin The binding of pcatenin and JMD is thought to retain cadherins at the plasma membrane thus providing stronger adhesion to the junction , In addition to stabilizing and strengthening junctions, pcatenin also regulates single and collective cell motility via small GTPases This finding raises the question of how adherens junctions are linked to the cytoskeleton.
Cohesiveness is usually associated with reduced migration speed. For this reason, whenever rapid migration occurs in nature, cells tend to downregulate E-cadherin and dissociate through a complete EMT. However, in many physiological situations, cells undergo an incomplete EMT in which E-cadherin adhesion is weakened to enable dynamic flexibility for each individual cell within the group while keeping a certain degree of cohesiveness.
This weakening of adherens junctions is regulated by several signaling networks including those triggered by tyrosine kinases such as hepatocyte growth factor HGF receptor , epidermal growth factor receptor EGFR , Eph receptor, Src, and Abl These and other kinases regulate adherens junction strength by cadherin endocytosis, proteolysis, or interaction with other transmembrane proteins 43 , 80 , , Tight junctions are located apically from adherens junctions both in static monolayers and in migrating epithelia , They are thought to play a double role: Tight junctions comprise three main types of transmembrane proteins: Occludin is a tetra-spanning-transmembrane protein with two extracellular loops that can be phosphorylated at multiple tyrosine, serine, and theonine residues 81 , , In the absence of phosphorylation, ocludins are localized throughout the basolateral cell membrane and in cytoplasmic vesicles, but phosphorylated occludins are only present at tight junctions Recently, a new protein with a similar structure and role as occludin, tricellulin was found to be enriched only at tricellular tight junctions Despite their ubiquitous presence in tight junctions, a number of studies demonstrated that cells and tissues deficient for occludin display proper barrier function This observation led to the identification of claudins Much like occludins, claudins are also tetra-span-transmembrane proteins with two extracellular loops.
The claudin family comprises at least 24 members that are specifically distributed across organs and tissues This distribution selectively tunes the size, strength, and transport specificity of the junctions In addition to tetra-span proteins, tight junctions also contain single spanning transmembrane proteins that mediate homotypic adhesion.
These proteins include the IgG-like JAMs , which mediate paracellular transmigration of leucocytes Given that occludins, claudins, and JAMs have not been found to interact directly, it is thought that the integrity of tight junctions is mediated by scaffolding proteins such as ZO-1, ZO-2, and ZO-3 These proteins interact with claudins and occludins though their PDZ domains, and with actin through their C-terminus thus providing a direct connection between the extracellular environment and the cytoskeleton.
Tight junctions are thought to play a central role in finely tuning apical-basolateral polarity within moving groups but mechanism remains poorly understood A wealth of evidence supports that preservation of intact tight junctions prevents tumor dissemination by inhibiting cell proliferation and migration However, several studies have demonstrated the existence of epithelial polarity among invasive tumors suggesting that tight junctions remain functional during certain modes of invasion Tight junction proteins have also been reported to contribute to enhanced invasion and collective cell migration.
For example, ZO-1 was found to be upregulated in a high proportion of highly metastatic melanoma cell lines Similarly, overexpression of claudin-3 and claudin-4 in human ovarian epithelial cells resulted in increased collective migration in wound healing experiments 5.
Tight junctions also play a central role during collective cell migration in various developmental processes. In Drosophila , mutations in the ZO-1 homologues result in defects in tracheal morphogenesis and in the formation of extrasensory organs , In zebrafish, the posterior LLP elicits a homogeneous distribution of cadherin among all cell-cell junctions, but ZO-1 is absent in the first few rows behind the leading edge However, toward the trailing edge of the migrating primordium, the emergent proneuromast rosettes display an apical formation of tight junctions before being deposited.
These findings indicate that within a cohesive moving group tight junctions can be selectively formed to control apical-basolateral polarity Desmosomes are intercellular junctions that connect the intermediate filaments from adjacent cells 89 , They are commonly found in tissues that are subjected to substantial mechanical forces such as the epithelia and muscle.
