Transcriptional dynamics of the oligodendrocyte lineage and its regulation by the brain erythropoietin system

Liu Ye, Vinicius Daguano Gastaldi, Yasmina Curto, Anne-Fleur Wildenburg, Xuan Yu, Martin Hindermann, Simone Eggert, Anja Ronnenberg, Qing Wang, Umer Javed Butt, Riki Kawaguchi, Daniel Geschwind, Wiebke Möbius, Susann Boretius, Manvendra Singh, Klaus-Armin Nave () and Hannelore Ehrenreich ()
Additional contact information
Liu Ye: City Campus
Vinicius Daguano Gastaldi: City Campus
Yasmina Curto: City Campus
Anne-Fleur Wildenburg: City Campus
Xuan Yu: City Campus
Martin Hindermann: City Campus
Simone Eggert: City Campus
Anja Ronnenberg: City Campus
Qing Wang: University of California Los Angeles
Umer Javed Butt: City Campus
Riki Kawaguchi: University of California Los Angeles
Daniel Geschwind: University of California Los Angeles
Wiebke Möbius: City Campus
Susann Boretius: Leibniz Institute for Primate Research
Manvendra Singh: City Campus
Klaus-Armin Nave: City Campus
Hannelore Ehrenreich: City Campus

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Oligodendrocytes differentiate from oligodendrocyte progenitor cells (OPC) in early postnatal development, but some oligodendrogenesis is maintained throughout adulthood, where oligodendrocyte lineage dynamics may contribute to neuroplasticity, adaptive myelination, and myelin repair. Here, we studied the effect of erythropoietin (EPO) and its receptor (EPOR) on oligodendrocyte lineage dynamics employing murine hippocampus and its myelinated fibers as model region. Using multiple stage-specific markers and single-nuclei-RNA-seq data, we find that EPO stimulates all oligodendroglial lineage cells directly, driving differentiation/maturation. Differential gene expression analysis reveals multiple EPO-regulated mRNAs, including downregulated transcripts for GABA-A receptors, fitting the known inhibition of oligodendrocyte maturation by GABA. Importantly, analogous oligodendrocyte responses are seen when endogenous EPO expression in brain is stimulated by hypoxia. Mice lacking EPOR from mature oligodendrocytes show subtle deficiencies of adult myelination in hippocampal fimbria and mild working memory deficits. These gain- and loss-of-function experiments may further suggest EPO as clinically safe treatment for remyelination therapies.

Date: 2025
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DOI: 10.1038/s41467-025-62791-x

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