Heo Dongeun, Kim Anya A, Neumann Björn, Doze Valerie N, Xu Yu Kang T, Mironova Yevgeniya A, Slosberg Jared, Goff Loyal A, Franklin Robin J M, Bergles Dwight E
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA.
Vollum Institute, Oregon Health and Science University, Portland, OR, USA.
Nat Aging. 2025 Apr;5(4):675-690. doi: 10.1038/s43587-025-00840-2. Epub 2025 Mar 31.
Oligodendrocyte progenitor cells (OPCs) are highly dynamic, widely distributed glial cells of the central nervous system responsible for generating myelinating oligodendrocytes throughout life. However, the rates of OPC proliferation and differentiation decline dramatically with aging, which may impair homeostasis, remyelination and adaptive myelination during learning. To determine how aging influences OPCs, we generated a transgenic mouse line (Matn4-mEGFP) and performed single-cell RNA sequencing, providing enhanced resolution of transcriptional changes during key transitions from quiescence to proliferation and differentiation across the lifespan. We found that aging induces distinct transcriptomic changes in OPCs in different states, including enhanced activation of HIF-1α and WNT pathways. Pharmacological inhibition of these pathways in aged OPCs was sufficient to increase their ability to differentiate in vitro. Ultimately, Matn4-mEGFP mouse line and the sequencing dataset of cortical OPCs across ages will help to define the molecular changes guiding OPC behavior in various physiological and pathological contexts.
少突胶质前体细胞（OPCs）是中枢神经系统中高度动态、广泛分布的神经胶质细胞，负责在整个生命周期中生成髓鞘形成少突胶质细胞。然而，随着年龄的增长，OPCs的增殖和分化速率显著下降，这可能会损害学习过程中的体内平衡、髓鞘再生和适应性髓鞘形成。为了确定衰老如何影响OPCs，我们构建了一个转基因小鼠品系（Matn4-mEGFP）并进行了单细胞RNA测序，从而在从静止到增殖和分化的关键转变过程中，跨生命周期提供了更高分辨率的转录变化。我们发现，衰老在不同状态的OPCs中诱导了不同的转录组变化，包括HIF-1α和WNT信号通路的激活增强。在衰老的OPCs中对这些信号通路进行药理抑制足以提高它们在体外的分化能力。最终，Matn4-mEGFP小鼠品系以及不同年龄皮质OPCs的测序数据集将有助于定义在各种生理和病理背景下指导OPC行为的分子变化。
