Cell-Cell Contact Mediated Coordination of Cell Migration: Contact Following and Contact Inhibition of Locomotion

Li and Wang,  Proc. Natl. Acad. Sci. USA 105:10678-10683 (2018)

Cell–cell contact-mediated responses play key roles in coordinating cell migration, which is conventionally described in terms of repulsive responses of contact inhibition of locomotion (CIL).  However, many aspects of collective migration are not fully recapitulated by repulsive responses.  As repulsive responses have been found to arise from collisions between the heads of approaching cells, we hypothesize that cells exhibit different responses upon contact with other regions of a neighbor.  Based on studies of tail-following in Dictyostelium discoidium, it is reasonable to hypothesize that contact with the tail regions of neighboring cells may induce a different response.  The following videos, recorded on micropatterned substrates to facilitate cell-cell contact, indicate a following behavior, which we term contact following of locomotion, upon head-tail contact.  Each video starts with a still image showing the micropattern. The scale bar indicates 50 μm.

Cells Migrate Away from the Front of Approaching Neighbors

NRK-52E cells are initially stalled at a micropatterned X (left) or T (right) intersection.  Contact with the front of an approaching cell causes the cell to leave the intersection, in a direction away from the approaching cell.  Otherwise these cells would spend an extended period of time stalling at the intersection.  This behavior parallels the phenomenon of contact inhibition of locomotion.  Images are taken at 10 minute intervals for a total of 750 minutes.

Cells Follow the Tail of Retreating Neighbors

NRK-52E cells are initially stalled at a micropatterned X (left) or T (right) intersection.  Contact with the tail of a retreating cell causes the cell to leave the intersection, in a direction toward the retreating cell.  Otherwise these cells would spend an extended period of time stalling at the intersection.  This behavior, distinct from contact inhibition, is referred to as contact following of locomotion.  Images are taken at 10 minute intervals for a total of 740 minutes.

Contact Following Is Common among Different Epithellial and Fibroblastic Cell Lines

Similar to NRK-52E cells, MDCK (left) and NIH3T3 (right) cells also exhibit contact following of locomotion -- contact with the tail of a retreating cell also causes these cell to leave the intersection.  Images are taken at 10 minute intervals for a total of 740 (left) and 550 minutes (right) respectively.

Inhibition of Wnt Signaling Pathways Disrupts Contact Following

NRK-52E cells are treated overnight withWnt inhibitors NSC 668036 at 50 μM (left) or 3289-8625 at 10 μM (right).  Treated cells no longer exhibit the ability to follow retreating cells out of micropatterned intersections.  Frames are taken at 10 minute intervals for a total of 800 (left) and 750 minutes (right) respectively.

Contact Following Mediates Collective Migration

NRK-52E cells are placed on a micropattern of Y junctions to obtain a 1D train collective that migrate toward a fork.  Cells within the train follow the tail of the cell in front, and perfer to maintain the integrity of the collective as the train enounters a fork (left), rather than migrate into a cell-free branch.  This is no longer the case if cells are treated with 50 μM if NSC 668036 to inhibit the Wnt signaling pathway.  Frames are taken at 10 minute intervals for a total of 400 minutes (left) and 700 minutes (right) respectively.