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Cell migration
Cell migration
Cell migration
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Cell migration is a central process in the development and maintenance of multicellular organisms. 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.[1] Errors during this process have serious consequences, including intellectual disability, vascular disease, tumor formation and metastasis.[2][3] 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 continuously 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.[4][5] A paradigmatic example of crawling motion is the case of fish epidermal keratocytes, which have been extensively used in research and teaching.[6]

Cell migration studies

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The migration of cultured cells attached to a surface or in 3D is commonly studied using microscopy.[7][8][5] As cell movement is very slow, a few μm/minute, time-lapse microscopy videos are recorded of the migrating cells to speed up the movement. 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.

Common features

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The processes underlying mammalian cell migration are believed to be consistent with those of (non-spermatozooic) locomotion.[9] Observations in common include:

  • cytoplasmic displacement at leading edge (front)
  • laminar removal of dorsally-accumulated debris toward trailing edge (back)

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.[10]

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.[11]

Two different models for how cells move. A) Cytoskeletal model. B) Membrane Flow Model
(A) Dynamic microtubules are necessary for tail retraction and are distributed at the rear end in a migrating cell. Green, highly dynamic microtubules; yellow, moderately dynamic microtubules and red, stable microtubules. (B) Stable microtubules act as struts and prevent tail retraction and thereby inhibit cell migration.

Molecular processes of migration

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There are two main theories for how the cell advances its front edge: the cytoskeletal model and membrane flow model. It is possible that both underlying processes contribute to cell extension.

Cytoskeletal model (A)

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Leading edge

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Experimentation has shown that there is rapid actin polymerisation at the cell's front edge.[12] This observation has led to the hypothesis that formation of actin filaments "push" the leading edge forward and is the main motile force for advancing the cell's front edge.[13][14] In addition, cytoskeletal elements are able to interact extensively and intimately with a cell's plasma membrane.[15]

Trailing edge

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Other cytoskeletal components (like microtubules) have important functions in cell migration. It has been found that microtubules act as "struts" that counteract the contractile forces that are needed for trailing edge retraction during cell movement. 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.[16] The morphology of cells with suppressed microtubule dynamics indicate that cells can extend the front edge (polarized in the direction of movement), but have difficulty retracting their trailing edge.[17] On the other hand, high drug concentrations, or microtubule mutations that depolymerize the microtubules, can restore cell migration but there is a loss of directionality. It can be concluded that microtubules act both to restrain cell movement and to establish directionality.

Membrane flow model (B)

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The leading edge at the front of a migrating cell is also the site at which membrane from internal membrane pools is returned to the cell surface at the end of the endocytic cycle.[18][19] This suggests that extension of the leading edge occurs primarily by addition of membrane at the front of the cell. If so, the actin filaments that form there might stabilize the added membrane so that a structured extension, or lamella, is formed — rather than a bubble-like structure (or bleb) at its front.[20] For a cell to move, it is necessary to bring a fresh supply of "feet" (proteins called integrins, which attach a cell to the surface on which it is crawling) to the front. It is likely that these feet are endocytosed [21] toward the rear of the cell and brought to the cell's front by exocytosis, to be reused to form new attachments to the substrate.

In the case of Dictyostelium amoebae, three conditional temperature sensitive mutants which affect membrane recycling block cell migration at the restrictive (higher) temperature;[22][23][24] they provide additional support for the importance of the endocytic cycle in cell migration. Furthermore, these amoebae move quite quickly — about one cell length in ~5 mins. If they are regarded as cylindrical (which is roughly true whilst chemotaxing), this would require them to recycle the equivalent of one cell surface area each 5 mins, which is approximately what is measured.[25]

Rearward membrane flow (red arrows) and vesicle trafficking from back to front (blue arrows) drive adhesion-independent migration.[26]

Mechanistic basis of amoeboid migration

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Adhesive crawling is not the only migration mode exhibited by eukaryotic cells. Importantly, several cell types — Dictyostelium amoebae, neutrophils, metastatic cancer cells and macrophages — have been found to be capable of adhesion-independent migration. Historically, the physicist E. M. Purcell theorized (in 1977) that under conditions of low Reynolds number fluid dynamics, which apply at the cellular scale, rearward surface flow could provide a mechanism for microscopic objects to swim forward.[27] After some decades, experimental support for this model of cell movement was provided when it was discovered (in 2010) that amoeboid cells and neutrophils are both able to chemotax towards a chemo-attractant source whilst suspended in an isodense medium.[28] It was subsequently shown, using optogenetics, that cells migrating in an amoeboid fashion without adhesions exhibit plasma membrane flow towards the cell rear that may propel cells by exerting tangential forces on the surrounding fluid.[26][29] Polarized trafficking of membrane-containing vesicles from the rear to the front of the cell helps maintain cell size.[26] Rearward membrane flow was also observed in Dictyostelium discoideum cells.[30] These observations provide strong support for models of cell movement which depend on a rearward cell surface membrane flow (Model B, above). The migration of supracellular clusters has also been found to be supported by a similar mechanism of rearward surface flow.[31]

Schematic representation of the collective biomechanical and molecular mechanism of cell motion [32]

Collective biomechanical and molecular mechanism of cell motion

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Based on some mathematical models, recent studies hypothesize a novel biological model for collective biomechanical and molecular mechanism of cell motion.[32] It is proposed that microdomains weave the texture of cytoskeleton and their interactions mark the location for formation of new adhesion sites. According to this model, microdomain signaling dynamics organizes cytoskeleton and its interaction with substratum. As microdomains trigger and maintain active polymerization of actin filaments, their propagation and zigzagging motion on the membrane generate a highly interlinked network of curved or linear filaments oriented at a wide spectrum of angles to the cell boundary. It is also proposed that microdomain interaction marks the formation of new focal adhesion sites at the cell periphery. Myosin interaction with the actin network then generate membrane retraction/ruffling, retrograde flow, and contractile forces for forward motion. Finally, continuous application of stress on the old focal adhesion sites could result in the calcium-induced calpain activation, and consequently the detachment of focal adhesions which completes the cycle.

