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. 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. Cells often migrate in response to specific external signals, including chemical signals and mechanical signals. Due to the highly viscous environment (low Reynolds number), cells need to permanently 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 motion (most commonly studied) and blebbing motility.
Cell migration studies
The migration of cultured cells attached to a surface is commonly studied using 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.
- cytoplasmic displacement at leading front
- laminar removal of dorsally-accumulated debris toward trailing end
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.
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 behaviour.
Molecular processes at the front
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)
Through experiment, it is found that the cell's front is a site of rapid actin polymerisation: soluble actin monomers polymerise there to form filaments. This has led to the view that it is the formation of these actin filaments, which pushes the leading front forward and is the main motile force for advancing the cell’s front. In addition, cytoskeletal elements are able to interact extensively and intimately with a cell's plasma membrane.
Membrane flow model (B)
Studies have also shown that the front is the site at which membrane is returned to the cell surface from internal membrane pools at the end of the endocytic cycle. This has led to the view 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 the cell's blowing bubbles (or "blebs") at its front. For a cell to move, it is necessary to bring a fresh supply of "feet" (those molecules called 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.
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 arrow 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. Thus, the phospholipid PIP3 and activated Rac and CDC42 are found at the front of the cell, whereas Rho GTPase[disambiguation needed] and PTEN are found toward the rear.
It is believed that filamentous actins and microtubules 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 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 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. However, within extracellular matrix, microtubules are required for both directional and random movement.
- 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
- Time-lapse microscopy videos showing proliferating and migrating cells
- Cell migration tracking by Phase Holographic Imaging AB
- Huber, F; Schnauss, J; Roenicke, S; Rauch, P; Mueller, K; Fuetterer, C; Kaes, J (2013). "Emergent complexity of the cytoskeleton: from single filaments to tissue". Advances in Physics 62 (1): 1–112. doi:10.1080/00018732.2013.771509. online
- "HoloMonitor - Non-invasive image cytometers". Phase Holographic Imaging AB.
- "What is Cell Migration?". Cell Migration Gateway. Cell MIgration Consortium. Retrieved 24 March 2013.
- Abercrombie, M; Heaysman, JE; Pegrum, SM (1970). "The locomotion of fibroblasts in culture III. Movements of particles on the dorsal surface of the leading lamella". Experimental Cell Research 62 (2): 389–98. doi:10.1016/0014-4827(70)90570-7. PMID 5531377.
- Wang, Y. L. (1985). "Exchange of actin subunits at the leading edge of living fibroblasts: possible role of treadmilling". The Journal of Cell Biology 101 (2): 597–602. doi:10.1083/jcb.101.2.597. PMC 2113673. PMID 4040521.
- Mitchison, T; Cramer, LP (1996). "Actin-Based Cell Motility and Cell Locomotion". Cell 84 (3): 371–9. doi:10.1016/S0092-8674(00)81281-7. PMID 8608590.
- Pollard, Thomas D; Borisy, Gary G (2003). "Cellular Motility Driven by Assembly and Disassembly of Actin Filaments". Cell 112 (4): 453–65. doi:10.1016/S0092-8674(03)00120-X. PMID 12600310.
- Doherty, Gary J.; McMahon, Harvey T. (2008). "Mediation, Modulation, and Consequences of Membrane-Cytoskeleton Interactions". Annual Review of Biophysics 37: 65–95. doi:10.1146/annurev.biophys.37.032807.125912. PMID 18573073.
- Bretscher, M. S. (1983). "Distribution of receptors for transferrin and low density lipoprotein on the surface of giant HeLa cells". Proceedings of the National Academy of Sciences 80 (2): 454–8. doi:10.1073/pnas.80.2.454. PMC 393396. PMID 6300844.
- Bretscher, M (1996). "Getting Membrane Flow and the Cytoskeleton to Cooperate in Moving Cells". Cell 87 (4): 601–6. doi:10.1016/S0092-8674(00)81380-X. PMID 8929529.
- Parent, C. A.; Devreotes, PN (1999). "A Cell's Sense of Direction". Science 284 (5415): 765–70. doi:10.1126/science.284.5415.765. PMID 10221901.
- Ridley, A. J.; Schwartz, MA; Burridge, K; Firtel, RA; Ginsberg, MH; Borisy, G; Parsons, JT; Horwitz, AR (2003). "Cell Migration: Integrating Signals from Front to Back". Science 302 (5651): 1704–9. doi:10.1126/science.1092053. PMID 14657486.
- Ganguly, A; Yang, H; Sharma, R; Patel, K; Cabral, F (2012). "The Role of Microtubules and Their Dynamics in Cell Migration.". J Biol Chem. 4 (52): 253–65. doi:10.1074/jbc.M112.423905. PMID 23135278.
- Meyer, A; Hughes, S; Kay, J; Castillo, A; Lauffenburger, D (2012). "2D protrusion but not motility predicts growth factor–induced cancer cell migration in 3D collagen.". J Cell Biol. 194 (6): 721–729. doi:10.1083/jcb.201201003. PMC 3373410. PMID 22665521.
- Doyle, A; Wang, F; Matsumoto, K; Yamada, K (2009). "One-dimensional topography underlies three-dimensional fibrillar cell migration.". J Cell Biol. 184 (4): 481–490. doi:10.1083/jcb.200810041.