Collective cell migration describes the movements of group of cells and the emergence of collective behavior from cell-environment interactions and cell-cell communication. Collective cell migration is an essential process in the lives of multicellular organisms, e.g. embryonic development, wound healing and cancer spreading. Cells can migrate as a cohesive group or have transient cell-cell adhesion sites. They can also migrate in different modes like sheets, strands, tubes, and clusters. While single-cell migration has been extensively studied, collective cell migration is a relatively new field with applications in preventing birth defects or dysfunction of embryos. It may improve cancer treatment by enabling doctors to prevent tumors from spreading and forming new tumors.
Cell-environment interactions
The environment of the migrating cell can affect its speed, persistence and direction of migration by stimulating it. The extracellular matrix provides not only the structural and biochemical support, but also plays a major role in regulating cell behavior. Different ECM proteins allow cells to adhere and migrate, while forming focal adhesions in the front and disassembling them in the back. Using these adhesion sites, cells also sense the mechanical properties of the ECM. Cells can be guided by a gradient of those proteins or a gradient of soluble substrates in the liquid phase surrounding the cell. Cells sense the substrate through their receptors and migrate toward the concentration. Another form of stimulation can be rigidity gradients of the ECM.
Confinement
Collective cell migration is enhanced by geometrical confinement of an extracellular matrix molecule, that acts as a barrier, to promote the emergence of organized migration in separated streams. Confinement is also observed in vivo, where the optimal width is a function of the number of migrating cells in different streams of different species.
Cell-cell communication
Migrating isolated cell responds to cues in its environment and changes its behavior accordingly. As cell-cell communication does not play a major role in this case, similar trajectories are observed in different isolated cells. However, when the cell migrates as part of the collective, it not only responds to its environment but also interacts with other cells through soluble substrates and physical contact. These cell-cell communication mechanisms are the main reasons for the difference between efficient migration of the collective and random walk movements of the isolated cell. Cell-cell communication mechanisms are widely studied experimentally, and computationally.
Co-attraction
Co-attraction between collectively migrating cells is the process by which cells of the same type secrete chemo-attractant, that stimulates other cells in the group that have the receptors to that chemo-attractant. Cells sense the secreted substrate and respond to the stimulation by moving towards each other's and maintain high cell density.
Contact inhibition of locomotion is a process in which the cell changes its direction of movement after colliding into another cell. Those cells could be of the same cell type or different types. The contacts are created by transmembrane glycoproteins named cadherins and other proteins. After cell-cell contact, the protrusions of cells in the contact direction are inhibited. In the CIL process, cells migrate away from each other by repolarizing in the new direction, so that new protrusions are formed in the front while contractions pull the back from contact.
Contact inhibition of proliferation is the inhibition of cell division with increasing percent of confluency. CIP and CIL are two different processes, which are sometimes mistakenly interrelated.
Examples of studied systems
Collective cell migration is studied over many model species. Border cells in flies : the border cells migrate during the differentiation of egg cells to be ready for fertilization. The lateral line in zebrafish: collective cell migration from head to tails is essential to the development of the sensory system of the fish. The sensors of the lateral line measure the flow over the body-surface of the fish. Wound healing: collective cell migration is an essential part in this healing process, wound area is closed by the migrating cells. Wound healing is commonly studied in vitro using cell lines such as Madin-Darby Canine Kidney cells. Neural crest cells in mice, Leghorn chicks, amphibians, and fish : collective migration of neural crest cells occurs during embryo development of vertebrates. They migrate long distances from the head to give rise to different tissues. Spreading of cancer : common complication of cancer involve formation of new tumors, as a result of migration of cancer cells from the primary tumor. Similar to collective cell migration in development and wound healing, cancer cells also undergo epithelial to mesenchymal transition, that reduces cell-cell adhesions and allows cancer spreading.
