Ye Liu, Daguano Gastaldi Vinicius, Curto Yasmina, Wildenburg Anne-Fleur, Yu Xuan, Hindermann Martin, Eggert Simone, Ronnenberg Anja, Wang Qing, Butt Umer Javed, Kawaguchi Riki, Geschwind Daniel, Möbius Wiebke, Boretius Susann, Singh Manvendra, Nave Klaus-Armin, Ehrenreich Hannelore
Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, City Campus, Göttingen, Germany.
Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, China.
Nat Commun. 2025 Sep 16;16(1):8291. doi: 10.1038/s41467-025-62791-x.
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.
少突胶质细胞在出生后早期发育中从少突胶质前体细胞（OPC）分化而来，但在成年期仍有一些少突胶质细胞生成，少突胶质细胞谱系动态可能有助于神经可塑性、适应性髓鞘形成和髓鞘修复。在这里，我们以小鼠海马及其有髓纤维为模型区域，研究了促红细胞生成素（EPO）及其受体（EPOR）对少突胶质细胞谱系动态的影响。使用多种阶段特异性标记物和单核RNA测序数据，我们发现EPO直接刺激所有少突胶质谱系细胞，驱动分化/成熟。差异基因表达分析揭示了多个EPO调节的mRNA，包括GABA-A受体的下调转录本，这与已知的GABA对少突胶质细胞成熟的抑制作用相符。重要的是，当缺氧刺激大脑中内源性EPO表达时，会出现类似的少突胶质细胞反应。成熟少突胶质细胞缺乏EPOR的小鼠在海马伞中显示出成人髓鞘形成的细微缺陷和轻度工作记忆缺陷。这些功能获得和功能丧失实验可能进一步表明EPO作为髓鞘再生治疗的临床安全治疗方法。
