Cell-specific isotope labeling identifies myo -inositol transfer between neurons and oligodendroglia to support myelin repair

Abstract Neurons and glial cells are biochemically coupled through the exchange of nutrients, but our knowledge of which metabolites are transferred between them remains limited due to technical challenges. Here, we introduce a strategy to label specific cell types with isotopic tracers so that metabolite transfer can be measured directly in the intact brain. By engineering neurons in mice to metabolize 13C-labeled cellobiose, a glucose dimer that wild-type cells cannot catabolize, we selectively track neuron-derived metabolites by using mass spectrometry-based metabolomics. Applying this approach enabled us to identify myo-inositol as a critical metabolite synthesized by neurons and transferred to oligodendrocyte progenitor cells (OPCs) via the SLC5A3 transporter. The transfer of myo-inositol from neurons to OPCs promotes OPC proliferation and differentiation by enhancing phosphatidylinositol synthesis and upregulating expression of myelin-associated genes. During demyelination, deficient nutrient transfer can be rescued by dietary supplementation of myo-inositol, which accelerates myelin repair. These findings establish a generalizable technology for tracing intercellular metabolite transfer in vivo and identify a previously unrecognized mechanism of myo-inositol transfer from neurons to glial cells in support of CNS regeneration, revealing a potential metabolic target for therapeutic intervention in neurodegenerative disease. Competing Interest Statement The Patti laboratory has research collaboration agreements with Thermo Fisher Scientific and Agilent Technologies. G.J.P. is the chief scientific officer of Panome Bio.