Mature Schwann Cells Derived From Human Induced Pluripotent Stem Cells Promote Peripheral Nerve Regeneration In Vivo.

Abstract

Peripheral nerve injuries (PNIs) often cause persistent sensory and motor deficits that impair quality of life. To improve outcomes, cell-based therapies have been explored, and Schwann cells (SCs) are considered a promising option because of their essential roles in myelination and neurotrophic support. However, the clinical use of autologous SCs is limited by donor site morbidity and challenges in large-scale expansion, leading to growing interest in human induced pluripotent stem cell (iPSC)-derived SCs. This study aimed to verify the therapeutic effects of iPSC-derived SCs in vivo and to determine whether the differentiation stage of the SCs influences their efficacy. We generated dibutyryl-cAMP-treated mature SCs and untreated immature SCs from iPSCs and transplanted them into a rat sciatic nerve crush injury model. Morphometric analysis showed that myelinated fiber density (fibers/mm²) was significantly higher in the mature SC group than in the control group (12 602 ± 1419 vs 10 105 ± 1673). Myelinated axon diameter (µm) was also significantly greater in the mature SC group (4.73 ± 0.25) compared with the immature SC (4.06 ± 0.28) and control (3.86 ± 0.15) groups. Electrophysiological testing demonstrated that compound muscle action potentials in the pedal adductor muscle were detected only in the mature SC group within 28 days after surgery. Western blot analysis of the tibialis anterior muscle showed significantly higher myosin heavy chain 1 (MYH1) expression in the mature SC group than in the control group. Quantitative reverse transcription-polymerase chain reaction revealed higher expression of bNGF, CCL2, and LAMA2 in mature SCs than in immature SCs. Pathological analysis suggested accelerated Wallerian degeneration in the mature SC group. These results demonstrate that mature iPSC-derived Schwann cells, rather than immature ones, most effectively promote nerve regeneration both histologically and functionally in vivo, highlighting the critical importance of the SC differentiation stage for therapeutic efficacy.