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