Contact inhibition of locomotion probabilities drive solitary versus collective cell migration

Abstract

Contact inhibition of locomotion (CIL) is the process whereby cells collide, cease migrating in the direction of the collision, and repolarize their migration machinery away from the collision. Quantitative analysis of CIL has remained elusive because cell-to-cell collisions are infrequent in traditional cell culture. Moreover, whereas CIL predicts mutual cell repulsion and 'scattering' of cells, the same cells in vivo are observed to undergo CIL at some developmental times and collective cell migration at others. It remains unclear whether CIL is simply absent during collective cell migration, or if the two processes coexist and are perhaps even related. Here, we used micropatterned stripes of extracellular matrix to restrict cell migration to linear paths such that cells polarized in one of two directions and collisions between cells occurred frequently and consistently, permitting quantitative and unbiased analysis of CIL. Observing repolarization events in different contexts, including headto-head collision, head-to-tail collision, collision with an inert barrier, or no collision, and describing polarization as a two-state transition indicated that CIL occurs probabilistically, and most strongly upon head-to-head collisions. In addition to strong CIL, we also observed 'trains' of cells moving collectively with high persistence that appeared to emerge from single cells. To reconcile these seemingly conflicting observations of CIL and collective cell migration, we constructed an agent-based model to simulate our experiments. Our model quantitatively predicted the emergence of collective migration, and demonstrated the sensitivity of such emergence to the probability of CIL. Thus CIL and collective migration can coexist, and in fact a shift in CIL probabilities may underlie transitions between solitary cell migration and collective cell migration. Taken together, our data demonstrate the emergence of persistently polarized, collective cell movement arising from CIL between colliding cells.

Tight coupling between nucleus and cell migration through the perinuclear actin cap

“…3). Previous studies reported that the centrosome in polarized motile cells is highly related to the directional cell migration but its location varies depending on cell type (Danowski et al, 2001;Desai et al, 2013;Niu et al, 1997;Pouthas et al, 2008;Ueda et al, 1997;Yvon et al, 2002), contact inhibition (Desai et al, 2013) and physical constraint (Jiang et al, 2005); our group recently demonstrated that MTOC position was highly correlated with cell polarization: the distance between MTOC and cell centroid was larger in polarized single cells (Hale et al, 2011). Consistent with the observation using EGFP-a-tubulintransfected cells (Fig.…”

Polarity mechanisms such as contact inhibition of locomotion regulate persistent rotational motion of mammalian cells on micropatterns

“…14, 18, 45); (ii) velocity alignment (VA), in which cells align their polarity to their own velocity (13,15,47,48); (iii) contact inhibition of locomotion (CIL), in which cell polarity is inhibited by contact with other cells (10,12); and (iv) cell front-front inhibition (FF), a generalization of CIL in which only contact with the cell front is inhibitory. FF is supported by experiments of Desai et al (49) that show head-head collisions lead to repolarization at a greater rate than head-tail collisions. There is also some historical precedent; in early papers on CIL, Abercrombie and Dunn (44) argued for a distinction between head-head and head-tail collisions; see also ref.…”

“…The mechanisms of CIL and FF are very similar and may be difficult to distinguish from unconstrained collision data (5). In adhesive stripe assays, collision statistics are simpler to obtain (43, 49); Desai et al (49) note that head-tail collisions are less likely to lead to repolarization of both cells, consistent with FF rather than our CIL mechanism. However, other mechanisms, such as VA, could also lead to both PRM and asymmetry between head-head and head-tail collisions.…”

Emergent structures and dynamics of cell colonies by contact inhibition of locomotion

“…Subsequently, repolarization of the cell's cytoskeleton creates a new front away from the adhesion zone, and the two cells thus separate (20,21). This interaction has been shown to be crucial in determining the collective behavior of cell groups in several contexts (22). For example, CIL guides the directional migration of neural crest cells (23) and also ensures the correct dispersion of Cajal-Retzius cells in the cerebral cortex (24) or of hemocytes in the embryo (25).…”