Wound-Induced Hair Follicle Neogenesis as a Promising Approach for Hair Regeneration

Abstract

The mammalian skin contains hair follicles, which are epidermal appendages that undergo periodic cycles and exhibit mini-organ features, such as discrete stem cell compartments and different cellular components. Wound-induced hair follicle neogenesis (WIHN) is the remarkable ability to regenerate hair follicles after large-scale wounding and occurs in several adult mammals. WIHN is comparable to embryonic hair follicle development in its processes. Researchers are beginning to identify the stem cells that, in response to wounding, develop into neogenic hair follicles, as well as to understand the functions of immune cells, mesenchymal cells, and several signaling pathways that are essential for this process. WIHN represents a promising therapeutic approach to the reprogramming of cellular states for promoting hair follicle regeneration and preventing scar formation. In the scope of this review, we investigate the contribution of several cell types and molecular mechanisms to WIHN.

Keywords: hair follicle neogenesis; regeneration; stem cell; wound epithelialization; wound-induced hair follicle neogenesis.

Fig. 1. Wound-induced hair follicle neogenesis (WIHN) in the center of large murine wounds.

(A) Scar formation occurs during the repair of small wounds in the mouse skin. (B) Adult mice display WIHN only if they had a large, full-thickness wound. ECM, extracellular matrix.

Fig. 2. Multiple signaling pathways involved in wound-induced hair follicle neogenesis (WIHN).

Shh activation in the epidermis or fibroblasts is important for WIHN. An increase in Wnt/β-catenin in the epidermis induces WIHN, whereas an increase in Wnt/β-catenin in fibroblasts prevents WIHN. dsRNA binding to TLR3 is important for WIHN via the IL-6/STAT3 pathway and RA accumulation. γδ T cells secrete FGF-9, which induced the release of Wnt2a. CX3CR1⁺ macrophges release TGF-β1 and TNF-α, thereby activating the AKT/β-catenin pathway. IGF-1 and FGF-2 are produced by M2 macrophages for WIHN. Shh, Sonic hedgehog; FGF-9, fibroblast growth factor 9; dsRNA, double-stranded RNA; TLR3, Toll-like receptor 3; IL-6, interleukin-6; TGF-β1, transforming growth factor β1; TNF-α, tumor necrosis factor α; IGF-1, insulin-like growth factor 1; FGF-2, fibroblast growth factor 2.

Fig. 3. The distinct phases of skin wound healing.

There are four stages involved in the process of wound healing which include hemostasis, inflammation, proliferation, and remodeling. ECM, extracellular matrix.