Multiple sclerosis (MS) is a multifocal and progressive inflammatory disease of the central nervous system (CNS). However, the compartmentalized pathology of the disease affecting various anatomical regions including gray and white matter and lack of appropriate disease models impede understanding of the disease. Utilizing single-nucleus RNA-sequencing and multiplex spatial RNA mapping, we generated an integrated transcriptomic map comprising leukocortical, cerebellar and spinal cord areas in normal and MS tissues that captures regional subtype diversity of various cell types with an emphasis on astrocytes and oligodendrocytes. While we found strong cross-regional diversity among glial subtypes in control tissue, regional signatures become more obscure in MS. This suggests that patterns of transcriptomic changes in MS are shared across regions and converge on specific pathways, especially those regulating cellular stress and immune activation. In addition, we found evidence that a subtype of white matter oligodendrocytes appearing across all three CNS regions adopt pro-remyelinating gene signatures in MS. In summary, our data suggest that cross-regional transcriptomic glial signatures overlap in MS, with different reactive glial cell types capable of either exacerbating or ameliorating pathology.

多发性硬化症 (MS) 是中枢神经系统 (CNS) 的多灶性和进行性炎症性疾病。然而，影响包括灰质和白质在内的各种解剖区域的疾病的分隔病理学和缺乏适当的疾病模型阻碍了对该疾病的理解。利用单核 RNA 测序和多重空间 RNA 作图，我们生成了一个整合的转录组图谱，包括正常和 MS 组织中的白皮层、小脑和脊髓区域，捕获各种细胞类型的区域亚型多样性，重点是星形胶质细胞和少突胶质细胞。虽然我们在对照组织中发现神经胶质亚型之间具有很强的跨区域多样性，但区域特征在 MS 中变得更加模糊。这表明 MS 中转录组学变化的模式跨区域共享并集中在特定通路上，尤其是那些调节细胞应激和免疫激活的通路。此外，我们发现证据表明，出现在所有三个 CNS 区域的白质少突胶质细胞亚型在 MS 中采用促髓鞘形成基因特征。总之，我们的数据表明跨区域转录组神经胶质特征在 MS 中重叠，不同的反应性神经胶质细胞类型能够加剧或改善病理。