Collective cell migration of epithelial and mesenchymal cells

Abstract

Directional cell migration is required for proper embryogenesis, immunity, and healing, and its underpinning regulatory mechanisms are often hijacked during diseases such as chronic inflammations and cancer metastasis. Studies on migratory epithelial tissues have revealed that cells can move as a collective group with shared responsibilities. First thought to be restricted to proper epithelial cell types able to maintain stable cell-cell junctions, the field of collective cell migration is now widening to include cooperative behavior of mesenchymal cells. In this review, we give an overview of the mechanisms driving collective cell migration in epithelial tissues and discuss how mesenchymal cells can cooperate to behave as a collective in the absence of bona fide cell-cell adhesions.

Fig. 1

Epithelial-mesenchymal transition and epithelial collective migration. a Epithelial-mesenchymal transition (EMT). EMT is a complex, non-linear multi-step process that, when completed, converts epithelial cells into archetypal mesenchymal cells. Epithelial cells have a clear apico-basal polarity with cell–matrix adhesion at their basal side and cell–cell adhesion at their apical side. EMT includes: loss of apico-basal polarity; loss of cell–cell adhesion, and acquisition of cell motility. Each of these aspects is controlled by an array of transcription factors and can, to some extent, be regulated independently. Despite having no cell–cell adhesions, mesenchymal cells often express cell–cell adhesion molecules at their cell membrane. Cell–matrix and cell–cell adhesion molecules are shown in red and brown, respectively. b Collective migration of epithelial cells. When epithelial cells undergo collective migration, they maintain part of their epithelial characteristics. For instance, they maintain stable cell–cell junctions throughout migration and part of their apico-basal polarity. Such an intermediate phenotype is often called metastable

Fig. 2

Epithelial versus mesenchymal collective cell migration. a Epithelial collective cell migration showing stable cell–cell contact (red lines). b Mesenchymal collective cell migration showing transient cell–cell contact (red lines), which are sufficient to polarize the cells. c Some examples of cell–cell adhesion molecules expressed during epithelial or mesenchymal collective cell migration. References: Zebrafish lateral line [–, –140]; Drosophila border cells [–, –143]; Xenopus mesoderm [, –146]; Xenopus NC cells [, , , –150]

Fig. 3

Contact-inhibition of locomotion. a CIL consists of a series of events. First, cells make a physical contact. This contact triggers the collapse of cell protrusions. The colliding cells quickly lose their polarity and repolarize in the opposite direction. This repolarization often makes the cells move away from each other. b Diagram representing two colliding cells undergoing CIL. c Molecular pathways involved in CIL in Xenopus NC cells

Fig. 4

Contact-inhibition of locomotion promotes collective NC guidance. a NC cells exhibit different chemotactic abilities depending on cell density/cell–cell contacts. From left to right: isolated cells have no interactions with other cells and unstable cell polarity. Under these conditions, the chemoattractant Sdf1 is unable to impose a clear front-rear polarity and cells chemotax poorly. When cell density increases, cells can interact with each other. Each collision establishes a new front-rear polarity owing to CIL. Well-polarized cells have their cell protrusions further stabilized by the external chemoattractant, which leads to better chemotaxis. When cell–cell interactions are inhibited, chemotaxis efficiency is reduced. Cell paths are shown as dotted lines. Cell–cell contacts are shown in red. b Sdf1-Cxcr4 chemotaxis reinforces CIL-dependent cell polarity. CIL imposes a rear identity via RhoA activation. Sdf1/Cxcr4 increases Rac1, stabilizing cell protrusions at the front

Fig. 5

Integration of contact-inhibition of locomotion and co-attraction (CoA) promotes collective NC cell migration. a Co-attraction (CoA). When part of a group, cells display a radial polarity with cell protrusions pointing outward owing to CIL (1). Since cells are migratory, over time the CIL-dependent outward polarity favors cell dispersion (2). When a cell detaches from the group, the polarity imposed by CIL is rapidly lost. Each cell is secreting C3a and expresses its cognate receptor C3aR. A local gradient of C3a repolarizes the wandering cell (3), thus promoting gathering (4). b Cell clusters are under the influence of two major driving forces: a centripetal force owing to the local C3a gradient, and a centrifugal force owing to CIL. C3a is shown as shades of blue. Local and overall gradients of C3a are shown as dotted lines. When physical contact between a cell and the rest of the group is disrupted, the influence of CIL diminishes, which in turn favors CoA. c Molecular pathways involved in CIL and CoA compete to impose a front–rear cell polarity. CIL favors outward migration back by establishing a rear identity at the site of contact via RhoA activation. CoA promotes inward migration by inducing Rac1 activity. Since CIL and CoA counterbalance each other, collective cell migration is possible even in the absence of stable cell–cell adhesion