Journal Article Epublish
PubMed: 40678260 DOI: 10.1016/j.bioactmat.2025.06.042
Inhibition of neuronal necroptosis via disruption of RIPK1-RIPK3 Interactions: The role of neural stem cell-derived exosomes in spinal cord injury recovery.
Bioact Mater 51:889-908
Authors: Shiming Li, Guoliang Chen, Kuileung Tong, Yunshu Che, Yifan Xie, Wenxiao Shi, Anquan Huang, Yefeng Wang, Jianfeng Li, Genlong Jiao, Dacheng He, Jun Shen, Fuxin Wei, Ningning Chen
Affiliations
- Department of Orthopedics Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu Province, China. Suzhou Key Laboratory of Orthopedic Medical Engineering, Suzhou, Jiangsu Province, China. Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong Province, China.
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China. Dongguan Key Laboratory of Central Nervous System Injury and Repair / Department of Orthopedic Surgery, The Sixth Affiliated Hospital of Jinan University (Dongguan), Dongguan, Guangdong Province, China.
- Department of Orthopedic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
- Department of Orthopedics Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu Province, China. Suzhou Key Laboratory of Orthopedic Medical Engineering, Suzhou, Jiangsu Province, China.
- Department of Orthopedics Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu Province, China.
- Suzhou Key Laboratory of Orthopedic Medical Engineering, Suzhou, Jiangsu Province, China.
- Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong Province, China.
- Dongguan Key Laboratory of Central Nervous System Injury and Repair / Department of Orthopedic Surgery, The Sixth Affiliated Hospital of Jinan University (Dongguan), Dongguan, Guangdong Province, China.
Abstract
Spinal cord injury (SCI) poses a significant economic and public health burden. Exosomes derived from neural stem cells (NSC-Exos) are emerging as a promising therapeutic strategy for SCI repair, overcoming several limitations associated with both autologous and allogeneic neural stem cell therapies. This study demonstrates that NSC-Exos are efficiently internalized by the injured spinal cord after co-injection, resulting in substantial motor function recovery in murine models. Additionally, NSC-Exos effectively limit the expansion of the injury site, reduce neuronal degeneration, and attenuate neuroinflammatory responses. Notably, this is the first study to identify necroptosis as a novel therapeutic target for NSC-Exos in SCI recovery. We show that NSC-Exos inhibit neuronal necroptosis both in vivo and in vitro by disrupting the RIPK1-RIPK3 interaction, thereby preventing necrosome assembly. Furthermore, comprehensive transcriptomic analysis reveals that the ubiquitin-mediated proteolysis (UPS) pathway plays a crucial role in this process, a finding supported by experimental inhibition of ubiquitination. In conclusion, this study highlights the therapeutic potential of NSC-Exos in SCI treatment, particularly through the inhibition of necroptosis via disruption of the RIPK1-RIPK3 interaction, potentially involving UPS activation. These findings provide a foundation for future investigations into the molecular mechanisms underlying SCI recovery.
MeSH
Cells, Neural Stem Cells, Ubiquitin, Spinal Cord, Microscopy, Electron, Scanning Transmission, Necroptosis, Spinal Cord Injuries, Stem Cells, Recycling, Exosomes, Therapeutics, Spine