Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells.
Rawji, Khalil S
McClain, Crystal R
van Wijngaarden, Peter
Franklin, Robin JM
Cell Stem Cell
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Neumann, B., Baror, R., Zhao, C., Segel, M., Dietmann, S., Rawji, K. S., Foerster, S., et al. (2019). Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells.. Cell Stem Cell, 25 (4), 473-485.e8. https://doi.org/10.1016/j.stem.2019.08.015
The age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS). Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases. Here, we show that the differentiation potential of adult rodent OPCs decreases with age. Aged OPCs become unresponsive to pro-differentiation signals, suggesting intrinsic constraints on therapeutic approaches aimed at enhancing OPC differentiation. This decline in functional capacity is associated with hallmarks of cellular aging, including decreased metabolic function and increased DNA damage. Fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following focal demyelination. Aged OPCs treated with metformin regain responsiveness to pro-differentiation signals, suggesting synergistic effects of rejuvenation and pro-differentiation therapies. These findings provide insight into aging-associated remyelination failure and suggest therapeutic interventions for reversing such declines in chronic disease.
Central Nervous System, Oligodendroglia, Cells, Cultured, Animals, Humans, Rats, Multiple Sclerosis, DNA Damage, Metformin, Hypoglycemic Agents, Rejuvenation, Stem Cell Transplantation, Cell Differentiation, Aging, Female, Male, Oligodendrocyte Precursor Cells, Remyelination
This work was supported by funding from the UK Multiple Sclerosis Society, MedImmune, The Adelson Medical Research Foundation and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. We thank Dr Daniel Morrison for assistance with the electron microscopy, the NIHR Cambridge BRC Cell Phenotyping Hub for all flow cytometry work and staff at the Cambridge Advanced Imaging Centre.
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF) (unknown)
Medical Research Council (MC_PC_12009)
External DOI: https://doi.org/10.1016/j.stem.2019.08.015
This record's URL: https://www.repository.cam.ac.uk/handle/1810/296382
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/