Extracellularly, desmosomes are similar to adherens junctions in that extracellular linkers are transmembrane proteins with five domain repeats homologous to classical cadherins. A functional desmosome contains at least one desmosomal cadherin from the desmocollin family and another one from the desmoglein family. The cytoplasmic domains of desmosomal cadherins interact with the armadillo proteins, plakoglobin gamma-catenin , and plakophilins.
Plakoglobin binds to the N-terminal of desmoplakin, the protein that ultimately binds desmosomes to intermediate filaments. The role of plakophilin is more complex than that of plakoglobins as it involves interactions with desmosomal cadherins, plakoglobins, and intermediate filaments.
These complex cytoplasmic interactions constitute the molecular clustering that provides strength to desmosomes. Several lines of evidence indicate that desmosomal adhesion is regulated during collective cell migration.
The resulting loss of adhesion provides the epithelium with the flexibility required to achieve fast reepithelialization. It remains unclear, however, if the loss of desmosomal adhesion is complete or partial.
In colorectal tumors, two types of desmocollins Dsc1 and Dsc 2 are expressed de novo , suggesting collective cell invasion In squamous cell carcinomas of the skin, desmoglein 2 is upregulated and the levels of desmoglein activation correlate with risk of metastasis. These findings indicate that desmosomes might remain functional during tumor invasion in some forms of cancer Gap junctions are transmembrane channels that connect the cytoplasm of adjacent cells.
Each cell contributes to the junction with half a channel an hemichannel or connexon formed by six proteins, termed connexins. Each connexin comprises four transmembrane domains connected by two extracellular loops that mediate cell-cell recognition and intercellular docking.
Connexins are arranged in a cylindrical patterns that leave a hollow central channel for transit of ions, second messengers, and small metabolites with molecular weights lower than 1 kDa As central mediators for cell-cell communication, gap junctions have long been implicated in the regulation of collective cell migration during cancer metastasis, wound healing, and morphogenesis.
Tumor cells from several human cancers such as skin, lung, gastric, and prostate cancers, exhibit reduced expression of gap junction proteins and reexpression of these proteins appears to play a tumorsuppressive role 63 , For example, overexpression of Cx26 has been shown to slow down collective migration of the breast cancer cell line MCF-7 and to reverse its malignant phenotype Contrary to this widespread notion, recent evidence demonstrates that during certain stages of metastasis Cx26 is reexpressed suggesting cell cooperativity during invasion 37 , These findings indicate that gap junctions might selectively regulate the transition from single- to collective cell migration during different stages of cancer progression.
Further support for gap junction activity during collective cell migration comes from wound-healing experiments. During epidermal wound healing, the expression of connexins is altered as a function of the distance from the wound Specifically, Cx26 was found to be downregulated at the wound edge, but upregulated away from the wound.
In an in vitro wound-scratch assay using MCFA cells, knocking down Cx43 accelerated collective cell migration, whereas silencing Cx26 and Cx40 had no net effect Perhaps the clearest illustration of the pivotal role of gap junctions in regulating collective cell migration can be found in development, where mutations or silencing of genes associated with gap junctions result in abnormal migration.
For example, mutations of innexin, the connexin homolog expressed in invertebrates, prevent collective epithelial cell migration during proventriculus organogenesis in Drosophila In mouse models, the levels of expression of Cx43 correlate positively with speed and directionality of neural crest migration Taken together, the studies mentioned previously support the notion that gap junctions play a central role in the regulation of collective cell migration, but the molecular mechanisms underlying this regulation and the interaction between gap junctions and other cell-cell junctions remain largely unknown.
One of the great advantages of collective versus single-cell migration is that each cell within the moving group can exhibit different patterns of expression to carry out specialized functions according to its position within the group. Polarization of this kind can arise as a consequence of internal genetic programs or external environmental cues.
