A novel cell-free regenerative therapy for hair loss: human fetal cartilage progenitor cell secretome.

Hair loss, particularly androgenic alopecia, is driven by testosterone-induced apoptosis and impaired dermal papilla (DP) cell function, disrupting epithelial-mesenchymal interactions and hindering hair follicle regeneration. Current non-surgical treatments, such as minoxidil and finasteride, provide limited and temporary benefits. Here, we report the development of a novel, cell-free regenerative therapy using the secretome of human fetal cartilage progenitor cells (ShFCPC), enriched with extracellular matrix (ECM) proteins and bioactive factors critical for tissue remodeling and cell survival. Proteomic analysis of ShFCPC identified key biomolecules involved in cell survival, adhesion, and tissue remodeling. In vitro, ShFCPC significantly enhanced DP cell viability, proliferation, and migration, particularly under testosterone-induced apoptosis, restoring β-catenin signaling and integrin-mediated ECM interactions. In a co-culture model, ShFCPC promoted the formation of hair follicle germs (HFGs) and improved the expression of trichogenic markers and cell organization. In vivo, ShFCPC-treated HFGs successfully regenerated functional hair follicles in nude mice and reversed testosterone-induced hair loss in rats. ShFCPC treatment led to a significant increase in hair regrowth (94.9 % coverage vs. 44.7 % in controls) and improved follicle structure, including sebaceous glands, dermal papillae, and hair shafts. Moreover, the expression of key hair follicle markers, such as β-catenin and CD34, which are critical for hair follicle regeneration, was significantly upregulated. Importantly, no toxicity was observed in ShFCPC-treated animals, confirming its safety profile. These findings demonstrate that ShFCPC enhances the hair-inductive potential of DP cells by modulating apoptosis and activating β-catenin signaling. ShFCPC has substantial potential as a novel disease-modifying agent for hair loss treatment.