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Migration 101 - An Introduction to Cell Migration

In this section, we provide a brief primer that serves as an entry point into cell migration and related disciplines. For a more detailed discussion, we refer the reader to the appropriate sections within this webpage. News and novel discoveries related or sponsored by the CMC are available in the CMC Activity Center.

What is Cell Migration?

Deconstructing Cell Migration: Overview of its Component Processes

Migration in Health and Disease

Embryonic Development and Organogenesis


Cell Migration: Implications in Pathobiology

What is Cell Migration?

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 environments, such as soil (e.g. the amoeba Dictyostelium discoideum) or on glass/plastic (common in vitro setups), or within complex, multicellular organisms. Cells migrate in response to multiple situations they encounter during their lives. Some examples include: the need to feed (Dictyostelium again); morphogenetic events that require the mobilization of precursors to generate new structures/layers/organs, sometimes at distant locations (during embryogenesis, organogenesis and regeneration); or the presence of environment cues that inform the cells of the need for their movement to accomplish a larger goal (e.g. wound healing or the immune response). In pathology, production of abnormal migratory signals may induce the migration of the wrong cell type to the wrong place, which may have catastrophic effects on tissue homeostasis and overall health. Some examples include autoimmune syndromes in which immune cells home to certain locations (joints in rheumatoid arthritis, and the CNS in multiple sclerosis are two examples) and destroy the supporting tissue, causing severe damage; or the process of metastasis, in which tumor cells abandon the primary tumor and migrate to distant tissues where they generate secondary tumors.

There are different modes of cell migration depending on the cell type and the context in which it is migrating. Cells can move as single entities, and the specifics of their motility depend on several factors, e.g., adhesion strength and the type of substratum (including extracellular matrix ligands and other cells), external migratory signals and cues, mechanical pliability, dimensionality, and the organization of the cellular cytoskeleton. The intrinsic properties of the cell interact with the environment to produce a migratory mode or phenotype. For example, nimble, fast-moving and -turning cells, like immune cells, do not have a highly organized cytoskeleton and tend to adhere weakly; their motion is sometimes termed 'amoeboid'. Some tumor cells can move by extending membrane blebs, and their actin cytoskeleton is not very organized, either. Fibroblasts and epithelial precursors lie at another extreme. They have elaborate cytoskeletal structures and adhesions, and their motion is generally slow. It is worth noting that some cell types can switch between these depending on their environment. Cells can also move in groups, including chains of cells and sheet-like layers.

It is generally convenient to parse migration into a useful set of component processes, which are often regulated by the same effectors regardless of the cell type and the mode of migration. These processes include polarization, protrusion and adhesion, translocation of the cell body and retraction of the rear. These processes are coordinated and integrated by extensive transient, signaling networks.

Deconstructing Cell Migration: Overview of its Component Processes


Cell polarization refers to the tendency of migrating cells to have a distinct, stable front and rear. The polarity is reinforced and often even arises from environments that provide a directional cue. These directional cues can be chemotactic, (induced by chemoattractants or morphogens), haptotactic (caused by varying concentrations of substrate), mechanotactic (breakdown of cell-cell contacts, as in wound healing), electrotactic (induced by electric fields), and 'durotactic', (due to differences in pliability), or combinations of any of these. The result is a defined cell front and a rear. The leading edge is usually characterized by intense actin polymerization that generates a protrusive structure, and by adhesion to the substratum. The trailing edge is characterized by stable bundles and the release and disassembly of adhesions. The central part of the cell usually contains the nucleus and microtubules (which exhibit different degrees of polarization depending on the cell type).

Some cells polarize by forming a front in response to an external agent. For example, in Dictyostelium and some immune cells, phosphatidylinositol triphosphate (PIP3), a lipid, is produced and localized to the leading edge. This results from polarization of the molecules that produce and degrade it, e.g., phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN), a lipid phosphatase. The small GTPase Cdc42, acting through partitioning proteins like PAR3/6, and signaling molecules like PKC also contribute to polarity. And in some cells the rear is established by the contractile protein, myosin II, which produces large actomyosin filaments and adhesions.


Protrusion is the de novo formation of membrane extensions, or protrusions, in the direction of migration, i.e. the leading edge. It has three major components: the expansion of the plasma membrane, the formation of an underlying backbone that supports membrane extension, and the establishment of contacts with the substratum, which provides traction for the movement of the rest of the cell body and signals that regulate actin polymerization.

The protrusion is produced by local actin polymerization. One kind of protrusion is flat and fan-like, the edge of which is often called the lamellipodium and within which actin is polymerizing and often branched. Spike-like filopodia are another kind of protrusion; these structures comprise polymerized actin filaments that are arranged into long parallel bundles. These two forms of protrusion are thought to serve different roles: filopodia act as mechanosensory, exploratory devices, whereas lamellipodia provide wide surfaces that generate traction for forward movement.