Polarity in migrating cells

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Migrating cells have a polarity—a front and a back. Without it, they would move in all directions at once, i.e. spread. How this polarity is formulated at a molecular level inside a cell is unknown. In a cell that is meandering in a random way, the front can easily give way to become passive as some other region, or regions, of the cell form(s) a new front. In chemotaxing cells, the stability of the front appears enhanced as the cell advances toward a higher concentration of the stimulating chemical. From biophysical perspective, polarity was explained in terms of a gradient in inner membrane surface charge between front regions and rear edges of the cell.[33] This polarity is reflected at a molecular level by a restriction of certain molecules to particular regions of the inner cell surface. Thus, the phospholipid PIP3 and activated Ras, Rac, and CDC42 are found at the front of the cell, whereas Rho GTPase and PTEN are found toward the rear.[34][35][36][37]

It is believed that filamentous actins and microtubules are important for establishing and maintaining a cell's polarity.[38] Drugs that destroy actin filaments have multiple and complex effects, reflecting the wide role that these filaments play in many cell processes. It may be that, as part of the locomotory process, membrane vesicles are transported along these filaments to the cell's front. In chemotaxing cells, the increased persistence of migration toward the target may result from an increased stability of the arrangement of the filamentous structures inside the cell and determine its polarity. In turn, these filamentous structures may be arranged inside the cell according to how molecules like PIP3 and PTEN are arranged on the inner cell membrane. And where these are located appears in turn to be determined by the chemoattractant signals as these impinge on specific receptors on the cell's outer surface.

Although microtubules have been known to influence cell migration for many years, the mechanism by which they do so has remained controversial. On a planar surface, microtubules are not needed for the movement, but they are required to provide directionality to cell movement and efficient protrusion of the leading edge.[17][39] When present, microtubules retard cell movement when their dynamics are suppressed by drug treatment or by tubulin mutations.[17]

Inverse problems in the context of cell motility

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An area of research called inverse problems in cell motility has been established. [40][41][32] This approach is based on the idea that behavioral or shape changes of a cell bear information about the underlying mechanisms that generate these changes. Reading cell motion, namely, understanding the underlying biophysical and mechanochemical processes, is of paramount importance.[42] The mathematical models developed in these works determine some physical features and material properties of the cells locally through analysis of live cell image sequences and uses this information to make further inferences about the molecular structures, dynamics, and processes within the cells, such as the actin network, microdomains, chemotaxis, adhesion, and retrograde flow.

Cell migration disruption in pathological conditions

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Cell migration could be affected in some pathological states. For example, in conditions of high lipoperoxidation, actin has been shown to be post-translationally modified by the lipoperoxidation product 4-hydroxynonenal (4-HNE).[43] This modification prevents the remodelling of the actin cytoskeleton, which is essential for cell motility. Additionally, another functional protein, coronin-1A, which stabilizes F-actin filaments, is also covalently modified by 4-HNE. These modifications may impair immune cell trans-endothelial migration or their phagocytic ability.[43] Another motility-related mechanism was described: the failure of MCP-1 receptor (CCR2, CD192), TNF receptor 1 (TNFR1, CD120a), and TNF receptor 2 (TNFR2, CD120b) on the monocytes after exposure to pathophysiological concentrations (10 μM) of 4-HNE or after the phagocytosis of malarial pigment hemozoin.[44] These immune cellular dysfunctions potentially lead to a decreased immune response in diseases characterized by high oxidative stress, such as malaria, cancer, metabolic syndrome, atherosclerosis, Alzheimer's disease, rheumatoid arthritis, neurodegenerative diseases, and preeclampsia.[45]

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cell migration

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Cell migration is the directed movement of cells from one location to another, a fundamental essential for establishing and maintaining the organization of multicellular organisms, including roles in , immune responses, , and tissue . It occurs through various modes, such as mesenchymal migration, which relies on strong adhesions to the (ECM) and actin-driven protrusions like lamellipodia and , and amoeboid migration, characterized by weak adhesions, rapid deformation, and high-speed movement (up to 10–15 μm/min in keratocytes). Collective migration, in contrast, involves coordinated groups of cells moving together while preserving cell-cell contacts via adhesions like cadherins, often featuring leader cells that guide followers through signaling and mechanical cues. The process is tightly regulated by intracellular mechanisms, including cytoskeletal dynamics (e.g., polymerization for protrusion and contraction for force generation), integrin-mediated adhesions to the ECM, and responses to environmental signals like chemoattractants, substrate stiffness, and confinement. Key steps encompass cell polarization to establish front-rear asymmetry, protrusion extension, traction force application, and rear retraction, enabling adaptation to diverse microenvironments such as 2D surfaces or 3D matrices. In physiological contexts, it drives embryonic development (e.g., cell dispersal), immune surveillance (e.g., leukocyte recruitment to infection sites), and tissue regeneration (e.g., epidermal sheet migration in closure). Aberrant cell migration underlies numerous pathologies, particularly cancer, where dysregulated facilitates tumor invasion and , as seen in collective invasion by breast or cells adapting mesenchymal or amoeboid strategies. Research models, from assays like Boyden chambers to in vivo systems such as embryos, have elucidated these dynamics, highlighting therapeutic potential in targeting migration pathways for disease intervention.

