Polyamine metabolic reprogramming in ependymal cells promotes endogenous repair after spinal cord injury.

The mechanisms underlying the activation of endogenous stem cells following spinal cord injury (SCI) remain a fundamental challenge in neural regeneration. Ependymal cells, which constitute a resident stem/progenitor population, possess latent regenerative potential, yet the metabolic cues governing their activation remain poorly understood. In this study, by integrating single-cell RNA sequencing with computational metabolic profiling, we systematically characterized the temporal transcriptional and metabolic reprogramming of injury-responsive ependymal cells after SCI. We found that SCI induces a metabolic switch characterized by marked upregulation of polyamine metabolism, which critically drives the transition of ependymal cells from quiescence to proliferation. Trajectory inference and metabolic analyses identified ornithine decarboxylase 1 (ODC1), a pyridoxal 5'-phosphate (PLP)-dependent rate-limiting enzyme in polyamine biosynthesis, as a key regulator of this fate transition. Mechanistically, molecular docking and molecular dynamics simulations revealed that PLP forms a stable covalent Schiff base with ODC1, thereby enhancing polyamine flux, remodeling the intracellular milieu and extracellular matrix, and ultimately establishing a regenerative niche. In a murine model of SCI, systemic PLP administration enhanced polyamine metabolism, promoted ependymal cell proliferation and tissue repair, and led to significant improvements in locomotor function. Collectively, this study identifies PLP-dependent ODC1-mediated polyamine metabolism as a mechanistically grounded and translationally actionable target for enhancing endogenous spinal cord regeneration.