Metformin alters mitochondria-related metabolism and enhances human oligodendrocyte function
- Nina-Lydia Kazakou
- Nadine Bestard-Cuche
- Laura J. Wagstaff
- Kellie Horan
- Luise Seeker
- Sunniva Bøstrand
- Rana Fetit
- Rebecca Sherrard Smith
- Fabio Baldivia Pohl
- Bjorn Neumann
- Patrick Keeler
- Robin J. M. Franklin
- Anna Williams
2025-08-30
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.