Human-Derived Motor Neuron Progenitor Cell Implantation Rescues Motor Endplates Following Peripheral Nerve Injury.

PURPOSE: Degradation of motor endplates (MEPs) following peripheral nerve injury (PNI) is a major determinant of functional recovery, as prolonged denervation renders target muscles progressively unreceptive to reinnervation. While prior studies have demonstrated that stem cell-based therapies may provide neurotrophic support following PNI, their potential effects on MEP preservation have not been well studied. We hypothesized that transplantation of human-induced pluripotent stem cell (hiPSC)-derived motor neuron progenitors (MNPs) into chronically denervated muscle would be associated with preservation of MEP architecture.

METHODS: With Institutional Animal Care and Use Committee approval, chronic denervation injuries were created in mice via sciatic nerve transection. After 4 months of denervation, when MEPs have consistently degraded in this animal model, the denervated tibialis anterior (TA) was injected with low-dose MNPs (10,000 cells), high-dose MNPs (500,000 cells), or phosphate-buffered saline (negative control). Using a previously established method, hiPSCs were differentiated into functional MNPs prior to injection. At selected time points post-injection, the TA was harvested and immunostained to confirm MNP viability and detect the presence of MEPs.

RESULTS: Transplanted MNPs remained viable within host muscle at both evaluated time points. No identifiable MEPs were detected in phosphate-buffered saline-treated chronically denervated muscle. In contrast, MNP-treated muscles demonstrated the presence of MEP-like structures following prolonged denervation. Qualitative differences in MEP density and morphologic complexity were observed between treatment groups, with greater preservation seen in the higher-dose cohort. Contralateral uninjured muscles demonstrated intact native MEP architecture.

CONCLUSIONS: Intramuscular transplantation of hiPSC-derived MNPs into chronically denervated muscle was associated with preservation of MEP morphology in this preclinical proof-of-concept model. These preliminary findings suggest that cellular therapies may represent a potential adjunctive strategy to preserve end-organ receptivity following delayed peripheral nerve injury.

TYPE OF STUDY/LEVEL OF EVIDENCE: Preclinical controlled animal study, Level V.