Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (10): 5035-5043.doi: 10.4103/NRR.NRR-D-25-01790

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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).

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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)