Leader cells typically exhibit a mesenchymal-like phenotype characterized by the extension of lamellipodia and filopodia into the surrounding tissue, a relatively loose cell-cell adhesion, enhanced expression of cell-matrix adhesion proteins, and polarized remodeling of actin filaments and MTs 65 , In addition, leader cells moving in 3D are capable of degrading and remodeling the ECM to create channels for the whole cell group to advance cohesively 84 , By contrast, followers retain epithelial features such as apical-basolateral polarity and tight junctions and express relatively low levels of guidance receptors.
Tip leader cells extend numerous filopodia that probe, guide, and presumably generate tractions to drive motion of the tubes to the avascular area of the embryo In contrast to their follower stalk cells, tip cells are nonlumenized and mostly nonproliferative. In addition, they exhibit a clearly distinct pattern of gene expression with higher levels of expression of VEGF receptor family, which tightly controls the generation of sprouts during angiogenesis A central question in angiogenesis is how the tip cell is initially selected from a large pool of endothelial cells exposed to similar VEGF gradients.
In other words, why do endothelial cells form sprouts and branches instead of sheets? The answer to these questions lies in the competitive advantage that tip cells gain by signaling their neighbors to become stalk cells. This is accomplished via the Notch signaling pathway. The resulting activation of Notch in the neighboring cells leads to downregulation of VEGFR2 and ultimately the acquisition of stalk phenotype.
Another example of collective cell migration guided by a chemoattractant gradient is border cell migration. In these cells, chemoattractant gradients are sensed by two receptors, EGFR and poliovirus receptor PVR , each of which can independently guide cell migration 58 , During the early phase of border cell migration, these receptors act at the sub-cellular level to drive polarization and guide migration much as in the case of single isolated cells.
Each cell individually senses the gradient and acts accordingly resulting in highly persistent directional migration of the cluster. In a later phase, the very same receptors and chemoattractant cues appear to act at a higher level of organization in which the intercellular differences in the levels of signaling from the guidance receptors cells determines the identity of the front cell In this case, cells within the cluster compete to guide the group thus constantly exchanging positions throughout the collective process.
This guidance strategy results in slower overall motion, but it offers a broader range of possibilities to probe the cluster environment To migrate from the anterior to the posterior regions of the embryo, the posterior LLP follows a track defined by a strip of the chemokine stromal-derived factor, SDF1a Although the precise values of the concentration of SDF1a along the strip remain unknown, it appears that SDF1a is uniformly distributed.
This notion is supported by the observation that the primordium is able to perform a U-turn and migrate backward In addition, recent evidence suggests that sequestration of SDF1a by CXCR7 might be a crucial event to determine the persistence of primordium migration The zebrafish LLP is also a representative model to illustrate that some cell collectives are able to achieve supracellular tissue patterning as they migrate.
Roughly behind the leading third of the primordium, a group of 12 to 16 cells organizes in rosettes to form the proneuromasts Fig. Cells within these rosettes display a marked epithelial phenotype characterized by columnar morphology, apical-basolateral polarization, and the presence of foci of the tight junction protein ZO1 After their formation, rosettes become progressively less motile until they are left behind and deposited at periodic length intervals.
The kinematics of collective cell migration has been the subject of experimental and theoretical investigation virtually since light microscopy was first applied to the observation of biological processes. Indeed, the first observations of tumor dissemination, growth of epithelial tissues, and wound closure date back more than one century , The advent of modern imaging techniques such as confocal microscopy, multiphoton microscopy, and intravital imaging, together with the development of improved fluorescent probes and computational methods now enable us to quantitatively analyze the kinematics of collective cell migration in vivo Outstanding advances in this field include visualization of cancer cells within a collective cluster as they escape a tumor to invade lymphatic vessels 96 , or tracking of hundreds of individual cells involved in mesoderm migration during development of the Drosophila embryo The study of cell kinematics combined with a variety of continuum and discrete physical models has provided substantial advances in our understanding of how cells move collectively.
