Enhanced nerve regeneration after transplantation of NCAM-positive neural crest-like cells derived from human iPSC.

Abstract

Background: Peripheral nerve injuries often cause persistent sensory and motor deficits, and autologous nerve grafting, the current standard, is limited by donor site morbidity and tissue availability. Human induced pluripotent stem cells (hiPSCs)-derived neural crest-like cells (NCLCs) have shown potential for nerve regeneration, but achieving high purity and safety remains a challenge.

Methods: Using a mouse model of large sciatic nerve defects, we evaluated the efficacy of transplanting NCLCs triple-positive for low-affinity nerve growth factor receptor (LNGFR), thymocyte antigen 1 (THY-1), and neural cell adhesion molecule (NCAM). Purified triple-positive cells induced from hiPSC-derived neural crest lineage were seeded in the conduit with collagen gel in the transplantation group and compared the regeneration with the autograft group and the negative control group without cells.

Results: NCAM-positive NCLCs promoted robust angiogenesis and recruited host Schwann cells, thereby establishing a supportive regenerative microenvironment. This facilitated axonal regrowth, thick myelination, and organized nerve architecture comparable to that of autografts. Functional recovery, assessed by electrophysiological conduction and motor performance, eventually matched autografts, with earlier improvement observed in the transplantation group. No tumor formation was detected, and the proliferative activity of transplanted cells declined over time. Selective marker-based purification likely contributed to the favorable safety profile.

Conclusion: NCAM-positive NCLCs derived from hiPSCs enhance peripheral nerve regeneration through vascularization and Schwann cell-mediated remyelination, resulting in structural and functional recovery equivalent to autografts. This strategy offers a safe, scalable alternative to donor nerve harvest, and integration with bioengineered conduits could further expand clinical applicability in peripheral nerve reconstruction.