BiologyClassroom
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 or within complex, multicellular organisms. Cells migrate in response to multiple situations they encounter during their lives. Some examples include: the need to feed ; 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.
Deconstructing Cell Migration: Overview of its Component Processes
Polarization
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), mechanotactic (breakdown of cell-cell contacts, as in wound healing), electrotactic (induced by electric fields) or a combination of any of these.
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).
Protrusion
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.
Adhesion
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 counter receptors 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. Another group of adhesion components links actin to the substratum through integrin. They include talin, vinculin, and α-actinin.
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.