Overview

Definition and basic principles

Cell migration is defined as the directed movement of individual cells or groups of cells through tissues or along substrates, a process essential for multicellular organization. This motility is primarily powered by actin-myosin contractility, where actin polymerization generates protrusive forces at the cell front, and myosin-mediated contraction enables rear retraction, all modulated by environmental cues such as chemical or mechanical signals. The plasma membrane plays a critical role as the interface for sensing these cues, facilitating membrane turnover and lipid flow that support protrusion formation and overall cell dynamics during migration. At its core, cell migration operates on several basic principles that dictate how cells respond to their surroundings. involves the directional movement of cells up or down chemical gradients, allowing navigation toward attractants like nutrients or signaling molecules. Haptotaxis refers to migration guided by gradients in substrate adhesiveness, where cells preferentially move toward regions of higher ligand via integrin-mediated interactions. Durotaxis describes the response to mechanical stiffness gradients in the , with cells typically migrating toward stiffer areas through mechanosensitive cytoskeletal adjustments. In contrast, random migration represents undirected motility, where cells explore their environment without specific guidance, often exhibiting persistent but stochastic paths. Key cellular components underpin these processes as prerequisites for effective migration. The , comprising filaments and , provides the structural framework: drives protrusion and contractility, while stabilize polarity and transport organelles to the . , as transmembrane receptors, link the to the , enabling traction generation and essential for adhesion dynamics. Historically, observations of cell migration trace back to the mid-19th century, with describing motile cells isolated from lymph fluid and cartilage tissue in 1863, highlighting leukocyte movement in pathological contexts. A pivotal advancement occurred in 1942, when Brúnó F. Straub discovered as a key protein in muscle extracts, later recognized for its central role in contractile across cell types.

Biological significance

Cell migration plays a pivotal role in embryonic development, enabling the reorganization of tissues and formation of complex structures. During gastrulation, cells undergo coordinated migrations to form the three primary germ layers—ectoderm, mesoderm, and endoderm—which lay the foundation for organogenesis. Neural crest cells, a transient multipotent population, delaminate from the neural tube and migrate extensively to contribute to diverse derivatives including peripheral neurons, craniofacial skeleton, and melanocytes. In angiogenesis, endothelial cells migrate directionally to form new vascular networks essential for oxygen and nutrient delivery during embryogenesis. These processes highlight how cell migration drives morphogenetic movements critical for establishing the body plan. In immune function, cell migration facilitates rapid responses to pathogens by directing leukocytes to infection sites. Neutrophils and other leukocytes extravasate from blood vessels through diapedesis, a process involving adhesion to and transmigration across the , allowing them to infiltrate tissues and initiate inflammatory responses. This recruitment is vital for containing infections and promoting clearance of debris. Cell migration maintains tissue in adult organisms, supporting repair and renewal. In , keratinocytes migrate from the wound edges to re-epithelialize the injury site, while fibroblasts migrate into the provisional matrix to produce components necessary for tissue remodeling. Epithelial renewal, such as in the intestinal mucosa, relies on active migration of epithelial cells from niches toward the tissue surface, ensuring barrier integrity and turnover. The mechanisms of cell migration exhibit remarkable evolutionary conservation, underscoring their fundamental importance across taxa. In the social Dictyostelium discoideum, drives single-celled migration toward nutrients or during multicellular aggregation, sharing signaling pathways like phosphoinositide gradients with vertebrate leukocytes. This conservation extends from unicellular eukaryotes to multicellular animals, reflecting an ancient for directed motility in response to environmental cues.

