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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, in contrast to a unicellular organism. All species of animals, Embryophyte, land plants and most fungi are multicellular, as are many algae, whereas a few ...
s. Tissue formation during
embryonic development An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism that consists of more than one cell (biology), cell, in contrast to a unicellular organism. All species of animals, Embryophyte, la ...

embryonic development
,
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 The epidermis is the outermost of the three layers that comprise the skin Skin is the layer of ...
and
immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, Parasitism, parasites, and Fungus, ...
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
chemical signals
and mechanical signals. Errors during this process have serious consequences, including
intellectual disability Intellectual disability (ID), also known as general learning disability and formerly mental retardation (MR),Rosa's Law Rosa's Law is a United States The United States of America (USA), commonly known as the United States (U.S. or US), or ...
,
vascular disease Vascular disease is a class of diseases of the blood vessel The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues ...
,
tumor formation
tumor formation
and
metastasis Metastasis is a pathogenic agent's spread 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, then, ...
. 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 The Reynolds number () helps predict flow patterns in different fluid flow situations. At low Reynolds numbers, flows tend to be dominated by laminar (sheet-like) flow, while at high Reynolds numbers flows tend to be turbulent In fluid dynam ...
), 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 (; ) is a hairlike appendage that protrudes from a wide range of microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism In biology, an organism () is any organic, life, living system that fu ...

flagella
or
cilia The cilium (; the plural is cilia) is an organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are ...

cilia
to propel themselves.
Eukaryotic Eukaryotes () are organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), tax ...
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 s present in the of all , excluding and . It extends from the to the and is composed of similar proteins in the various organisms. In , it is composed of three main components, , ...

cytoskeleton
. 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 attached to a surface or in 3D is commonly studied using
microscopy Microscopy is the technical field of using microscope A microscope (from grc, μικρός ''mikrós'' 'small' and ''skopeîn'' 'to look (at); examine, inspect') is a laboratory instrument used to examine objects that are too small to b ...

microscopy
. As cell movement is very slow, a few µm/minute,
time-lapse microscopy Time-lapse microscopy is time-lapse photography applied to microscopy. Microscope image sequences are recorded and then viewed at a greater speed to give an accelerated view of the microscopic process. Before the introduction of the video tape rec ...
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 Locomotion means the act or ability of an entity or person to transport or move oneself from place to place. Locomotion or Loco-Motion may refer to: Motion * Motion (physics) *Specific types of motion ** Animal locomotion *** Terrestrial locomoti ...
. 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), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique mo ...

antibody
or when small beads become artificially bound to the front of the cell. Other eukaryotic cells are observed to migrate similarly. The amoeba
Dictyostelium discoideum ''Dictyostelium discoideum'' is a species of soil-dwelling amoeba An amoeba (; less commonly spelt ameba or amœba; plural ''am(o)ebas'' or ''am(o)ebae'' ), often called an amoeboid, is a type of cell Cell most often refers to: * Cell (bio ...
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 Adenosine is an organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds tha ...
; they move more quickly than cultured mammalian cells; and they have a
haploid Ploidy () is the number of complete sets of chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones which, aided by ...
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 In , family (from la, familia) is a of people related either by (by recognized birth) or (by marriage or other relationship). The purpose of families is to maintain the well-being of its members and of society. Ideal ...
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)

Studies have also shown that the front of the migration is the site at which the membrane is returned to the cell surface from internal membrane pools at the end of the
endocytic cycle Endocytosis is a cellular process The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and biological unit of all known organisms. Cells are the smallest units of life, and hence are often referred to as ...
. This has led to the hypothesis 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 at the front 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 Cell surface receptors (membrane receptors, transmembrane receptors) are receptor (biochemistry), receptors that are embedded in the cell membrane, plasma membrane of cell (biology), cells. They act in cell ...

integrins
, 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.


Mechanistic basis of amoeboid migration

Adhesive crawling is not the only migration mode exhibited by eukaryotic cells. Importantly, metastatic cancer cells and immune cells like
macrophage Macrophages (abbreviated as Mφ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the ...

macrophage
s and
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

neutrophil
s have been found to be capable of adhesion-independent migration. The mechanistic basis of this migration mode is less understood than either eukaryotic cell crawling or flagella-based swimming by microorganisms. The physicist theorized that under conditions of low
Reynolds number The Reynolds number () helps predict flow patterns in different fluid flow situations. At low Reynolds numbers, flows tend to be dominated by laminar (sheet-like) flow, while at high Reynolds numbers flows tend to be turbulent In fluid dynam ...
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 was provided using
optogenetics Optogenetics () most commonly refers to a biological technique that involves the use of light to control neurons that have been genetically modified to express light-sensitive ion channels. As such, optogenetics is a neuromodulation Neuromodulat ...
. It was shown that cells migrating in an amoeboid fashion without adhesions exhibit plasma membrane flow towards the cell rear that can 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. Interestingly, 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 Polarity may refer to: Science *Polarity (mutual inductance), the relationship between components such as transformer windings *Polarity (projective geometry), in mathematics, a duality of order two *Polarity in embryogenesis, the animal and vegeta ...

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. This polarity is reflected at a molecular level by a restriction of certain molecules to particular regions of the inner
cell surface cell membrane vs. Prokaryotes A prokaryote is a typically unicellular organism that lacks a nuclear membrane-enclosed cell nucleus, nucleus. The word ''prokaryote'' comes from the Greek language, Greek (, 'before') and (, 'nut' or 'kernel').C ...

cell surface
. Thus, the phospholipid
PIP3 Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes ...
and activated Rac and
CDC42 Cell division control protein 42 homolog, also known as Cdc42, is a protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providing and , a ...

CDC42
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 polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecules, composed of many Repeat unit, rep ...

microtubule
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 Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features of ...
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 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 aco ...

inverse problem
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.


See also

* Cap formation *
Chemotaxis Chemotaxis (from '' chemo-'' + '' taxis'') is the movement of an organism in response to a chemical stimulus. Somatic cells, bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biological cell. They ...

Chemotaxis
*
Collective cell migrationCollective cell migration describes the movements of group of cells and the emergence In philosophy Philosophy (from , ) is the study of general and fundamental questions, such as those about reason, Metaphysics, existence, Epistemolo ...
* Durotaxis *
Endocytic cycle Endocytosis is a cellular process The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and biological unit of all known organisms. Cells are the smallest units of life, and hence are often referred to as ...
* Mouse models of breast cancer metastasis * Neurophilic *
Protein dynamics Proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these stat ...


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