Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (2): 396-403.doi: 10.4103/1673-5374.346463

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Knockdown of polypyrimidine tract binding protein facilitates motor function recovery after spinal cord injury

Ri-Yun Yang1, Rui Chai2, Jing-Ying Pan1, Jing-Yin Bao3, Pan-Hui Xia3, Yan-Kai Wang3, Ying Chen1, Yi Li1, Jian Wu1, Gang Chen2, 3, 4, *   

  1. 1Department of Histology and Embryology, Medical School of Nantong University, Nantong, Jiangsu Province, China; 2Key Laboratory of Neuroregeneration of Jiangsu Province and the Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China; 3Center for Basic Medical Research, Medical School of Nantong University, Nantong, Jiangsu Province, China; 4Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
  • Online:2023-02-15 Published:2022-08-09
  • Contact: Gang Chen, MD, PhD, chengang6626@ntu.edu.cn.
  • Supported by:
    The study was supported by the National Natural Science Foundation of China, Nos. 82101455 (to RYY), 31872773 (to GC), 82001168 (to JYP); the Key Research and Development Program (Social Development) of Jiangsu Province, No. BE2020667 (to GC); the Foundation of Jiangsu Province “333 Project High-level Talents”, No. BRA2020076 (to GC); the Nantong Civic Science and Technology Project of China, No. JC2020028 (to RYY); the Natural Science Research of Jiangsu Higher Education Institutions of China, No. 19KJB310012 (to RYY) and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Abstract: After spinal cord injury (SCI), a fibroblast- and microglia-mediated fibrotic scar is formed in the lesion core, and a glial scar is formed around the fibrotic scar as a result of the activation and proliferation of astrocytes. Simultaneously, a large number of neurons are lost in the injured area. Regulating the dense glial scar and replenishing neurons in the injured area are essential for SCI repair. Polypyrimidine tract binding protein (PTB), known as an RNA-binding protein, plays a key role in neurogenesis. Here, we utilized short hairpin RNAs (shRNAs) and antisense oligonucleotides (ASOs) to knock down PTB expression. We found that reactive spinal astrocytes from mice were directly reprogrammed into motoneuron-like cells by PTB downregulation in vitro. In a mouse model of compression-induced SCI, adeno-associated viral shRNA-mediated PTB knockdown replenished motoneuron-like cells around the injured area. Basso Mouse Scale scores and forced swim, inclined plate, cold allodynia, and hot plate tests showed that PTB knockdown promoted motor function recovery in mice but did not improve sensory perception after SCI. Furthermore, ASO-mediated PTB knockdown improved motor function restoration by not only replenishing motoneuron-like cells around the injured area but also by modestly reducing the density of the glial scar without disrupting its overall structure. Together, these findings suggest that PTB knockdown may be a promising therapeutic strategy to promote motor function recovery during spinal cord repair.

Key words: antisense oligonucleotides, astrocytes, glial scar, motoneuron-like cells, motor function, neurogenesis, neuron-like cells, polypyrimidine tract binding protein, short hairpin RNAs, spinal cord repair