Mesenchymal stem cell-derived exosomes promote scalp rejuvenation through type XVII collagen regulation via the miR-21-5p/DKK2/Wnt pathway

Background: Hair follicle aging is driven by COL17A1 proteolysis in hair follicle stem cells (HFSCs). Mesenchymal stem cell (MSC)-derived exosomes show promise in tissue regeneration, but their effects on COL17A1 and hair follicle aging remain unexplored. Methods: human hair follicle organ culture, and C57BL/6 mouse hair regeneration model. Small RNA sequencing, dual-luciferase reporter assay, and rescue experiments were performed to elucidate the mechanism. Results: Exosome treatment reduced SA-β-gal-positive cells from 67.5% to 21.4%, upregulated COL17A1 mRNA by 2.67-fold (with protein restoration to 0.89-fold of control levels), enhanced hair follicle elongation by 47.4%, and achieved 92.4% hair coverage in mice versus 45.6% for controls, outperforming minoxidil (78.3%). miR-21-5p was identified as the most abundant exosomal miRNA and confirmed to directly target DKK2, a Wnt antagonist. DKK2 suppression was associated with Wnt/β-catenin pathway activation and upregulation of COL17A1 expression. miR-21-5p inhibitor partially blocked exosome effects, validating this axis. Conclusion: hUC-MSC-derived exosomes attenuate hair follicle senescence and promote hair regeneration through the miR-21-5p/DKK2/Wnt/β-catenin/COL17A1 axis, providing a promising cell-free strategy for scalp rejuvenation.