Modulating embryonic signaling pathways paves the way for regeneration in wound healing

Abstract

Epithelial tissues, including the skin, are highly proliferative tissues with the capability to constant renewal and regeneration, a feature that is essential for survival as the skin forms a protective barrier against external insults and water loss. In adult mammalian skin, every injury will lead to a scar. The scar tissue that is produced to seal the wound efficiently is usually rigid and lacks elasticity and the skin's original resilience to external impacts, but also secondary appendages such as hair follicles and sebaceous glands. While it was long thought that hair follicles develop solely during embryogenesis, it is becoming increasingly clear that hair follicles can also regenerate within a wound. The ability of the skin to induce hair neogenesis following injury however declines with age. As fetal and neonatal skin have the remarkable capacity to heal without scarring, the recapitulation of a neonatal state has been a primary target of recent regenerative research. In this review we highlight how modulating dermal signaling or the abundance of specific fibroblast subsets could be utilized to induce de novo hair follicles within the wound bed, and thus to shift wound repair with a scar to scarless regeneration.

Keywords: WIHN; embryonic signaling pathways; fibroblast; hair follicle; skin regeneration.

FIGURE 1

Wound-induced hair follicle de novo formation is more frequent in neonatal than in adult wound beds. Immunofluorescence-stainings of reepithelialized wound beds from (A) adult wounds 14 days after injury, (B) neonatal wounds 7 days after injury and (C) magnification of de novo hair follicles (HFs) in neonatal wound beds. (A) and (B) Yellow dotted lines indicate wound margins, white dotted lines demarcate the border between epidermis and dermis, and white arrows indicate de novo HFs. (C) Red dotted lines demarcate epithelial and mesenchymal compartments of de novo HFs and red arrows indicate de novo dermal papillae. Scale bars represent 500 µm.

FIGURE 2

Reinstating a neonatal-like state during wounding promotes regeneration. (A) The reticular fibroblast lineage mediates the initial phase of wound repair including the deposition of collagens and other components of the ECM, while (B) the papillary fibroblast lineage repopulates the wound bed only at later stages of wound repair. Manipulation of the dermal cellular composition like (C) expanding the papillary fibroblast lineage or (D) modulation of embryonic signaling pathways such as the Wnt- and Hh-signaling pathways in fibroblasts increases WIHN and regeneration during wounding.