Wei Hu1,2 · Meng Li1  · Yicheng Ding1  · Xinyi Cheng1  · Junchao Luo3  · Junjie Niu1  · Xiaozhong Zhou3  · Huilin Yang1  · Lulu Zhang4  · Qin Shi1  · Xingzhi Liu5

1 Department of Orthopedics, The First Affiliated Hospital of Soochow University, Orthopedic Institute of Soochow University, Medical College of Soochow University, Suzhou 215000, China 

2 Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China 

3 Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215000, China 

4 Key Laboratory for Nano‑Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215000, China 

5 Central Laboratory, Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China

Abstract

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.

Keywords

Spinal cord injury; Nestin⁺ cells; PTBP1; Alternative splicing; Notch1 pathway

[SpringerLink]