Actin polymerization results from the nucleation of new filaments and the availability and addition of new monomers. The Arp2/3 complex is a molecular heptamer that attaches itself to the side of a pre-existing actin filament and nucleates de novo actin polymerization at a fixed angle. This is essential for branching in lamellipodia, and also important in the formation of the base of filopodia. Monomers are provided by severing of older filaments and their dissolution into actin monomers. This is mediated by an actin-filament severing protein, cofilin. Processive barbed end extension of actin filaments is carried out by formins, which attach to the barbed end and polymerize actin monomers.


Adhesion to the substratum occurs mainly via integrin receptors. The integrins are a large superfamily of heterodimeric receptors that bind to different extracellular matrix ligands or counterreceptors on other cells. Integrin ligation triggers signaling pathways that regulate protrusion. It also links the substratum to the actin cytoskeleton and thereby provides traction for migration. The sites of adhesion are usually spatially restricted and vary from small and dot-like (nascent adhesions or focal complexes) to large and elongated (focal adhesions). The shape, size and functional role of the adhesions vary with their subcellular localization and cell type. Those closer to the leading edge, i.e. embedded in the lamellipodium, or present in rapidly migrating amoeboid cells tend to be smaller, actively promote actin polymerization and assemble and disassemble rapidly. Those further away from the leading edge in mesenchymal cells can be larger, more stable and anchor large actin filament bundles.

Over 150 different molecules populate adhesions. Some are organized into signaling complexes that contain kinases and adapter proteins that serve to bring different signaling components together. Paxillin and FAK are two among many important signaling components in adhesions. Both are implicated in regulating Rho family GTPases, which for migration, are a major signaling hub. Most pathways converge on these GTPases, which in turn, regulate actin polymerization, actomyosin contraction and actin organization, and microtubule dynamics and thereby regulate migration. Another group of adhesion components links actin to the substratum through integrin. They include talin, vinculin, and α-actinin.

Regulation and integration

These component processes are regulated by complex signaling networks initiated by integrins and other receptors. The regulation occurs through local, transient signals that retain polarity of the cell and drive local processes, like actin polymerization, adhesion, actomyosin bundling and contraction, and microtubule dynamics. Large associated signaling scaffolds, organized by multidomain adapter proteins and membrane lipid or protein associations that localize and activate kinases and phosphatases, lie at the heart of this regulation. As mentioned above, paxillin and FAK are among the best studied in this context. Actin filaments, microtubules, and cycling lipid vesicles span the cell and contribute to integrating the processes that mediate migration.

Cell body translocation and retraction of the rear

Cell body translocation propelled by a coordinated contraction of the actomyosin cytoskeleton is not well understood. Myosin II and microtubule motors (e.g. dynein) also control translocation of the nucleus. Rear retraction requires the coordinated contraction of the actin cytoskeleton and disassembly of the adhesions at the trailing edge. Several mechanisms converge to promote adhesion disassembly: actomyosin contraction that exerts force against the adhesion promoting its ripping (many cell types even leave tracks of integrin receptors behind), microtubule-induced adhesion disassembly, integrin endocytosis, and proteolytic cleavage, by calpain, of focal adhesion proteins that link the integrins to the actin.

Migration in Health and Disease

Cell migration is fundamental to the morphogenesis of embryos. Migratory movements underlie gastrulation, the formation of the layers in the embryo, as well as the formation of organs and tissues. In addition to this morphogenetic component, cell migration is a key component of the homeostasis of the adult individual. Two common themes are the migration of cell sheets and the birth of undifferentiated cells in epithelial layers, and their migration to distant targets. The former is a prominent feature of gastrulation. Examples of the latter are migrations from the neural tube (and neural crest) and the somites. This provide cells that populate numerous organs and tissues including skin, brain, and limbs. Tissue regeneration and repair is a prominent homeostatic phenomenon in skin and intestine, for example. And the inflammatory cascade, which fights off disease throughout the body, involves the movement of immune cells from the lymph nodes to the circulation where they remain vigilant until tissue insult triggers an inflammatory reaction that attracts them to respond to insult, i.e., injury or infection.

Consequently, failure of cells to migrate, or inappropriate migratory movements, can result in severe defects (during development) or life-threatening scenarios, such as immunosuppresion, autoimmune diseases, defective wound repair, or tumor dissemination. Understanding the mechanisms underlying cell migration is also important to emerging areas of biotechnology which focus on cellular transplantation and the manufacture of artificial tissues, as well as for the development of new therapeutic strategies for controlling invasive tumor cells.

