Beyond scarring: immune-epithelial crosstalk in wound-induced hair follicle neogenesis

Wound-induced hair follicle neogenesis (WIHN) represents a remarkable regenerative phenomenon observed in adult mammalian skin (predominantly studied in mice), in which large full-thickness wounds bypass fibrotic scarring to generate fully functional de novo hair follicles. This process reflects the context-dependent reactivation of embryonic morphogenetic programs, driven by a coordinated tripartite immune-microbial-epithelial axis (defined here as the integrated multi-directional signaling network among localized immune cells, epithelial stem cells, and the skin microbiota/fibroblasts). Mechanistically, γδ T cells initiate dermal fibroblast reprogramming through an FGF9-Wnt feed-forward loop, while macrophages promote AKT/β-catenin signaling in Lgr5⁺ epithelial stem cells via TNF-α-driven non-canonical pathways. Regulatory T cells (Tregs) further support follicular morphogenesis by delivering Jagged1/Notch signals. In parallel, the skin microbiota acts as a key amplifier of regeneration, modulating the wound microenvironment through the IL-1β/MyD88 signaling axis. Taken together, WIHN illustrates the remarkable functional plasticity of immune signaling, which can be repurposed from host defense to orchestrating tissue regeneration. By elucidating this dynamic murine skin-immune dialogue, this mini-review provides a conceptual framework for speculative precision immunomodulatory therapies and emerging translational approaches-such as laser-assisted tissue remodeling-aimed at treating inflammatory and scarring alopecia, as well as achieving scarless and functionally restorative wound healing.