Typical continuum models are governed by reaction-diffusion equations 40 , The first term on the right hand side of Eq 1 accounts for random cell migration and the second term models chemotaxis or haptotaxis. Conversely, the first term on the right hand side of Eq. This system of reaction diffusion equations can be generalized to any number of cell types and tactic agents present in the system under investigation.
Further coupling between equations can be obtained by taking the diffusion coefficient as a function of cell concentration 29 , 46 , Continuum models are limited by their relative inability to take into account dynamics of cell adhesion as well as local variability of the cell mechanical properties. These factors are introduced in the so-called vertex models or cellular Potts models, in which cell geometry is discretized and different mechanical and adhesive properties can be associated with each constitutive element of the system 98 , In these models, the cell collective explores an energy landscape determined by a 3-term Hamiltonian H:.
For a given Hamiltonian, the dynamics of the system are obtained by energy minimization using Monte-Carlo strategies. Each element in the system is sampled in a random manner and given a new configuration. If this new configuration decreases the energy of the system the change is always accepted, otherwise it accepted with a given probability.
This approach can be coupled to continuum reaction-diffusion equations to take into account the dynamics of diffusive chemicals associated with chemotaxis The modeling approaches described previously have been successful in reproducing the kinematics of collective cell migration in a variety of biological processes including tumor angiogenesis, wound healing, and cell sorting 40 , , , But even if the kinetics is captured, the underlying mechanisms remain far from being elucidated.
Consider, for example, the relatively simple case of 2D wound-scratch assays. The kinematics of this process has been captured by continuum and discrete models in which the key ingredient is the establishment of a chemotactic gradient , However, other models based on purely mechanical principles in which chemotaxis has been deliberately ignored, have also been able to reproduce experimental data in great detail 20 , Thus, models of collective cell migration need to formulate further experimentally testable predictions to elucidate the relative contribution of both the biochemical and the biophysical mechanisms that drive collective cell migration.
Our relatively poor understanding of the mechanisms underlying collective cell migration is not so much due to the lack of suitable physical models as it is due to the lack of key experimental information.
Perhaps the most important piece of experimental information we are lacking is a physical picture of the forces that drive collective cell migration.
Without this information, it is not possible to determine whether collective cell motion is a local process in which each cell is mechanically self-propelled or an integrated process in which physical forces are transmitted across long distances to coordinate the action of each individual cell within a moving group. The technique that has provided most information about the dynamics of living tissues in vivo is laser microsurgery.
This technique is based on the selective ablation of single cells within tissues. The analysis of the resulting tissue relaxation enables the inference of the actual state of stress of the tissue By applying this technique to dorsal closure in Drosophila embryos, Kiehart et al.
In a later study, Hutson et al. Other findings obtained by laser ablation include the measurement of contractile forces associated with cell apoptosis , and the guidance of tissue morphogenesis by anisotropic forces While laser ablation methods enable the inference of the state of stress of tissues as well as their dynamic relaxation, they do not provide maps of the forces associated with cell migration.
The first such maps were obtained by the joint of effort of the groups of B. The authors seeded epithelial cell colonies on top of a micropillar array and observed the time evolution of the forces exerted by the cells on the pillars. They showed that forces at the leading edge are tensile, thus ruling out that the epithelial tissue advances as a result of pushing forces from submarginal cells Fig.
In addition, the authors remarked that submarginal cells are also able to generate traction forces of substantial magnitude, which is consistent with the observation by Farooqui and Fenteany that submarginal cells extend cryptic lamellipodia under their neighbors at the margin A later study by Trepat et al. The existence of such stress gradients combined with mechanotransduction events at cell-cell junctions might provide novel mechanisms of positional sensing within moving groups. Mechanics of collective cell migration.
A The forces exerted by the leading edge of an MDCK epithelial cell sheet migrating on top of a microneedle array are tensile. Adapted, with permission, from reference B, C, D Patterns of force generation and transmission in an epithelial cell sheet. B An active leader cell generates forces at the leading edge and transmits these forces to follower cells via cell-cell junctions.