Types of Cell Migration

Individual migration modes

Individual cell migration encompasses several distinct modes characterized by differences in cell morphology, adhesion to the (ECM), and propulsion mechanisms. These modes allow cells to navigate diverse environments, from fluid-filled spaces to dense tissues, adapting to physical constraints and biochemical cues. The primary modes include amoeboid, mesenchymal, and blebbing migration, each optimized for specific contexts such as immune surveillance or tissue invasion. Amoeboid migration features a rounded cell shape with minimal adhesions to the substrate, relying on high actomyosin contractility to squeeze through 3D matrices without significant ECM degradation. This mode is prevalent in leukocytes, such as neutrophils and dendritic cells, enabling rapid traversal of tissues during immune responses. Actomyosin-driven cortical tension generates intracellular pressure that propels the cell forward, often through weak, transient attachments rather than stable focal adhesions.00008-2) In contrast, mesenchymal migration involves an elongated, fibroblast-like morphology with strong, integrin-mediated s to the ECM, coupled with proteolytic degradation of matrix barriers by matrix metalloproteinases (MMPs). This mode is typical of fibroblasts during and metastatic cancer cells invading stromal tissues, where cells extend lamellipodia or at the to probe and remodel the environment. The process requires coordinated cycles of formation, maturation, and disassembly, making it energy-intensive but effective for persistent directional movement.00206-3) Blebbing migration, often considered a subtype of , is characterized by dynamic protrusions called blebs, formed by localized rupture of the cortex and subsequent inflation via intracellular hydrostatic pressure. These blebs expand rapidly and retract through polymerization at their bases, facilitating in confined or low-adhesion settings, such as within tumor microenvironments or during embryonic development. This mode is observed in various cancer cells and amoeboid leukocytes under spatial constraints, where blebs enable cells to bypass adhesion-dependent mechanisms. Key differences among these modes include migration speed and energy demands: amoeboid and blebbing cells typically achieve velocities of 10–30 μm/min, far exceeding the 0.1–1 μm/min of mesenchymal migration, due to reduced reliance on turnover and matrix remodeling. Amoeboid and blebbing modes demand less for but higher contractility, while mesenchymal migration invests in proteolytic and signaling pathways for sustained traction. Environmental factors, particularly substrate dimensionality, profoundly influence mode selection and switching. On 2D surfaces, cells often default to mesenchymal migration with prominent lamellipodia, but in 3D dense ECM, mesenchymal cells can transition to faster amoeboid or blebbing modes to navigate confinement without , as seen in tumor cells encountering high matrix density. This plasticity enhances invasion efficiency by allowing adaptation to varying mechanical barriers.00008-2)

Collective migration

Collective cell migration refers to the coordinated movement of groups of cells, such as sheets, strands, or clusters, that maintain intercellular connections while advancing as a unit. This process is distinct from individual cell motility, as the behavior of one cell influences its neighbors through physical and chemical interactions, enabling tissue-scale dynamics without complete disruption of cell-cell contacts. Prominent examples include epithelial closure, where collectively migrate to seal gaps in the skin, and neural crest streams, where multipotent cells form elongated chains that delaminate from the and invade surrounding tissues during embryogenesis. Key mechanisms underlying collective migration involve cadherin-mediated adherens junctions, which transmit mechanical forces across cells to synchronize protrusions and retractions. These junctions, primarily E-cadherin in epithelial contexts, couple the cytoskeletons of adjacent cells, allowing traction forces generated at the to propagate rearward and guide follower cells. A hallmark feature is leader-follower dynamics, in which specialized leader cells at the front extend protrusions via and form focal adhesions, while follower cells in the rear adopt a more passive role, relying on intercellular tugs to maintain cohesion and directionality. Classic examples illustrate these principles in vivo. In Drosophila border cell migration, a cluster of 6-10 cells detaches from the follicular epithelium during oogenesis and invades the egg chamber as a cohesive group, guided by chemotactic signals and maintained by cadherin junctions that ensure collective polarity. Similarly, vertebrate epiboly during gastrulation involves the collective spreading of a blastodermal cell sheet over the yolk, driven by radial intercalation and purse-string contractility at the margin, which expands the epithelial layer to envelop the embryo. Biomechanically, collective migration relies on stress propagation through cell-cell contacts, where contractile forces from myosin II at junctions create anisotropic tension fields that align cell orientations and velocities across the group. In stream-like formations, such as chains, velocity gradients emerge with front cells moving faster due to stronger protrusive activity, while rear cells experience drag from adhesions, resulting in a tapered speed profile that sustains stream integrity over distances exceeding 100 cell diameters. Recent post-2020 studies have highlighted the role of YAP/TAZ signaling in collective durotaxis, where groups of mammary gland cells preferentially migrate toward softer substrates by modulating focal adhesion maturation and cytoskeletal dynamics, enabling persistent motility in mechanically heterogeneous environments. This mechanotransductive pathway integrates substrate stiffness gradients with intercellular force transmission, promoting coordinated invasion in breast tissue models.

