The regenerative role of neural crest stem cells in physical stimuli-enhanced peripheral nerve repair

Neural crest stem cells (NCSCs), capable of differentiating into neurons and Schwann cells, are essential for peripheral nerve regeneration. This study investigates the role of endogenous NCSC-like cells in mechano-electrical stimulation (MES)-enhanced peripheral nerve repair. In a critical-sized nerve injury model, MES leads to complete nerve reconnection, accompanied by a significant increase in NCSC-like cells at the injury sites. In vitro, MES promotes the simultaneous differentiation of NCSC-like cells into neurons and Schwann cells, with elevated neuregulin 1 (NRG1) expression, a key factor in Schwann cell development. Mechanistically, MES activates BMP/Smad signaling, driving neuronal differentiation and subsequent NRG1 secretion, which in turn promotes Schwann cell maturation through the ErBB/NFAT pathway. These findings demonstrate that MES enhances peripheral nerve regeneration by activating and directing stem cell differentiation, supporting a novel therapeutic approach that utilizes physical stimulation for stem cell modulation for nerve repair.