Integrative snRNA-seq analysis reveals oligodendrocyte lineage changes in MS progression

Multiple sclerosis (MS) is a chronic disease of the central nervous system. The occurrence of MS is a phased process while its cause is still unclear. Here, by combining white matter single-nucleus transcriptomic datasets from MS and control samples, we found molecular crosstalk between oligodendrocytes (OLs) and immune cells involved in MS pathology. Using a machine learning approach, we identified oligodendrocyte precursor cells (OPCs) and OL subtypes at various developmental stages. We highlighted their unique molecular characteristics and analyzed their distribution throughout development, adulthood, and in different regions impacted by MS. We also found an increased number of Pre-OPCs and newly formed oligodendrocytes (NFOLs) in normal appearing white matter (NAWM), which were scarcely detected in MS lesions. By cell communication analysis and in vitro coculture, we found the interaction between SIRPA on microglia and CD47 on stressed oligodendrocytes was significantly reduced in MS lesions compared with NAWM, potentially preventing microglial phagocytosis of OLs. In contrast, CD74-MIF signaling between microglia and OLs was increased in lesions, which may lead to their retention around OLs.多发性硬化（Multiple Sclerosis，MS）是一种中枢神经系统慢性疾病。MS的发生呈现阶段性进程，但具体病因迄今尚未明确。本研究整合了MS患者与对照样本的白质单细胞核转录组数据集，发现参与MS病理过程的少突胶质细胞（Oligodendrocytes，OLs）与免疫细胞之间存在分子串扰。通过机器学习方法，我们鉴定出不同发育阶段的少突胶质前体细胞（Oligodendrocyte Precursor Cells，OPCs）与少突胶质细胞亚型，阐明了其独特的分子特征，并分析了它们在发育、成年阶段以及MS受累的不同脑区中的分布模式。我们还观察到，在正常外观白质（Normal Appearing White Matter，NAWM）中，Pre-OPCs与新生少突胶质细胞（Newly Formed Oligodendrocytes，NFOLs）的数量显著增多，而此类细胞在MS病灶中几乎难以检测到。通过细胞通讯分析与体外共培养实验，我们发现相较于正常外观白质，MS病灶中小胶质细胞（Microglia）表面的SIRPA与应激少突胶质细胞表面的CD47之间的相互作用显著减弱，这可能会抑制小胶质细胞对少突胶质细胞的吞噬作用。与之相反，病灶中小胶质细胞与少突胶质细胞间的CD74-MIF信号通路活性增强，这可能会导致小胶质细胞在少突胶质细胞周围滞留。