Molecular and Cellular Mechanisms

Establishment of cell polarity

Cell polarity establishment is a fundamental process in directed cell migration, where cells develop a front-rear asymmetry that defines the direction of movement. This asymmetry arises through the coordinated activation of signaling pathways that localize protrusive and contractile machinery to specific cellular regions, enabling persistent motion toward environmental cues. In migrating cells, such as fibroblasts or leukocytes, polarity is initiated by external stimuli that break the initial symmetry, leading to the recruitment of key regulatory proteins to the and suppression at the rear.00469-4) Central to this process are Rho family GTPases, which establish asymmetric signaling gradients. Cdc42 activates at the front to promote protrusion and directional sensing, while RhoA predominates at the rear to drive contractility and tail retraction. This spatial segregation is mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that respond to upstream signals, ensuring mutually inhibitory interactions between Cdc42 and RhoA. For instance, in migrating , Cdc42 activation via triggers polarity by orienting cytoskeletal elements toward the wound edge.00469-4) The PI3K-Akt pathway further reinforces front-rear asymmetry by localizing to the leading edge, where it generates phosphatidylinositol (3,4,5)-trisphosphate (PIP3) gradients that recruit effectors for protrusion. In chemotaxing Dictyostelium cells, PI3K accumulates rapidly at the front in response to stimuli, activating Akt to stabilize polarity through downstream targets that inhibit rear signaling. This localization depends on receptor-mediated activation and is essential for maintaining the PIP3 bias, which in turn confines Akt activity to the advancing edge.00755-9)00833-5) Organelle repositioning contributes to polarity by aligning the secretory apparatus with the migration direction. The Golgi apparatus and microtubule-organizing center (MTOC) reorient toward the , facilitating targeted vesicle delivery and microtubule stabilization at the front. In migrating epithelial cells, Cdc42 coordinates this reorientation by coupling the MTOC to the actin cytoskeleton via dynein motors, positioning the Golgi between the nucleus and the direction of travel. This alignment enhances directional persistence, as seen in fibroblasts during .00188-1) External cues, such as chemoattractant gradients, trigger polarity via G-protein-coupled receptors (GPCRs) that activate heterotrimeric G proteins. In neutrophils, binding of formyl peptides to GPCRs initiates asymmetric Gβγ signaling, leading to front enrichment of activators like PI3K within seconds. This receptor-mediated response decodes shallow gradients (1-2% difference across the cell) to establish a single . Feedback loops amplify and stabilize these asymmetries. Positive reinforcement at the front involves Arp2/3-mediated actin nucleation, which sustains protrusion and recruits additional signaling molecules to amplify the signal. Conversely, inhibitory signals at the rear, driven by II contractility, suppress ectopic protrusions and promote detachment. In motile cells like Dictyostelium, these reciprocal loops—linking to PI3K at the front and II to RhoA at the rear—ensure robust polarity. Such mechanisms are critical in immune cells, where rapid polarization enables efficient to infection sites. Temporally, polarity establishment occurs rapidly, typically within 5-10 minutes in response to uniform chemoattractant exposure, allowing cells to break and initiate directed migration. In neutrophils, this involves sequential waves of signaling that stabilize the front within 30-90 seconds, followed by full consolidation.

Cytoskeletal remodeling

Cytoskeletal remodeling is essential for cell migration, involving the dynamic reorganization of filaments and to generate protrusive forces at the and contractile forces for rear retraction. In migrating cells, polymerization drives the formation of protrusions such as lamellipodia and , while provide structural support and directional cues. Non-muscle II contributes to force generation, enabling the cell to propel forward against substrate resistance. These processes are powered by , which sustains continuous cytoskeletal turnover. Actin dynamics form the core of protrusive activity during cell migration. In lamellipodia, branched actin networks are assembled by the , which nucleates new filaments at approximately 70° angles from existing ones, creating a dendritic array that pushes the plasma membrane forward. This branching is crucial for broad, sheet-like protrusions in adherent cells. In contrast, feature linear bundles of unbranched actin filaments, polymerized by formins that elongate filaments from their barbed ends without branching. Actin polymerization rates in these structures typically range from 0.1 to 1 μm/s, allowing rapid extension of protrusions under physiological monomer concentrations. Microtubules play a supportive role in cytoskeletal remodeling by stabilizing the and facilitating directed . They polymerize toward the front of the cell, where their plus ends anchor to the cortex, providing a for vesicle and transport essential for protrusion maintenance. motors, anchored at the cortex, pull on minus ends to the -organizing toward the direction of migration, enhancing overall polarity and force transmission. Myosin contractility, mediated by non-muscle myosin II, generates the traction forces necessary to counterbalance protrusive expansion and drive cell body advancement. Assemblies of minifilaments hydrolyze ATP to cross-link and slide filaments, producing forces in the range of 10-100 pN per focal contact, which propel the cell forward while inducing retrograde flow at the . This contractility ensures coordinated rearward movement of the relative to the substrate. Key regulatory proteins fine-tune these dynamics. The WAVE/Scar complex activates the at the by recruiting it to sites of Rac signaling, promoting efficient branched network formation for lamellipodial protrusion. In filopodia, fascin bundles parallel actin filaments into rigid shafts, stabilizing them against disassembly and supporting sensing of the extracellular environment. The energy for these remodeling events derives from , which powers —the continuous addition of ATP-actin at barbed ends and dissociation of ADP-actin from pointed ends—maintaining filament flux without net length change under steady-state conditions. Recent structural insights from cryo-EM have refined our understanding of Arp2/3-mediated branching, confirming the canonical 70° branch angle in mature junctions and highlighting conformational changes upon activation.

Adhesion dynamics and signaling

Cell adhesion to the (ECM) during migration is primarily mediated by (), dynamic protein complexes that assemble at -based sites. clusters bind ECM ligands, recruiting talin to link to the actin cytoskeleton, followed by for structural reinforcement and () for signaling initiation. This assembly begins with nascent adhesions forming small clusters (<250 nm) in the lamellipodium, which mature into sliding focal complexes at the lamellipodium-lamella transition under initial tension, and further develop into stable anchored to upon sustained force application. FA signaling integrates mechanical cues with biochemical pathways to drive migration. Upon integrin engagement, FAK undergoes autophosphorylation at Tyr397, recruiting and activating Src kinase, which in turn phosphorylates FAK at additional sites to form a complex that stimulates the ERK/MAPK cascade, promoting changes and cytoskeletal reorganization essential for motility. Phosphoinositides such as (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) localize to FAs, with PIP2 levels rising during assembly to recruit effectors like talin and FAK, while PIP3 supports broader signaling; these facilitate FA maturation and turnover to sustain directed movement. FA dynamics involve rapid assembly and disassembly to enable protrusion and retraction. Nascent adhesions form within seconds of integrin binding, while mature FAs disassemble over minutes, allowing net forward translocation. In the molecular clutch model, retrograde actin flow engages adhesions like a clutch: at low loads, linkages slip, permitting actin polymerization to drive protrusion without traction; at higher loads, clutches grip the ECM, transmitting force for cell advancement, with slippage dominating at the cell rear to facilitate disassembly. Interactions with specific ECM components modulate adhesion strength. The α5β1 integrin binds with high affinity (Kd ≈ 1.5–1.7 nM), enabling stable anchorage, whereas collagen engagement via other integrins like α2β1 supports diverse migratory contexts. Growth factors such as (EGF) fine-tune adhesion dynamics to optimize migration. EGF enhances directional persistence by stabilizing lamellipodial protrusions and modulating adhesion strength, reducing detachment rates on substrates to balance speed and directionality. These adhesion processes interface briefly with cytoskeletal elements, where talin and transmit signals to networks for coordinated force generation.

