Ephrin-Bs Drive Junctional Downregulation and Actin Stress Fiber Disassembly to Enable Wound Re-epithelialization

For a skin wound to successfully heal, the cut epidermal-edge cells have to migrate forward at the interface between scab and healthy granulation tissue. Much is known about how lead-edge cells migrate, but very little is known about the mechanisms that enable active participation by cells further back. Here we show that ephrin-B1 and its receptor EphB2 are both upregulated in vivo, just for the duration of repair, in the first 70 or so rows of epidermal cells, and this signal leads to downregulation of the molecular components of adherens and tight (but not desmosomal) junctions, leading to loosening between neighbors and enabling shuffle room among epidermal cells. Additionally, this signaling leads to the shutdown of actomyosin stress fibers in these same epidermal cells, which may act to release tension within the wound monolayer. If this signaling axis is perturbed, then disrupted healing is a consequence in mouse and man. [Display omitted] •Ephrin-B/EphBs are upregulated in the migrating wound epidermis in mouse and man•Ephrin-B/EphB signaling drives junction loosening, thus enabling re-epithelialization•Ephrin-B/EphB signaling also leads to dissolution of stress fibers and tension release•In human chronic wounds ephrin-Bs are misregulated and may be a therapeutic target Epithelial migration is essential for skin wound healing. Nunan et al. show that ephrin-B1 is upregulated for the duration of repair and drives both loosening of adherens and tight junctions and release of actomyosin tension to enable re-epithelialization. Misregulation of Eph/ephrin-B signaling in mouse and man considerably hinders healing.