Wnt Signaling Across Adult Skin Mini-Organs: Interfollicular Epidermis, Hair Follicle, and Nail—Implications for Disease and Regeneration

Skin and its appendages form an integrated system of ectodermal mini-organs that rely on Wnt signaling for lifelong homeostasis and regeneration; yet, the pathway operates in a highly organ-specific manner in each compartment. In interfollicular epidermis, the Wnt activity is spatially graded, thus maintaining the balance between basal progenitor proliferation and terminal differentiation. The hair follicle is governed by an intrinsic oscillator based on cross-regulation between Wnt and BMP signaling, providing a cell-autonomous layer of control over hair cycle dynamics. Finally, the nail organ is characterized by the spatial compartmentalization of Wnt activity, with a distal matrix activation zone supported by specialized mesenchymal niche cells that sustain continuous nail plate growth and coordinate the digit tip regeneration. Understanding these divergent regulatory architectures provides a conceptual framework for targeted regenerative strategies aimed at enhancing repair in skin and its appendages. Therefore, in this review, we synthesize recent molecular studies on Wnt signaling in the adult skin, hair follicles, and nail mini-organs, highlighting appendage-specific features that underlie their distinct regenerative capacities. We further discuss how dysregulated Wnt signaling contributes to skin, hair, and nail pathologies such as alopecia, chronic wounds, excessive scarring, skin cancer, and nail deformations, and summarize the emerging strategies that target Wnt pathway to therapeutically enhance hair regrowth, wound repair, cancer treatment, and digit tip regeneration.