Cell migration
Cell migration is a central process in the development and maintenance of
Due to the highly viscous environment (low
Cell migration studies
The migration of cultured cells attached to a surface or in 3D is commonly studied using microscopy.[5][6][3] 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.[7] 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 the cell.[8]
Other eukaryotic cells are observed to migrate similarly. The amoeba
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 polymerisation at the cell's front edge.[10] 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.[11][12] In addition, cytoskeletal elements are able to interact extensively and intimately with a cell's plasma membrane.[13]
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.[14] 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.[15] 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
In the case of
Mechanistic basis of amoeboid migration
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 mechanism for microscopic objects to swim forward.[25] 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.[26] 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 helps maintain cell size.[24] Rearward membrane flow was also observed in Dictyostelium discoideum cells.[28] 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 of rearward surface flow.[29]
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.[30] 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
It is believed that filamentous actins and
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.[15][35] 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
An area of research called inverse problems in cell motility has been established. [36][37][30] 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. [38] [39] 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
- Collective cell migration
- Durotaxis
- Endocytic cycle
- Mouse models of breast cancer metastasis
- Neurophilic
- Protein dynamics
References
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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