Embryonic Development and Organogenesis

Gastrulation is the robust morphogenetic movement that shapes the early embryo. Large groups of cells inside the blastocyst migrate to form embryonic layers (endoderm, mesoderm and ectoderm). These cells commit to differentiation programs and evolve into precursors that migrate to their final destinations where they undergo terminal differentiation and produce the different organs and limbs. A relatively simple example is the migration of muscle precursors from somites to emerging limbs. In the developing brain, neuronal precursors migrate out of the neural tube and take up residence in the distinct layers that will form the brain. These cells move within the layers and send projections (axons and dendrites) through the layers of developing cells to their final targets and then form specific connections. These intercellular connections (synapses) constitute highly specialized interfaces that underlie complex processes such as learning and memory. Finally, migration of cells from the neural crest is among the best studied embryonic migrations. These cells arise from the top of the neural tube and migrate to a plethora of locations including bone, cartilage, PNS, and skin (melanocytes).


Wound repair and the inflammatory response are the examples of homeostatic processes in which cell migration features prominently. In skin, cells from the basal cell layer of the epidermis proliferate and migrate to close the wound. Fibroblastic cells that surround the wound also migrate. The wound triggers mechanical signals as well as the secretion of chemotactic molecules that attract the cells into the wound. Wounding can also trigger an inflammatory cascade and immune response. The injured cells secrete pro-inflammatory signals; also, the bacteria that cause infection secrete their own chemotactic and pro-inflammatory signals. Together, these phenomena transform the wound into a 'hotspot' of pro-inflammatory signals that recruit immune cells to combat infection. This process occurs in discrete steps: initially, the inflammatory signals reach the endothelial cells that form the inner walls of the blood vessels in the vicinity of the lesion. These endothelial cells respond by exposing new receptors that slow down, and eventually immobilize, immune cells. The leukocytes then probe the endothelial surface, selecting an extravasation point through which they translocate from the lumen of the blood vessel to the affected tissue. They then navigate throughout the tissue until they reach the focus of inflammation, where they exert their immune function (phagocytosis, activation, lysis, etc). Other, highly specialized, antigen-presenting cells e.g. tissue macrophages or follicular dendritic cells, can do this process in reverse: they sample the components of the infectious agents (bacterial products, etc.) and subsequently leave the area, homing to lymph nodes, where they present their collected samples to additional immune cells (usually B or T lymphocytes) that are thus instructed to fight the infection.

Cell Migration: Implications in Pathobiology

The regulation of cell migration is a complex process involving hundreds of molecules. As such, it is far from failsafe and deregulation may occur. Which molecules are implicated, which cells are affected, where, when and how determine the outcome of such deregulation(s).

The most common alterations are those that impair cell migration. In development, this may have catastrophic consequences: for example, genetic deletion of a key chemotactic receptor, CXCR4, or its ligand SDF-1α/CXCL12 causes major alterations in development, including brain and heart abnormalities and defective lymphopoiesis. In homeostasis, migratory impairment delays wound healing and/or impairs the immune response. Interestingly, defective migration is a major caveat in cell-based therapy, for example, stem-cell grafting.

There are other types of alteration that cause abnormal migrations. For example, chronic inflammatory syndromes, such as asthma, rheumatoid arthritis, multiple sclerosis, psoriasis and Crohn′s disease share a migratory component, i.e. the constant infiltration of immune cells into inappropriate places. Once these cells localize to their abnormal target tissues, they become activated and can cause massive damage and progressive deterioration of the tissue. Some therapies against multiple sclerosis and psoriasis are based on preventing immune cells from reaching their target tissues by counteracting receptors implicated in the abnormal homing to the CNS and skin, respectively.

Cell migration also contributes to the process of metastasis formation. Cancer cells migrate as single cells or in small groups to spread from the initial site of tumor growth. They acquire an invasive phenotype characterized by both the loss of cell-cell interactions and increased cell motility. These cells are able to enter the blood or lymph vessels (intravasation) and cross the vessel wall to exit the vasculature (extravasation) in distal organs where they can continue to proliferate forming a second tumor mass. Cancer cell migration is typically regulated by integrins, matrix-degrading enzymes, and cell-cell adhesion molecules. Several cytokines and growth factors have been shown to stimulate invasion and to be upregulated in a variety of tumor types.

Finally, the migration and proliferation of vascular smooth muscle cells is a key event in progressive vessel thickening leading to atherosclerosis and other vascular diseases. Vascular injury leads to endothelial dysfunction, which, in turn, promotes the expression of inflammatory markers and transendothelial leukocyte migration. Recruitment of leukocytes from the circulation into the vessel intima is a crucial step for the development of fibrous plaques. Cytokines are among the molecules known to upregulate endothelial cell adhesion molecules, recruit leukocytes and induce smooth muscle cell migration and proliferation.

For more detailed reading please go to Review papers.