Rewiring of Nestin+ Cells Through PTBP1/PKM2 Axis Restores Notch-Dependent Neural Circuit Regeneration After Spinal Cord Injury.

Spinal cord injury (SCI) leads to irreversible neurological deficits because of the limited regenerative capacity of the central nervous system. Endogenous Nestin-positive (Nestin+) cells are activated after injury and contribute to repair; however, their neurogenic potential remains severely restricted after SCI. In this study, we investigated the molecular mechanisms underlying the fate restriction of Nestin+ cells by focusing on polypyrimidine tract-binding protein 1 (PTBP1). Transcriptomic and spatial analyses revealed synchronized expression of Nestin and PTBP1 after SCI, suggesting the presence of a coordinated regulatory axis following injury. Notably, Ptbp1 knockdown in Nestin+ cells enhanced neurogenesis and functional recovery. PTBP1 depletion shifted pyruvate kinase (PKM) splicing from PKM2 toward PKM1, which inhibited Notch1 signaling and enhanced oxidative phosphorylation, thereby promoting the differentiation of Nestin+ cells into neurons and diverting them from a glial fate. Collectively, our findings identify PTBP1 as a pivotal target for amplifying endogenous neuroregeneration, offering a potential therapeutic strategy for improving functional recovery after SCI.