Theoretical Models of Motility

Cytoskeletal protrusion model

The cytoskeletal protrusion model posits that cell migration is primarily driven by the of filaments at the , generating protrusive forces that push the plasma membrane forward. In this framework, monomers (G-actin) assemble into filamentous (F-actin) networks, particularly in structures like lamellipodia, creating a polymerizing front that advances the cell edge against mechanical resistance. This model emphasizes the role of directed assembly and disassembly, known as , where at the barbed (plus) ends near the membrane exceeds at the pointed (minus) ends, resulting in net forward protrusion. Originally conceptualized for , it was adapted to eukaryotic cell migration, highlighting how enable filament growth despite spatial constraints imposed by the membrane. A key quantitative aspect of the model is the protrusion velocity, derived from the balance of polymerization and depolymerization fluxes. The net velocity vv is given by v=(Jpolymer−Jdepolymer)⋅δ,v = (J_{\text{polymer}} - J_{\text{depolymer}}) \cdot \delta, where JpolymerJ_{\text{polymer}} is the flux of actin subunits adding to the filament barbed end (typically kon⋅Ck_{\text{on}} \cdot C, with konk_{\text{on}} the on-rate constant and CC the free G-actin concentration), JdepolymerJ_{\text{depolymer}} is the flux from the pointed end (koffk_{\text{off}}), and δ\delta is the size of an actin subunit, approximately 2.7 nm. This equation captures how the steady-state treadmilling rate translates into membrane advancement, with protrusion stalling when loads equal the polymerization force, estimated at 1-10 pN per filament. Central components include the mechanism, which rectifies thermal to prevent backward of the membrane and allow continuous subunit addition by transiently separating the filament tip from the membrane barrier. Complementing this, the elastic clutch hypothesis describes how linkage proteins (e.g., ENA/VASP family members) transmit polymerization-generated forces to the substrate via adhesions, with clutch slippage under high loads enabling adaptive force distribution across the actin network. These elements ensure efficient force generation, with polymerization rates of 1-10 subunits per second per filament supporting observed protrusion speeds of 0.1-1 μm/min in motile cells. The model predicts that protrusion speed inversely correlates with mechanical load, such as viscous drag from the extracellular medium, where drag force scales as Fdrag≈ηvF_{\text{drag}} \approx \eta v, with η\eta as ; higher loads reduce effective by compressing the ratchet space, leading to slower migration. Experimental perturbations, like increasing availability, enhance velocity until saturation, aligning with the flux-based formulation. Despite its explanatory power, the model is most applicable to two-dimensional lamellipodial protrusion in adherent cells on flat substrates, where branched networks dominate. It applies less effectively to three-dimensional environments or bleb-based migration, where hydrostatic or cortical actomyosin contractility play larger roles in force balance. Updates in the refined it to incorporate multi-filament interactions and load-dependent kinetics, but it remains a foundational framework for -centric .

Membrane flow and traction models

The membrane flow model posits that cell migration arises from retrograde flow of the plasma originating at the , which is subsequently recycled through primarily at the cell rear. This flow is driven by cortical tension generated by actomyosin contractility, creating a continuous circulation of material that propels the cell forward without requiring strong substrate adhesions. Experimental evidence from studies in Dictyostelium discoideum supports this "fountain flow" mechanism, where components move rearward at speeds correlating with migration velocity, with a of approximately 60 seconds in fast-moving cells. at the rear, an energy-dependent process inhibited by metabolic blockers like , ensures balance and sustains the flow. In contrast, the traction model emphasizes myosin-generated contractile forces pulling on substrate adhesions to achieve net cell displacement. Non-muscle II assembles at adhesions, generating rearward tension that detaches the cell body and advances the relative to the substrate. Traction force measurements reveal typical stress magnitudes of around 50 pN/μm² in migrating epithelial cells on compliant substrates, highlighting the scale of these forces in mesenchymal migration. This model underscores how clutch-like engagement of adhesions modulates force transmission, with activity directly linking contractility to . A unifying framework in these models describes net cell velocity as the difference between protrusion velocity and retrograde flow velocity: vnet=vprotrusion−vretrogradev_{\text{net}} = v_{\text{protrusion}} - v_{\text{retrograde}} Here, vretrogradev_{\text{retrograde}} represents the backward actin-membrane flow, given by vretrograde=Fclutch/βv_{\text{retrograde}} = F_{\text{clutch}} / \beta, where FclutchF_{\text{clutch}} is the force transmitted through adhesion clutches and β\beta is the viscous drag coefficient opposing flow. This equation captures how effective clutch engagement reduces retrograde flow, enhancing forward migration. Hybrid models integrate membrane flow with cytoskeletal protrusions, simulating scenarios where both mechanisms coexist for adaptive . Recent biophysical simulations demonstrate that in amoeboid cells, membrane flow dominates , particularly in low-adhesion environments, optimizing speed and efficiency over pure protrusion-based modes. These integrations reveal an optimal for transitioning between migration modes. Such models notably explain bleb-based amoeboid migration, where adhesion-independent relies on cortical flow and transient bleb expansion driven by intracellular pressure, as observed in RhoA-activated leukocytes.

