中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (8): 3687-3695.doi: 10.4103/NRR.NRR-D-24-01376

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

巨噬细胞分泌的转化生长因子β1可通过SMAD2磷酸化加剧脊髓损伤后神经元的衰老

  

  • 出版日期:2026-08-18 发布日期:2026-04-27

Exacerbation of neuronal senescence after spinal cord injury: Role of the macrophage-derived transforming growth factor-β1–SMAD2 signaling axis

Haiwen Feng1, #, Hongda Wang1, #, Junjin Li1, #, Jie Ren1, Yuanquan Li1, Chuanhao Li1, Junyu Chen1, Xiaomeng Song1, *, Guangzhi Ning1, *, Shiqing Feng1, 2, *   

  1. 1Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin, China; 
    2Orthopedic Research Center of Shandong University and Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
  • Online:2026-08-18 Published:2026-04-27
  • Contact: Shiqing Feng, MD, sqfeng@tmu.edu.cn; Guangzhi Ning, MD, gzning@tmu.edu.cn; Xiaomeng Song, MD, songxiaomeng@tmu.edu.cn.
  • Supported by:
    This study was supported by grants from Tianjin Key Medical Discipline (Specialty) Construct Project, No. TJYXZDXK-027A (to SF); National Key Research and Development Project of Stem Cell and Transformation Research, No. 2019YFA0112100 (to SF); the National Natural Science Foundation of China, Nos. 81930070 (to SF), 82402825 (to XS); Tianjin Health Science and Technology Project Key Discipline Special Project, No. hUCMSC preferred subgroup, No.TJWJ2022XK002 (to SF);2022 Beijing-Tianjin-Hebei Basic Research Cooperation Project, No. 22JCZXJC00050 (to SF), and Youth Research Incubation Fund of School of Basic Medical Sciences, Tianjin Medical University, No. 023FY05 (to XS).

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摘要：

神经元变性和炎症是严重阻碍脊髓损伤后神经功能恢复的重要因素。巨噬细胞作为损伤后微环境重要的调节因子，可促进组织修复或加剧损伤。在巨噬细胞分泌的细胞因子中，转化生长因子β1已成为调节病理变化的重要因子。实验旨在阐明巨噬细胞分泌的转化生长因子β1在脊髓损伤后加剧神经元衰老和损害神经功能恢复的作用，体内实验可见，小鼠脊髓损伤后，损伤脊髓中转化生长因子β1水平显著上调，SMAD2磷酸化受到抑制，且神经元衰老标志物P16INK4α和β-半乳糖苷酶活性上调。而以SMAD2磷酸化抑制剂LY-364947腹腔注射则能显著减少衰老神经元数量，减轻脊髓组织退化，改善其运动功能。进一步研究以巨噬细胞耗竭剂氯屈膦酸盐脂质体清除巨噬细胞可降低脊髓损伤小鼠损伤部位转化生长因子β1的水平，并缓解神经元的衰老。上述发现表明，巨噬细胞分泌的转化生长因子β1加剧脊髓损伤后神经元衰老和神经功能损害，且转化生长因子β1-SMAD2信号轴是减轻脊髓损伤后神经元衰老和促进功能恢复的潜在靶点。


https://orcid.org/0000-0001-9437-7674 (Shiqing Feng); 

https://orcid.org/0000-0002-1635-9902 (Guangzhi Ning); 

https://orcid.org/0000-0003-2725-5372 (Xiaomeng Song)

关键词: 细胞衰老, 巨噬细胞, 神经再生, 神经退行性疾病, 神经炎症, 神经元, 神经元修复, 脊髓挫伤, 脊髓损伤, 转化生长因子β1, SMAD2

Abstract: Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery. As key regulators of the post-injury microenvironment, macrophages can promote either tissue repair or exacerbate damage. Among macrophage secreted factors, transforming growth factor-beta 1 has emerged as a critical mediator of pathological changes. In this study, we show the pivotal role of macrophage-derived transforming growth factor-beta 1 in driving neuronal senescence and impairing functional recovery after spinal cord injury. In a mouse spinal cord injury model, transforming growth factor-beta 1 levels were significantly increased at the injury site, accompanied by increased mothers against decapentaplegic homolog 2 (SMAD2) phosphorylation and upregulation of neuronal senescence markers such as p16INK4a and β-galactosidase activity. Treatment with LY-364947, a SMAD2 phosphorylation inhibitor, markedly reduced the number of senescent neurons, mitigated tissue degeneration, and improved motor function recovery. Additionally, macrophage depletion using clodronate liposomes lowered transforming growth factor-beta 1 levels at the injury site and attenuated neuronal senescence. These findings highlight the transforming growth factor-beta 1–SMAD2 signaling axis as a potential therapeutic target to reduce neuronal senescence and enhance functional recovery following spinal cord injury. 

Key words: cellular senescence, macrophage, neural regeneration, neurodegenerative disease, neuroinflammation, neuron, neuronal repair, spinal cord contusion, spinal cord injury, TGF-β1–SMAD2