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CRISPR-edited human ES-derived oligodendrocyte progenitor cells improve remyelination in rodents

Author

Listed:
  • Laura J. Wagstaff

    (University of Edinburgh)

  • Nadine Bestard-Cuche

    (University of Edinburgh)

  • Maja Kaczmarek

    (University of Edinburgh)

  • Antonella Fidanza

    (University of Edinburgh)

  • Lorraine McNeil

    (University of Edinburgh)

  • Robin J. M. Franklin

    (University of Cambridge)

  • Anna C. Williams

    (University of Edinburgh)

Abstract

In Multiple Sclerosis (MS), inflammatory demyelinated lesions in the brain and spinal cord lead to neurodegeneration and progressive disability. Remyelination can restore fast saltatory conduction and neuroprotection but is inefficient in MS especially with increasing age, and is not yet treatable with therapies. Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure, and we hypothesised that the transplantation of ‘improved’ OPCs, genetically edited to overcome these obstacles, could improve remyelination. Here, we edit human(h) embryonic stem cell-derived OPCs to be unresponsive to a chemorepellent released from chronic MS lesions, and transplant them into rodent models of chronic lesions. Edited hOPCs display enhanced migration and remyelination compared to controls, regardless of the host age and length of time post-transplant. We show that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS.

Suggested Citation

  • Laura J. Wagstaff & Nadine Bestard-Cuche & Maja Kaczmarek & Antonella Fidanza & Lorraine McNeil & Robin J. M. Franklin & Anna C. Williams, 2024. "CRISPR-edited human ES-derived oligodendrocyte progenitor cells improve remyelination in rodents," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52444-w
    DOI: 10.1038/s41467-024-52444-w
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    1. Michael Segel & Björn Neumann & Myfanwy F. E. Hill & Isabell P. Weber & Carlo Viscomi & Chao Zhao & Adam Young & Chibeza C. Agley & Amelia J. Thompson & Ginez A. Gonzalez & Amar Sharma & Staffan Holmq, 2019. "Niche stiffness underlies the ageing of central nervous system progenitor cells," Nature, Nature, vol. 573(7772), pages 130-134, September.
    2. Fadi J. Najm & Mayur Madhavan & Anita Zaremba & Elizabeth Shick & Robert T. Karl & Daniel C. Factor & Tyler E. Miller & Zachary S. Nevin & Christopher Kantor & Alex Sargent & Kevin L. Quick & Daniela , 2015. "Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo," Nature, Nature, vol. 522(7555), pages 216-220, June.
    3. Michael Segel & Björn Neumann & Myfanwy F. E. Hill & Isabell P. Weber & Carlo Viscomi & Chao Zhao & Adam Young & Chibeza C. Agley & Amelia J. Thompson & Ginez A. Gonzalez & Amar Sharma & Staffan Holmq, 2019. "Author Correction: Niche stiffness underlies the ageing of central nervous system progenitor cells," Nature, Nature, vol. 573(7773), pages 3-3, September.
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