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  2. Inhibition of Neural Stem Cell Necroptosis Mediated by RIPK1/MLKL Promotes Functional Recovery After SCI

Inhibition of Neural Stem Cell Necroptosis Mediated by RIPK1/MLKL Promotes Functional Recovery After SCI

  • Mol Neurobiol. 2023 Jan 5. doi: 10.1007/s12035-022-03156-z.
Kuileung Tong # 1 Shiming Li # 1 Guoliang Chen # 1 Chao Ma 2 Xizhe Liu 3 Shaoyu Liu 1 Ningning Chen 4
Affiliations

Affiliations

  • 1 Guangdong Provincial Biomedical Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-Sen University, No.628 Zhenyuan Road, Shenzhen, 518107, China.
  • 2 Department of Anesthesiology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China. mach@mail.sysu.edu.cn.
  • 3 Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology/Orthopaedic Research Institute, Department of Spine Surgery,, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. gzxzhliu@qq.com.
  • 4 Guangdong Provincial Biomedical Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-Sen University, No.628 Zhenyuan Road, Shenzhen, 518107, China. chennn8@mail.sysu.edu.cn.
  • # Contributed equally.
Abstract

Endogenous neural stem cells (eNSCs) are a new therapeutic strategy for the noninvasive repair of spinal cord injury (SCI). Necroptosis is a necrosome-dependent cell death process that serves as a significant regulatory mechanism in SCI. Current research shows that neurons, oligodendrocytes, and astrocytes all undergo Necroptosis after SCI. However, it is unclear whether eNSCs are associated with Necroptosis after SCI. By performing immunofluorescence analysis, we found that eNSCs undergo Necroptosis during spinal cord injury repair in mice. Our present work demonstrates that receptor-interacting protein kinase 1 (RIPK1)/Mixed Lineage Kinase domain-like protein (MLKL) are involved in Necroptosis pathway in SCI mice. In vitro, the Necroptosis induced by TNF-α/Smac-mimetic/Z-VAD-FMK (TSZ) treatment regulates phenotype of NSCs. In detail, the proliferative capacity of NSCs was significantly decreased in the presence of continual TSZ treatment, and the transcription of proinflammatory genes was upregulated, while the transcription of Neurotrophic Factors was inhibited. NSCs exhibited an obvious tendency to differentiate into glial cells under short-duration TSZ stimulation (6 h and 12 h); as the stimulus duration increased (24 h), the differentiation ability of the NSCs was significantly inhibited. These phenotypic changes are not conducive to neural cell survival and neural repair. Moreover, we examined the effect of Necroptosis inhibitors on TSZ-treated NSCs. Necrostatin-1 and necrosulfonamide significantly reduced the Necroptosis of NSCs after TSZ treatment and improved the phenotypic function of NSCs under TSZ stimulation. In additional in vivo experiments, after 2 weeks of administration, the Necroptosis inhibitors reduced the Necroptosis of NSCs and improved functional recovery in SCI mice. Taken together, these data indicate that the inhibition of NSC Necroptosis with Necroptosis inhibitors facilitates survival and phenotype maintenance in vitro and contributes to neuroprotection and repair in vivo. Our findings suggest that blocking Necroptosis of eNSCs may be a potential therapeutic strategy for treating SCI.

Keywords

NSCs; Necroptosis; Necroptosis Inhibitor; Spinal cord injury.

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