Hair follicle stem cell differentiation is inhibited through cross‐talk between Wnt/β‐catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia

TLDR

Hair follicle regeneration is initiated by dermal papilla signals to epidermal stem cells, and while Wnt/β‑catenin promotes hair growth, androgen‑driven miniaturization in androgenetic alopecia occurs through an as‑yet‑unidentified mechanism. The study aims to elucidate how circulating androgens affect dermal papilla‑mediated differentiation of hair follicle stem cells. Using a coculture system of human DPC from AGA patients with hair follicle stem cells and conditioned media, the authors examined androgen and Wnt/β‑catenin signaling interactions by measuring downstream Wnt targets and β‑catenin dynamics. Androgens suppress hair follicle stem cell differentiation by inhibiting canonical Wnt/β‑catenin signaling in dermal papilla cells, but activation of Wnt signaling rescues this effect, restoring keratin 6 expression.

Abstract

Hair follicle (HF) regeneration begins when signals from the mesenchyme-derived dermal papilla cells (DPC) reach multipotent epidermal stem cells in the bulge region. Wnt/β-catenin signalling is known to affect mammalian hair growth positively. In androgenetic alopecia (AGA), androgens cause HF miniaturization through a mechanism that remains unclear. Circulating androgens act on DPC and alter paracrine factors that influence hair epithelial cells.To elucidate the role of androgens in dermal papilla-induced differentiation of HF stem cells.HF stem cell differentiation was evaluated in a coculture model with DPC or culturing with media conditioned by DPC after activation of androgen and Wnt/β-catenin signalling pathways. To study the molecular cross-talk between the androgen and Wnt signalling pathway in DPC, we analysed the expression and activation of downstream Wnt signalling molecules in the presence of androgens.In a coculture model with human DPC from patients with AGA and HF stem cells, we observed that androgens abrogate hair differentiation evaluated by hair-specific keratin 6 expression. Wnt signalling activation restored the ability of androgen-treated DPC to induce differentiation. Androgen treatment revealed a significant decrease in the cytoplasmic/total β-catenin protein ratio and upregulation of the activity of glycogen synthase kinase-3β in DPC, indicative of canonical Wnt pathway inhibition.These results suggest that androgens deregulate DPC-secreted factors involved in normal HF stem cell differentiation via the inhibition of the canonical Wnt signalling pathway.