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
[1]
and mechanical signals. Errors during this process have serious consequences, including
intellectual disability, vascular disease, tumor formation and metastasis. 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
[2][3]
motion (most commonly studied) and blebbing motility. A paradigmatic example of crawling
motion is the case of fish epidermal keratocytes, which have been extensively used in research
[4]
and teaching.

Cell migration studies[edit]

The migration of cultured cells attached to a surface or in 3D is commonly studied using

[5][6][3]
microscopy. 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[edit]
The processes underlying mammalian cell migration are believed to be consistent with those of
[7]
(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 or when small beads become artificially bound to the front of
[8]
the cell.

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
[9]
behaviour.

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[edit]

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)[edit]

Leading edge[edit]

[10]
Experimentation has shown that there is rapid actin polymerisation at the cell's front edge.
This observation has led to the hypothesis that formation of actin filaments "push" the leading
[11][12]
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
[13]
membrane.

Trailing edge[edit]

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
[14]
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
[15]
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)[edit]

The leading edge at the front of a migrating cell is also the site at which membrane from internal
[16][17]
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)
[18]
at its front. 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
 [19]
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
[20][21][22]
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
[23]
measured.

Rearward membrane flow (red arrows) and vesicle trafficking from back to front (blue arrows) drive
[24]
adhesion-independent migration.

Mechanistic basis of amoeboid migration[edit]

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
[25]
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
[26]
whilst suspended in an isodense medium. 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.
[24][27]
Polarized trafficking of membrane-containing vesicles from the rear to the front of the cell
[24]
helps maintain cell size. Rearward membrane flow was also observed in Dictyostelium
 [28]
discoideum cells. These observations provide strong support for models of cell movement
which depend on a rearward cell surface membrane flow (Model B, above). Interestingly, the
migration of supracellular clusters has also been found to be supported by a similar mechanism
[29]
of rearward surface flow.

[30]
Schematic representation of the collective biomechanical and molecular mechanism of cell motion

Collective biomechanical and molecular mechanism of cell

motion[edit]

Based on some mathematical models, recent studies hypothesize a novel biological model for
[30]
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[edit]

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
[31]
gradient in inner membrane surface 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 Rac and CDC42 are
[32][33]
found at the front of the cell, whereas Rho GTPase and PTEN are found toward the rear.

It is believed that filamentous actins and microtubules are important for establishing and
[34]
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 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
[15][35]
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.
[15]

Inverse problems in the context of cell motility[edit]

[36][37][30]
An area of research called inverse problems 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
[38] [39]
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[edit]

Biology portal
● Cap formation
● Chemotaxis
● Collective cell migration
● Durotaxis
● Endocytic cycle
● Mouse models of breast cancer metastasis
● Neurophilic
● Protein dynamics

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