Metformin alters mitochondria-related metabolism and enhances human oligodendrocyte function
Metformin rejuvenates adult rat oligodendrocyte progenitor cells (OPCs) allowing more efficient differentiation into oligodendrocytes and improved remyelination, and therefore is of interest as a therapeutic in demyelinating diseases such as multiple sclerosis (MS). Here, we test whether metformin has a similar effect in human stem cell derived-OPCs. We assess how well human monoculture, organoid and chimera model culture systems simulate in vivo adult human oligodendrocytes, finding most close resemblance in the chimera model. Metformin increases myelin proteins and/or sheaths in all models even when human cells remain fetal-like. In the chimera model, metformin leads to increased mitochondrial area both in the human transplanted cells and in the mouse axons with associated increase of mitochondrial function/metabolism transcripts. Human oligodendrocytes from MS brain donors treated pre-mortem with metformin also express similar transcripts. Metformin's brain effect is thus not cell-specific, alters metabolism in part through mitochondrial changes and leads to more myelin production. This bodes well for clinical trials testing metformin for neuroprotection.
Authors
- Rebecca Sherrard Smith (ORCID: https://orcid.org/0009-0000-7216-0706)
- Robin J.M. Franklin (ORCID: https://orcid.org/0000-0001-6522-2104)
- Patrick S. Keeler
- Rana Fetit (ORCID: https://orcid.org/0000-0003-1152-8292)
- Nina-Lydia Kazakou (ORCID: https://orcid.org/0000-0003-3381-2390)
- Anna Williams (ORCID: https://orcid.org/0000-0002-6329-382X)
- Fabio Baldivia Pohl (ORCID: https://orcid.org/0000-0003-1695-4936)
- Nadine Bestard-Cuche
- Laura Wagstaff (ORCID: https://orcid.org/0000-0003-3816-6113)
- Sunniva M. K. Bøstrand (ORCID: https://orcid.org/0000-0003-1689-8583)
- Kellie Horan (ORCID: https://orcid.org/0009-0009-1632-5241)
- Luise A. Seeker (ORCID: https://orcid.org/0000-0001-6375-6372)
- Björn Neumann (ORCID: https://orcid.org/0000-0003-3827-6291)
Institutions
- University of Copenhagen (DK)
- Oslo University Hospital (NO)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Novo Nordisk Foundation (DK)
- Karolinska Institutet (SE)
- MRC Centre for Regenerative Medicine (GB)
- Granta Design (United Kingdom) (GB)
- RWTH Aachen University (DE)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-30
- DOI
- https://doi.org/10.1038/s41467-025-63279-4
- Citations
- 4
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 4.66
Funders
- Roche
- Wellcome
- F. Hoffmann-La Roche
- Wellcome Trust
- Multiple Sclerosis Society
- Karolinska Institutet
- Medical Research Council