Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (8): 3687-3695.doi: 10.4103/NRR.NRR-D-24-01376

Previous Articles     Next Articles

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).

PDF

8

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