Cutaneous wound healing: recruiting developmental pathways for regeneration

Abstract

Following a skin injury, the damaged tissue is repaired through the coordinated biological actions that constitute the cutaneous healing response. In mammals, repaired skin is not identical to intact uninjured skin, however, and this disparity may be caused by differences in the mechanisms that regulate postnatal cutaneous wound repair compared to embryonic skin development. Improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for wound healing complications. Here we focus on the roles of several key developmental signaling pathways (Wnt/β-catenin, TGF-β, Hedgehog, Notch) in mammalian cutaneous wound repair, and compare this to their function in skin development. We discuss the varying responses to cutaneous injury across the taxa, ranging from complete regeneration to scar tissue formation. Finally, we outline how research into the role of developmental pathways during skin repair has contributed to current wound therapies, and holds potential for the development of more effective treatments.

Fig. 1

Proliferative phase of murine cutaneous wound healing. a Illustrative histological section of a murine cutaneous wound during the proliferative phase of repair. Healing dermis is enriched with higher numbers of fibroblasts and macrophages compared to intact skin. b The effect of the developmental signaling pathways on keratinocyte behavior in epidermal closure, and fibroblast behavior and matrix deposition in dermal reconstitution, respectively, is depicted. Red arrows indicate a positive or stimulatory effect of a pathway on a cell type/outcome. Blue “inhibitory” symbols indicate an inhibitory effect. Solid lines indicate that the effect of a pathway on each cell type and/or outcome is supported by substantial in vivo evidence in the literature. Dotted lines indicate effects which either lack sufficient in vivo evidence or are based mainly on in vitro work. Dotted gray lines with a question mark indicate unknown or unclear outcomes. Colored diagrams represent outcomes of pathways in each cell type (or matrix deposition) that are supported by substantial in vivo evidence in the literature. In contrast, gray diagrams represent outcomes that are based mainly on in vitro evidence or require further in vivo investigation; Gray diagrams linked by a simple dotted line indicate that there is either no effect, or that the effect is not known. Refer to the text for a detailed explanation of the effect of each signaling pathway on keratinocyte and fibroblast behavior during wound repair