C Each cell within the monolayer generates its own contractile forces. Forces are balanced locally in such a way that there is no force transmission through cell-cell junctions. D Tug-of-war force generation and transmission. The local tractions that each cell generates are transmitted through cell-cell junctions to generate a global gradient of tensile stress.
Recently, force microscopy technology was improved to enable the measurement of inter- and intracellular forces , , Using this technology the authors showed that intracellular stresses vary abruptly across a migrating monolayer sheet, and that force transmission through cell-cell junctions expands several cell diameters. In addition, the authors showed in a variety of cell types that cell collectives move along the direction of maximum normal stress—or, equivalently, minimum shear stress.
Undoubtedly, the field of cell migration will produce exciting science over the next decade, at the least. Advances in optical techniques to image tissues deep within the organism, combined with expression of FP fusions to key proteins will enable us to perform detailed, real-time studies of the migration of cells in their native physiological environment.
Super-resolution microscopy will reveal the 3D molecular architecture of elements of the migratory cell. Biosensors will produce high-resolution spatial and temporal maps of the molecular activities that underlie cell migration. Photomanipulation of proteins involved in cell motility by either photactivation or chromophore assisted laser inactivation of selected proteins will illuminate their precise roles in migration.
Structural biology and biophysical tools will identify the structure and mechanics of individual molecules important to cell movement. Multicenter efforts in genomics and proteomics will provide a comprehensive census of migration related proteins, their binding partners, their phosphorylation sites, and their posttranslation modifications in diverse tissues and pathological conditions.
This effort will be paralleled by the development of genetically engineered animals, from invertebrates to mammals, to study the functional role of each of these proteins. High throughput screening of chemical libraries will help identify novel compounds that may impair the progression of migration-related diseases such as cancer or chronic inflammation.
Multidisciplinary approaches will unravel how the chemical composition and the physical architecture of the ECM regulates the migratory machinery and how this machinery in turn impacts the matrix on which and through which cells migrate. Each of the tasks highlighted previously is a formidable challenge on its own but perhaps the most daunting goal ahead lies in integrating all of this forthcoming information. The amount high quality data relevant to cell migration will increase by orders of magnitude in the next decade but a proper conceptual framework that integrates this information into comprehensive models with predictive power remains unknown.
While this limitation is a general problem in all biology, it is particularly fundamental in the field of cell migration in which any integrative picture must include not only comprehensive networks that are purely chemical in nature, but also the interaction of such networks with physical forces.
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Abstract Cell migration is fundamental to establishing and maintaining the proper organization of multicellular organisms. Single-Cell Migration In this section, some representative migrating cells will be introduced citing appropriate reviews, as there is by now a vast literature on cell migration.
Types of cell migration and related phenomena Fibroblasts In vivo , fibroblasts are typically found in connective tissue where they synthesize collagens, glycosaminoglycans, and other important glycoproteins of the extracellular matrix ECM including fibronectin, for example. Open in a separate window. Keratocytes At the other end of the spectrum of cell locomotion, fish or amphibian keratocytes migrate in rapid, highly persistent mode in which protrusion, contraction, and retraction are smoothly coordinated so that the cell maintains a nearly constant shape.
Lamellipodium structure Keratocytes have a large fan-like lamellipodium Fig. Cytoskeletal dynamics and migration Considerable work has been devoted to the cytoskeletal mechanisms involved in keratocyte migration 73 , , Shape and migration Recently, the shape and movement of keratocytes has been described in detail following an initial description by Lee et al.
Leukocytes Leukocytes, or white blood cells WBCs , are cells of the immune system defending the body against infecting organisms and foreign materials. Single-cell migration in three dimensions Although cell migration has been studied extensively in essentially 2D cell culture conditions where cells grow on a substrate, increasing attention has been paid to the movement of cells in 3D environments.
