中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (10): 5035-5043.doi: 10.4103/NRR.NRR-D-25-01790

• 原著:退行性病与再生 • 上一篇    下一篇

间充质干细胞来源的外泌体修复具有肌萎缩侧索硬化遗传背景的诱导多能干细胞来源运动神经元

  

  • 出版日期:2026-10-15 发布日期:2026-06-15

Mesenchymal stem cell–derived extracellular vesicle treatment of induced pluripotent stem cell–derived motor neurons with different amyotrophic lateral sclerosis genetic backgrounds.

Suzy Varderidou-Minasian1, Channa E. Jakobs1, Svetlana Pasteuning-Vuhman1, Lars Gal1, Annabel Timmers1, Maarten Altelaar2, 3, Magdalena J. Lorenowicz4, 5, §, R. Jeroen Pasterkamp1, *, §   

  1. 1Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; 
    2Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, The Netherlands; 
    3Netherlands Proteomics Center, Utrecht, The Netherlands; 
    4Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands; 
    5Regenerative Medicine Center, Utrecht, The Netherlands
  • Online:2026-10-15 Published:2026-06-15
  • Contact: R. Jeroen Pasterkamp, PhD, r.j.pasterkamp@umcutrecht.nl.
  • Supported by:
    This work was supported by Stichting ALS Nederland (TOTALS, MUSALS, ATAXALS, GoALS), ALS CURE project, the ERANet for Research on Rare Diseases (E-rare-3, INTEGRALS and MAXOMOD), the Joint Programming Initiative for Neurodegenerative Diseases (JPND, TRIAGE) (to RJP) and The Netherlands Organization for Scientific Research (NWO-XS) (to SVM).

摘要:

源自人类诱导多能干细胞的运动神经元为研究肌萎缩侧索硬化症等运动神经元疾病提供了强大模型。尽管应用广泛,但我们对这些模型中蛋白质组变化的认知仍相当有限。实验对携带C9ORF72TARDBPFUS基因肌萎缩侧索硬化相关突变的诱导多能干细胞来源运动神经元进行了比较蛋白质组学分析。结果揭示了突变特异性与共有的蛋白质组学特征,阐明了疾病机制的共通点与差异性。基于这些新发现,实验评估了间充质干细胞外囊泡的治疗潜力。实验表明,间充质干细胞来源的细胞外囊泡在体外对FUS突变型肌萎缩侧索硬化运动神经元具有功能性影响,并能更广泛地逆转不同遗传背景的肌萎缩侧索硬化运动神经元中的蛋白质组学改变。这些发现揭示了肌萎缩侧索硬化在蛋白质水平的关键分子通路,并支持间充质干细胞来源的细胞外囊泡作为多功能治疗手段的潜力。


https://orcid.org/0000-0003-1631-6440 (R. Jeroen Pasterkamp)

关键词: 肌萎缩侧索硬化症, C9ORF72基因, 细胞外囊泡, FUS蛋白, 诱导多能干细胞, 间充质基质/干细胞, 运动神经元, 蛋白质组学, TDP-43蛋白

Abstract:

Motor neurons derived from induced human pluripotent stem cells offer a powerful model to study motor neuron diseases, such as amyotrophic lateral sclerosis. While widely used, our knowledge of the proteomic changes in these models is rather rudimentary. In this study, we conducted a comparative proteomic analysis of induced pluripotent stem cell–derived motor neurons carrying amyotrophic lateral sclerosis–associated mutations in C9ORF72, TARDBP, or FUS. This revealed both mutation-specific and shared proteomic signatures, unveiling common and divergent disease mechanisms. Using these new insights, we then evaluated the therapeutic potential of mesenchymal stem cell–derived extracellular vesicles. These experiments showed a functional effect of mesenchymal stem cell–derived extracellular vesicles in amyotrophic lateral sclerosis-FUS motor neurons in vitro and their ability to reverse proteomic changes more generally in motor neurons with different amyotrophic lateral sclerosis genetic backgrounds. These findings highlight key molecular pathways involved in amyotrophic lateral sclerosis at the protein level and support the potential of mesenchymal stem cell–derived extracellular vesicles as a versatile therapeutic approach.

Key words: amyotrophic lateral sclerosis, C9ORF72, extracellular vesicles, FUS, induced pluripotent stem cells, mesenchymal stromal/stem cells, motor neurons, proteomics, transactive response (TAR) DNA-binding protein 43 (TDP-43)