Recent theoretical advances

Post-2020 developments have expanded these frameworks to include novel force-generation mechanisms. The osmotic engine model proposes that ion and water fluxes, mediated by channels like NHE-1 and aquaporins, create gradients that drive protrusion and migration, particularly in confined or 3D environments; this synergizes with actin-based , as disrupting halves speeds in cells. Similarly, the nuclear piston mechanism posits that the nucleus acts as a , generating hydrostatic pressure (~2400 Pa at the front versus ~900 Pa at the rear) to expand in mesenchymal-like migration. Hybrid models further integrate blebbing with adhesions, explaining rapid transitions in cancer cells within matrices, with theoretical predictions matching observed physiological speeds up to 2025.

Experimental Approaches

In vitro migration assays

In vitro migration assays provide controlled environments to quantify cell movement under defined conditions, enabling the study of , haptotaxis, and durotaxis without the complexities of living tissues. These assays typically involve two-dimensional or three-dimensional substrates that mimic aspects of the (ECM), allowing researchers to manipulate variables such as chemoattractant gradients and substrate properties. Common setups include transwell systems and scratch assays, which facilitate and precise measurement of migratory behaviors. The Boyden chamber assay, first described in , consists of two compartments separated by a porous , where cells in the upper chamber migrate toward a chemoattractant in the lower chamber, assessing directed or . Modern adaptations, known as Transwell assays, use inserts with polycarbonate featuring pore sizes of 3-8 μm, suitable for various cell types such as leukocytes (3 μm pores) or epithelial cells (8 μm pores). To evaluate invasion, the is coated with , a matrix that requires cells to degrade and traverse the ECM-like barrier, quantifying metastatic potential through cell counts on the underside of the after a fixed incubation period. The , also called the scratch assay, involves creating an artificial gap in a confluent of cells using a tip or stamp, followed by monitoring collective migration to close the via time-lapse microscopy. This method assesses both individual and coordinated cell movements in a two-dimensional setting, with wound closure rates calculated as the reduction in gap area over time, typically over 12-48 hours depending on cell type. Key metrics in these assays include , which measures directionality as the average distance a cell travels in a straight path before changing direction, reflecting the stability of migratory polarity. Another fundamental metric is (MSD), defined for two-dimensional diffusive motion as MSD=4Dt,\text{MSD} = 4Dt, where DD is the coefficient and tt is time, providing insight into random versus directed by analyzing trajectory deviations from . These assays offer advantages such as high throughput, with Transwell formats supporting parallel testing of multiple conditions in 96-well plates, and precise control over environmental cues like linear chemoattractant gradients generated via microfluidic devices. Microfluidics enable stable, tunable gradients over micrometer scales, improving reproducibility compared to diffusion-based systems. Recent advances include organ-on-chip models, which integrate three-dimensional ECM hydrogels with tunable stiffness (e.g., 0.1-50 kPa) to simulate tissue mechanics, allowing real-time observation of cell migration in vascularized or tumor-like environments.

In vivo imaging and analysis

In vivo imaging techniques enable the observation of cell migration within living organisms, providing insights into physiological contexts that in vitro assays cannot replicate. Two-photon microscopy, which uses near-infrared light to excite fluorophores, facilitates deep tissue imaging by reducing scattering and compared to single-photon methods, allowing visualization up to several hundred micrometers in depth. This approach has been instrumental in tracking immune cell dynamics and tumor cell movements in intact tissues. Intravital imaging windows, such as cranial or abdominal chambers implanted in mice, further enhance access to internal sites like tumors or mammary glands, enabling repeated, longitudinal monitoring of tumor cell invasion and without disrupting the native microenvironment. For instance, these windows have revealed how cancer cells navigate through stromal barriers in real time during orthotopic pancreatic tumor progression. Despite these advances, imaging faces significant challenges, including tissue opacity from light scattering in dense structures like or , which limits , and motion artifacts from or heartbeat that blur dynamic processes. Typical resolutions achieve approximately 1 μm laterally and 2-3 μm axially, sufficient for single-cell tracking but constraining subcellular details in deeper layers. To mitigate these, stabilized mounts and are employed, though they cannot fully eliminate physiological movements in non-anesthetized models. Analysis of in vivo migration data relies on computational tools to extract quantitative metrics from complex, noisy datasets. Particle image velocimetry (PIV) processes time-lapse images to compute velocity fields and trajectories of individual or collective cell movements, revealing patterns like swirling flows in epithelial sheets during zebrafish lateral line primordium migration. Segmentation algorithms, often based on deep learning networks like U-Net, delineate cell boundaries in phase-contrast or fluorescence images, enabling the quantification of collective flows and neighbor interactions in dense tissues. For assessing cell-cell interactions, correlation spectroscopy techniques, such as spatiotemporal image correlation spectroscopy (STICS), measure flux rates and co-diffusion of molecules between migrating cells, providing rates of adhesive or signaling exchanges during epithelial wound closure. Key insights from these methods highlight the dynamic regulation of migration in development. Real-time imaging in zebrafish has shown that neural crest cells establish polarity through planar cell polarity (PCP) signaling, with asymmetric localization of proteins like Prickle1 directing oriented migration along axon tracts. These approaches underscore the interplay between individual polarity and collective coordination in vivo.

