Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
Nature. 2019 Sep;573(7772):75-82. doi: 10.1038/s41586-019-1404-z. Epub 2019 Jul 17.
Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.
多发性硬化症（MS）是一种神经炎症性疾病，在早期阶段具有复发缓解的病程，在皮质灰质与皮质下白质之间存在明显的病变特征，在慢性阶段存在神经退行性变。在这里，我们使用单核 RNA 测序来评估 MS 病变中多个细胞谱系表达的变化，并使用多重原位杂交技术验证了结果。我们发现脑膜炎症下上皮质层中兴奋性 CUX2 表达的投射神经元存在选择性易损性和丧失；这些 MS 神经元群体表现出应激途径基因和长非编码 RNA 的上调。应激性少突胶质细胞、反应性星形胶质细胞和激活的小胶质细胞的特征图谱与 MS 斑块的边缘最强相关。值得注意的是，单核 RNA 测序通过摄取和核周导入髓鞘转录本鉴定了吞噬性小胶质细胞和/或巨噬细胞，这在功能上的小鼠和人类培养实验中得到了证实。我们的研究结果表明，与选择性皮质神经元损伤和神经胶质激活相关的谱系和区域特异性转录组变化，导致 MS 病变的进展。
