Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (9): 4367-4377.doi: 10.4103/NRR.NRR-D-25-00544

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Rictor/mTORC2 signaling pathway protects endogenous neural stem cells to promote recovery after spinal cord injury

Kuileung Tong1, 2, #, Shiming Li3, #, Guoliang Chen4, #, Dacheng He1, Chengkai Lin1, *, Yuhang Li2, *, Ningning Chen1, *   

  1. 1Guangdong Provincial Biomedical Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopedic Surgery, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong Province, China; 
    2Department of Orthopedics, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China; 
    3Department of Orthopedics Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; 
    4Department of Orthopedic Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong Province, China
  • Online:2026-09-15 Published:2026-05-22
  • Contact: Ningning Chen, PhD, MD, chennn8@mail.sysu.edu.cn; Yuhang Li, PhD, MD, hqyylyh@126.com; Chengkai Lin, MD, linchk@mail2.sysu.edu.cn.
  • Supported by:
    This study was partly supported by grants from the Shenzhen Committee of Science and Technology, No. JCYJ20230807110310021 (to NC); Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, No. ZDSYS20230626091402006 (to NC); China Postdoctoral Science Foundation, Nos. GZC20242074, 2024M763788 (both to KT); National Natural Science Foundation of China for the Youth, No. 82402846 (to GC); and Science and Technology Projects in Guangzhou, Nos. 2025A03J4170, 2023B03J0211 (both to GC and YL).

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Abstract: Although endogenous neural stem cells represent a promising target for noninvasive spinal cord injury repair, inflammatory lesion environments frequently trigger their death. Our prior work identified necroptosis as a key death pathway for endogenous neural stem cells migrating to spinal cord injury lesions. Rapamycin-insensitive companion of mTOR (Rictor; a core component of the mechanistic target of rapamycin complex 2 [mTORC2] complex) regulates neural stem cell self-renewal and differentiation, and our preliminary data implicate it in spinal cord injury repair; however, its role in promoting endogenous neural stem cell survival post-spinal cord injury remains unclear. Here, we generated conditional endogenous neural stem cell-specific Rictor knockout mice using the Cre-loxP system. Although the endogenous neural stem cell-specific Rictor knockout mice displayed normal baseline spinal cord morphology and function, they exhibited impaired functional recovery after spinal cord injury compared with wild-type controls. This deficit correlated with elevated inflammatory responses and the increased susceptibility of endogenous neural stem cells to necroptosis. Mechanistically, lentiviral-mediated Rictor knockdown in neural stem cells in vitro impaired lysosomal function, leading to heightened sensitivity to tumor necrosis factor-alpha- and lipopolysaccharide-induced necroptosis. Collectively, these findings indicate that Rictor/mTORC2 signaling protects endogenous neural stem cells against receptor-interacting protein kinase 1-mediated necroptosis following spinal cord injury. Consequently, the modulation of intrinsic Rictor activity represents a potential therapeutic strategy to enhance endogenous neural stem cell survival and functional recovery post-spinal cord injury.

Key words: endogenous neural stem celll glial scarl inflammationl intracellular Ca2+l lysosomel mTORC2l necroptosisl Rictorl RIPK1l spinal cord injury