The Role and Mechanism of Hair Follicle Neural Crest Stem Cells and Their Small Extracellular Vesicles in Repair of Peripheral Nerve Injury.

Peripheral nerve injury (PNI) remains a vital clinical challenge due to the limited efficacy of current therapeutic strategies. Autologous nerve grafting, the gold standard for repairing PNI, remains limited by certain donor site morbidity, and alternative approaches include cell therapy, nerve conduits, gene therapy, and electrical stimulation with immune rejection and ethical controversies. Yet, hair follicle neural crest stem cells (hfNCSCs), a pluripotent cell population originating from the embryonic neural crest, have emerged as a promising candidate. hfNCSCs exhibit high differentiation potential, ethical acceptability, and accessibility, possessing significant advantages in axonal regeneration and functional recovery. Concurrently, small extracellular vesicles (sEVs) derived from stem cells have garnered increasing attention for their low immunogenicity, non-tumorigenicity, and convenient storage. Preclinical studies highlight their synergistic potential in modulating neuroinflammation, enhancing Schwann cell (SC) activity, and promoting nerve repair. This review summarizes recent advances in hfNCSCs and sEVs for PNI repair, with a focus on molecular mechanisms and translational applications. We further discuss the challenges and future directions of hfNCSCs-sEVs as a cell-free therapeutic strategy in neural regeneration.