Collective cell migration

Collective cell migration describes the movements of group of cells and the

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

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The environment of the migrating cell can affect its speed, persistence and direction of migration by stimulating it. The

Collective cell migration is enhanced by geometrical confinement of an extracellular matrix molecule (e.g. the proteoglycan versican in neural crest cells), 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.^[4]

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 (in vivo and in vitro),^[5] and computationally (in silico).^[6]

Co-attraction between collectively migrating cells is the process by which cells of the same type secrete chemo-attractant (e.g. C3a in neural crest cells), 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.^[7][8]

Contact inhibition of locomotion (CIL) 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 (

• Contact inhibition of proliferation (CIP) is the inhibition of cell division with increasing percent of confluency. CIP and CIL are two different processes, which are sometimes mistakenly interrelated.^[9]

Collective cell migration is studied over many model species.

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.^[12]

• A: Border cell migration in a Drosophila embryo. (a) shows border cells migrating in a confined space surrounded by gigantic nurse cells.^[10]
• B: The initial position of
  primordia (pLLP) cells. (b) is a sagittal section showing how these cells migrate in a confined space between the somatic mesoderm and epidermis.^[10]
• C: The cephalic neural crest of the clawed frog Xenopus migrating in well-defined streams from dorsal to ventral and anterior. (c) is a transverse section across the head of a Xenopus embryo showing the high degree of confinement experienced by the neural crest while migrating sandwiched between the epidermis and underlying head mesoderm.^[10]

There are several mathematical models that describe collective cell motion. Typically, a Newtonian equation of motion for a system of cells is solved.^[21] Several forces act on each individual cell, examples are friction (between environment and other cells), chemotaxis and self-propulsion. The latter implies that cells are active matter far from thermal equilibrium that are able to generate force due to myosin-actin contractile motion. An overview over physical description of collective cell migration^[22] explains that the following types of models can be used:

• Lattice models (e.g. BIO-LGCA models)
• Models similar to Dissipative particle dynamics that solve Newton's equation of motion with dissipative and random forces
• Models where cells depict Voronoi regions and an effective potential (based on Voronoi graphs) for the tissue is used
• Continuum models, e.g. with the use of a phase field
• Kinetic theories similar to the Boltzmann equation^[23]

These mathematical models give some insight in complex phenomena like cancer, wound healing^[24] and ectoplasms.

Chemotaxis of a cell up a fixed (left, blue) and cell-induced, or self-generated, gradient (right, green) of chemoattractant. Lines show the concentration (c) of chemoattractant along space (x), in which cells (ellipses) migrate. Darker shapes illustrate successive time-points.^[25]

Spectrum of cell–cell interactions, from repulsive interactions (left, blue) to volume exclusion (right, green). With repulsive interactions, cells move away from the point of contact with another cell (second cell shown as stationary for simplicity). With volume exclusion, cells block each other's movement, but can move to any space not occupied by another cell.^[25]

In the diagram immediately below, different morphologies of collective cell migration are characterized by their cohesiveness during migration (inversely related to density), as well as the number of nearest neighbours with which a cell interacts while moving (i.e. the topological arrangement of individual cells in the population). Cells (ellipses) can migrate in linear chains (top left), with persistent contact to cells either side of them, or along trails formed by preceding cells (bottom left). In migrating sheets, cells may maintain most of their nearest neighbours over time (top right), whereas in streaming migration cell–cell contacts occur at longer range and with potentially frequent neighbour rearrangement (bottom right). These concepts easily extend to three-dimensional migration, in which case the place of migrating sheets can be taken by moving clusters or spheroids.^[25]

• Bacteria collective motion
• Boids
• Collective animal behavior
• Collective motion
• Embryogenesis