Cell morphology and migration in 3D environments Most migration modes previously observed in 2D environments also occur in 3D tissue environments. Regulation of cell migration in 3D matrices Three important factors regulate 3D cell migration: Adhesions in migrating cells Cells adhere to ECM or other cells by both nonspecific electrostatic interactions and specific binding of cell adhesion molecules such as selectins, integrins, and cadherins to ECM ligands and to cadherins on other cells. Focal adhesion dynamics FAs are dynamic structures that undergo cycles of assembly and disassembly; indeed, regulated FA turnover is integral to cell migration.
Focal adhesion assembly The role of integrin activation in FA assembly and in initiating downstream signaling has been extensively investigated. Focal adhesion disassembly Compared with extensive studies on FA formation, the disassembly process is not as clear.
Podosomes Podosomes are specialized integrin-mediated adhesions often found in highly migratory monocytic cells that mediate the inflammatory response 25 , Outlook In addition to the extensive cataloging of adhesion components, there are recent developments in super-resolution microscopy and several live cell fluorescence microscopy methods that promise to enhance our understanding of structure-function relationships in the adhesive structures that enable the cell to exert traction on its environment 39 , 88 , Measurements of tractions in single migrating cells Elastic substrate traction measurements The effects of tractions exerted by migrating chick heart fibroblasts plated on a deformable silicone substrate a thin film of silicone cross linked by means of glow discharge were visualized as visible wrinkles in the film under the cell body and perpendicular to the direction of cell movement Force, cell adhesions, and cell migration There is a clear interplay between contractile force generated by the cell, adhesion to the substrate and the traction applied to the substrate that is beginning to be investigated in detail.
Collective Cell Migration Collective cell migration is the prevalent mode of migration during development, wound healing, and tissue regeneration 19 , 68 , 75 , , Collective cell migration in physiology and pathophysiology The EMT paradigm The transition from a static to a motile phenotype that multicellular collectives undergo during embryogenic movements, cancer metastasis, and wound repair is traditionally understood under the rubric of the epithelial to mesenchymal transition EMT.
Development From early embryogenesis to postnatal life, the development of living organisms is driven by the motion of cell collectives Wound repair The molecular machinery that governs collective cell migration during development remains largely dormant throughout adult life.
Cancer While collective cell migration is crucial in development and tissue repair, it also mediates devastating diseases such as cancer 45 , 75 , Mechanisms of collective cell migration Adhesion To move as cohesive groups, cells require both cell-matrix and cell-cell adhesions.
Adherens junctions Adherens junctions are responsible for a wide range of cellular functions including assembly and maintenance of cell-cell adhesions, stabilization of the actin cytoskeleton, and transcriptional regulation 34 , Tight junctions Tight junctions are located apically from adherens junctions both in static monolayers and in migrating epithelia , Desmosomes Desmosomes are intercellular junctions that connect the intermediate filaments from adjacent cells 89 , Gap junctions Gap junctions are transmembrane channels that connect the cytoplasm of adjacent cells.
Polarization and guidance One of the great advantages of collective versus single-cell migration is that each cell within the moving group can exhibit different patterns of expression to carry out specialized functions according to its position within the group. Mechanics of collective cell migration Kinematic observations and models The kinematics of collective cell migration has been the subject of experimental and theoretical investigation virtually since light microscopy was first applied to the observation of biological processes.
Dynamics Our relatively poor understanding of the mechanisms underlying collective cell migration is not so much due to the lack of suitable physical models as it is due to the lack of key experimental information. Outlook Undoubtedly, the field of cell migration will produce exciting science over the next decade, at the least.
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Cell migration is fundamental to establishing and maintaining the proper organization of multicellular organisms. Morphogenesis can be viewed as a. Having a fever helps T cells reach the site of infection, thanks to thermal sensing by heat shock proteins and induction of integrin-mediated T cell migration. Cell migration is an integrated multistep process that involves the coordination of complex biochemical and biomechanical signals to modulate cell morphology.