Transcriptional dynamics of the oligodendrocyte lineage and its regulation by the brain erythropoietin system
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.
Authors
- Liu Ye (ORCID: https://orcid.org/0009-0009-8745-3873)
- Daniel H. Geschwind (ORCID: https://orcid.org/0000-0003-2896-3450)
- Xuan Yu (ORCID: https://orcid.org/0000-0001-6826-7260)
- Umer Javed Butt (ORCID: https://orcid.org/0000-0001-6313-5939)
- Simone Eggert (ORCID: https://orcid.org/0000-0002-6792-5556)
- Klaus‐Armin Nave (ORCID: https://orcid.org/0000-0001-8724-9666)
- Anja Ronnenberg
- Yasmina Curto
- Riki Kawaguchi (ORCID: https://orcid.org/0000-0002-2489-4825)
- Hannelore Ehrenreich (ORCID: https://orcid.org/0000-0001-8371-5711)
- Susann Boretius (ORCID: https://orcid.org/0000-0003-2792-7423)
- Vinícius Daguano Gastaldi (ORCID: https://orcid.org/0000-0002-6249-6035)
- Martin Hindermann (ORCID: https://orcid.org/0000-0002-5123-7193)
- Manvendra Singh (ORCID: https://orcid.org/0000-0002-8626-5418)
- Anne-Fleur Wildenburg (ORCID: https://orcid.org/0009-0005-3534-3884)
- Qing Wang (ORCID: https://orcid.org/0000-0002-3882-6540)
- Wiebke Möbius (ORCID: https://orcid.org/0000-0002-2902-7165)
Institutions
- Guangxi Medical University (CN)
- University of California, Los Angeles (US)
- Heidelberg University (DE)
- German Primate Center (DE)
- University Hospital Heidelberg (DE)
- Central Institute of Mental Health (DE)
- Max Planck Institute for Solar System Research (DE)
- Max Planck Institute of Psychiatry (DE)
- Precision Research (United States) (US)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- University of Göttingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-16
- DOI
- https://doi.org/10.1038/s41467-025-62791-x
- Citations
- 1
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Max-Planck-Förderstiftung
- European Commission
- Deutsche Forschungsgemeinschaft
- National Natural Science Foundation of China
- Max-Planck-Gesellschaft
- China Scholarship Council
- International Max Planck Research School for Advanced Methods in Process and Systems Engineering
- Peter und Traudl Engelhorn Stiftung
- HORIZON EUROPE Framework Programme