Cell migration
   HOME

TheInfoList



OR:

Cell migration is a central process in the development and maintenance of
multicellular organism A multicellular organism is an organism that consists of more than one cell (biology), cell, unlike unicellular organisms. All species of animals, Embryophyte, land plants and most fungi are multicellular, as are many algae, whereas a few organism ...
s. Tissue formation during
embryonic development In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...
,
wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
and
immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...
s 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. Errors during this process have serious consequences, including
intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
,
vascular disease Vascular disease is a class of diseases of the vessels of the circulatory system in the human body, body, including blood vessels – the arteries and veins, and the lymphatic vessels. Vascular disease is a subgroup of cardiovascular disease. Diso ...
, tumor formation and
metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
. 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 In fluid dynamics, the Reynolds number () is a dimensionless quantity that helps predict fluid flow patterns in different situations by measuring the ratio between Inertia, inertial and viscous forces. At low Reynolds numbers, flows tend to ...
), 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 A flagellum (; : flagella) (Latin for 'whip' or 'scourge') is a hair-like appendage that protrudes from certain plant and animal sperm cells, from fungal spores ( zoospores), and from a wide range of microorganisms to provide motility. Many pr ...
or
cilia The cilium (: cilia; ; in Medieval Latin and in anatomy, ''cilium'') is a short hair-like membrane protrusion from many types of eukaryotic cell. (Cilia are absent in bacteria and archaea.) The cilium has the shape of a slender threadlike proj ...
to propel themselves.
Eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
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 The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
. Two very distinct migration scenarios are crawling motion (most commonly studied) and blebbing motility.online
/ref> A paradigmatic example of crawling motion is the case of fish epidermal keratocytes, which have been extensively used in research and teaching.


Cell migration studies

The migration of cultured cells attached to a surface or in 3D is commonly studied using
microscopy Microscopy is the technical field of using microscopes to view subjects too small to be seen with the naked eye (objects that are not within the resolution range of the normal eye). There are three well-known branches of microscopy: optical mic ...
. 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

The processes underlying mammalian cell migration are believed to be consistent with those of (non- spermatozooic) locomotion. 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 An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
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 ''Dictyostelium discoideum'' is a species of soil-dwelling Amoeboid, amoeba belonging to the phylum Amoebozoa, infraphylum Mycetozoa. Commonly referred to as slime mold, ''D. discoideum'' is a eukaryote that transitions from a collection of unic ...
is useful to researchers because they consistently exhibit chemotaxis in response to
cyclic AMP Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triph ...
; they move more quickly than cultured mammalian cells; and they have a
haploid Ploidy () is the number of complete sets of chromosomes in a cell (biology), cell, and hence the number of possible alleles for Autosome, autosomal and Pseudoautosomal region, pseudoautosomal genes. Here ''sets of chromosomes'' refers to the num ...
genome that simplifies the process of connecting a particular gene product with its effect on cellular behaviour.


Molecular processes of migration

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)


Leading edge

Experimentation has shown that there is rapid
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
polymerisation at the cell's front edge. 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. In addition, cytoskeletal elements are able to interact extensively and intimately with a cell's plasma membrane.


Trailing edge

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. 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. 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)

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. 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. For a cell to move, it is necessary to bring a fresh supply of "feet" (proteins called
integrins Integrins are transmembrane receptors that help cell–cell and cell– extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
, which attach a cell to the surface on which it is crawling) to the front. It is likely that these feet are endocytosed 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; 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.


Mechanistic basis of amoeboid migration

Adhesive crawling is not the only migration mode exhibited by eukaryotic cells. Importantly, several cell types — ''Dictyostelium'' amoebae,
neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
s, metastatic cancer cells and
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s — 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 In fluid dynamics, the Reynolds number () is a dimensionless quantity that helps predict fluid flow patterns in different situations by measuring the ratio between Inertia, inertial and viscous forces. At low Reynolds numbers, flows tend to ...
fluid dynamics, which apply at the cellular scale, rearward surface flow could provide a mechanism for microscopic objects to swim forward. 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. It was subsequently shown, using
optogenetics Optogenetics is a biological technique to control the activity of neurons or other cell types with light. This is achieved by Gene expression, expression of Channelrhodopsin, light-sensitive ion channels, Halorhodopsin, pumps or Photoactivated ade ...
, 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. Polarized trafficking of membrane-containing vesicles from the rear to the front of the cell helps maintain cell size. Rearward membrane flow was also observed in ''Dictyostelium discoideum'' cells. 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.


Collective biomechanical and molecular mechanism of cell motion

Based on some mathematical models, recent studies hypothesize a novel biological model for collective biomechanical and molecular mechanism of cell motion. 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

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 A surface charge is an electric charge present on a two-dimensional surface. These electric charges are constrained on this 2-D surface, and surface charge density, measured in coulombs per square meter (C•m−2), is used to describe the charge ...
between front regions and rear edges of the cell. 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 Cell division control protein 42 homolog (Cdc42 or CDC42) is a protein that in humans is encoded by the ''CDC42'' gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in ''S. cerevisiae'' (yeast) as a mediator of ...
are found at the front of the cell, whereas Rho GTPase and PTEN are found toward the rear. It is believed that filamentous actins and
microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nanometer, nm and have an inner diameter bet ...
s are important for establishing and maintaining a cell's polarity. 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
receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
s 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. When present, microtubules retard cell movement when their dynamics are suppressed by drug treatment or by tubulin mutations.


Inverse problems in the context of cell motility

An area of research called
inverse problem An inverse problem in science is the process of calculating from a set of observations the causal factors that produced them: for example, calculating an image in X-ray computed tomography, sound source reconstruction, source reconstruction in ac ...
s in cell motility has been established. 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.; 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

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). 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. 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. 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.


See also

* Cap formation *
Chemotaxis Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...
* Collective cell migration *
Durotaxis In cellular biology, durotaxis is a form of cell migration in which Cell (biology), cells are guided by Stiffness, rigidity gradients, which arise from differential structural properties of the extracellular matrix (ECM). Most normal cells migrat ...
* Endocytic cycle *
Mouse models of breast cancer metastasis Breast cancer metastatic mouse models are experimental approaches in which mice are Genetic engineering, genetically manipulated to develop a mammary tumor leading to distant focal lesions of mammary epithelium created by metastasis. Mammary cancer ...
* Neurophilic * Protein dynamics


References


External links


Cell Migration Gateway
The Cell Migration Gateway is a comprehensive and regularly updated resource on cell migration
The Cytoskeleton and Cell Migration
A tour of images and videos by the J. V. Small lab in Salzburg and Vienna {{DEFAULTSORT:Cell Migration Cellular processes Cell movement Articles containing video clips