Abstract
BACKGROUND: Peripheral nerve injuries are associated with significant morbidity, particularly when primary surgical repair is delayed or impossible due to extensive nerve gaps. While advances in biomedical engineering have led to commercially available nerve guidance conduits tailored for such injuries, rates of sensory and motor recovery remain suboptimal following neurotmesis with gap defects beyond 3 cm. Cell therapy represents a promising treatment strategy to heal the injured peripheral nervous system, thought to promote tissue regeneration and enhance endogenous mechanisms of nerve repair to restore functionality. In this study, we explore the potential utility and efficacy of subcutaneous adipose tissue-derived neural stem cells in a nerve transection injury model. METHODS: Plp1-EGFP mice, which express GFP in Schwann cells, underwent surgical excision of a 5 mm segment of the left sciatic nerve. Nerves were then immediately repaired using silicone nerve guidance conduits with a residual 5 mm defect between nerve stumps. Conduits were loaded with cell culture media alone or with subcutaneous adipose tissue-derived neural stem cells harvested from Wnt1-tdTomato neural crest reporter mice, the latter enabling cell tracing post-transplantation. RESULTS: Subcutaneous adipose tissue-derived neural stem cells persisted through postoperative day 56 and contributed structurally to the reformed sciatic nerve. Integration between Wnt1-tdTomato neural stem cells and endogenous Plp1-EGFP Schwann cells occurred at the distal and proximal transection margins. Furthermore, neural stem cells predominantly differentiated into Schwann-like cells following transplantation, aiding in myelination of the reformed nerve, but not undesirable cell types such as neurons. Gait testing indicated that adipose-derived neural stem cells significantly improved hindlimb motor recovery compared to conduit repair alone by postoperative day 56. CONCLUSIONS: Using cell tracer models, we confirm that adipose-derived neural stem cells can be therapeutically delivered to injured peripheral nerves, integrate with recipient axons and Schwann cells, and differentiate into myelinating Schwann-like cells to enhance motor recovery. These findings indicate that subcutaneous adipose tissue-derived neural stem cells could fill a critical gap in the treatment of peripheral nerve injuries, representing a readily available, autologous source of regenerative cells to optimize functional recovery after injury.