中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (5): 1067-1075.doi: 10.4103/1673-5374.355762

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

骨髓间充质干细胞和运动通过激活PI3K/AKT/mTOR通路恢复脊髓损伤后的运动功能

  

  • 出版日期:2023-05-15 发布日期:2022-11-01
  • 基金资助:
    国家重点研发计划和国家自然科学基金

Bone marrow mesenchymal stem cells and exercise restore motor function following spinal cord injury by activating PI3K/AKT/mTOR pathway

Xin Sun1, 2, Li-Yi Huang1, 2, Hong-Xia Pan1, 2, Li-Juan Li1, 2, Lu Wang1, 2, Gai-Qin Pei1, 2, Yang Wang1, 2, Qing Zhang1, 2, Hong-Xin Cheng1, 2, Cheng-Qi He1, 2, Quan Wei1, 2, *   

  1. 1Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China;  2Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
  • Online:2023-05-15 Published:2022-11-01
  • Contact: Quan Wei, PhD, weiquan@scu.edu.cn.
  • Supported by:
    This work was supported by the National Key R&D Program of China, No.2020YFC2008502 (to QW) and the National Natural Science Foundation of China, No. 82172534 (to QW).

摘要:

骨髓间充质干细胞移植和运动联合干预在促进损伤脊髓功能方面已显示出了效果,但作用机制仍值得进一步探讨。为此,实验建立了一个胸段脊髓挫伤小鼠模型,分析骨髓间质干细胞(BMMSCs)移植联合运动训练促进功能恢复的作用机制。应用Basso小鼠量表(BMS)、水平楼梯实验和足迹分析评估小鼠运动功能。8周运动训练后进行了磁共振成像、组织学检查、透射电子显微镜观察、免疫荧光染色和Western blotting,以进一步探索协同修复效应的潜在机制。与单纯BMMSCs移植或运动相比,BMMSCs移植联合运动对SCI小鼠运动功能显示出最佳的恢复效果。进一步研究发现,BMMSCs移植联合运动明显减少了纤维化的瘢痕组织,促进了神经生长因子的分泌,保护了神经元、轴突和髓鞘。此外,BMMSCs移植和运动对SCI恢复的协同作用是通过PI3K/AKT/mTOR通路实现的。另外,PC12细胞系和初级皮质神经元培养的实验证据也证明,阻断PI3K/AKT/mTOR通路会加重神经元的损伤。因此,BMMSCs移植联合运动训练可以通过激活PI3K/AKT/mTOR通路有效促进SCI后运动功能的恢复。

https://orcid.org/0000-0002-0541-905X (Quan Wei)

Abstract: Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury . In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3K/AKT/mTOR pathway. 

Key words: axon growth, bone marrow mesenchymal stem cell, exercise training, mTOR, neuroprotection, neurotrophin, remyelination, scar formation, spinal cord injury, synaptic plasticity