Pathological Dysregulation

Role in cancer progression

Cell migration plays a pivotal role in cancer progression by enabling the dissemination of tumor cells from the primary site to distant organs, a process central to metastasis. During epithelial-mesenchymal transition (EMT), transcription factors such as Snail and Twist reprogram epithelial cancer cells into a mesenchymal state, enhancing their migratory and invasive capabilities. Snail overexpression in carcinoma cells induces EMT, leading to loss of cell-cell adhesion and increased motility essential for tumor invasion. Similarly, Twist drives EMT in breast cancer cells, promoting their detachment from the primary tumor and subsequent migration to metastatic sites. This mesenchymal mode, characterized by elongated morphology and upregulated motility genes, facilitates cancer cell invasion through tissue barriers. Invasion mechanisms in cancer rely on proteolytic remodeling of the (ECM) and specialized structures like invadopodia. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, degrade ECM components such as and , creating paths for tumor cell advancement and promoting . These enzymes are upregulated in metastatic cancers, where they facilitate tissue remodeling and to support migratory spread. Invadopodia, actin-rich protrusions enriched with cortactin, enable localized ECM degradation and are critical for penetration into surrounding stroma. Cortactin at invadopodia regulates their maturation and turnover, directly enhancing invasive migration in breast and other carcinomas. In hypoxic tumor microenvironments, common in solid cancers, cells exhibit significantly enhanced migration rates, with increasing up to several-fold compared to normoxic conditions, driven by pathways like HIF-1α and PERK signaling. The metastatic cascade involves sequential steps where dysregulated cell migration drives tumor spread: local , intravasation into blood or lymphatic vessels, survival during circulation as circulating tumor cells, into distant tissues, and to form secondary tumors. is the primary cause of cancer mortality, accounting for an estimated 70-90% of cancer-related deaths, though recent studies suggest around 70% for tumors, as primary tumors are often treatable but metastases resist and lead to organ failure. Aberrant migration during intravasation and is particularly rate-limiting, with invadopodia aiding endothelial breaching. Therapeutic strategies targeting these migratory events have included MMP inhibitors like marimastat, a broad-spectrum blocker of MMP-2 and MMP-9, which showed preclinical promise but failed in Phase III trials in the early due to musculoskeletal toxicity and lack of efficacy in cancers like pancreatic and . Emerging approaches as of 2025 include CAR-T cell engineered to enhance infiltration and target tumors, with designs incorporating receptors like to improve trafficking and potentially disrupt metastatic migration dynamics in preclinical models.

Involvement in immune responses and inflammation

Cell migration plays a central role in immune responses by enabling leukocytes to extravasate from the bloodstream into inflamed tissues, where they combat pathogens and facilitate tissue repair. This process begins with leukocyte rolling along the vascular , mediated by selectins such as P-selectin and expressed on activated endothelial cells, which bind to carbohydrate ligands on leukocytes like , allowing initial tethering and slowing of rolling leukocytes. Firm arrest follows, driven by the activation of leukocyte such as LFA-1 (αLβ2) and Mac-1 (αMβ2), which transition to a high-affinity state in response to signaling and bind tightly to endothelial ligands and ICAM-2, halting the rolling leukocytes. Transmigration, or diapedesis, then occurs primarily through paracellular routes, facilitated by homophilic interactions of (CD31) between leukocytes and endothelial junctions, enabling leukocytes to cross the endothelial barrier and enter the subendothelial space. Chemokine gradients are essential for directing leukocyte migration to sites of . For instance, CXCL8 (also known as IL-8) forms gradients that potently attract neutrophils via CXCR1 and CXCR2 receptors, promoting their to infection or sites. Similarly, dendritic cells rely on CCR7 expression to sense CCL19 and CCL21 gradients in lymphatic vessels, enabling their homing to draining lymph nodes for and T cell priming. These gradients ensure precise recruitment, with neutrophils often exhibiting amoeboid migration modes to rapidly navigate through inflamed tissues. In the resolution phase of , cell migration contributes to tissue homeostasis by clearing apoptotic cells and dampening . Macrophages perform , phagocytosing apoptotic neutrophils and other dying cells, which prevents secondary and promotes the release of mediators to resolve . signals, such as TGF-β, further halt excessive leukocyte migration by suppressing production and activation in immune cells, thereby limiting ongoing and facilitating return to steady-state conditions. Dysregulated cell migration underlies chronic inflammatory conditions, including , where excessive into arterial walls drives plaque formation. , attracted by like , extravasate and differentiate into macrophages that accumulate , exacerbating and lesion progression. In , 2022 studies highlighted swarming, a migration behavior where rapidly converge on sites in relay waves, amplifying but self-limiting to prevent tissue damage. in inflamed tissues typically migrate at speeds of 10-20 μm/min, allowing swift responses while resolution mechanisms ensure controlled dispersal.

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