Department of OMNI Bioinformatics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Cell Rep. 2022 Aug 23;40(8):111189. doi: 10.1016/j.celrep.2022.111189.
Oligodendrocyte dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, so understanding oligodendrocyte activation states would shed light on disease processes. We identify three distinct activation states of oligodendrocytes from single-cell RNA sequencing (RNA-seq) of mouse models of Alzheimer's disease (AD) and multiple sclerosis (MS): DA1 (disease-associated1, associated with immunogenic genes), DA2 (disease-associated2, associated with genes influencing survival), and IFN (associated with interferon response genes). Spatial analysis of disease-associated oligodendrocytes (DAOs) in the cuprizone model reveals that DA1 and DA2 are established outside of the lesion area during demyelination and that DA1 repopulates the lesion during remyelination. Independent meta-analysis of human single-nucleus RNA-seq datasets reveals that the transcriptional responses of MS oligodendrocytes share features with mouse models. In contrast, the oligodendrocyte activation signature observed in human AD is largely distinct from those observed in mice. This catalog of oligodendrocyte activation states (http://research-pub.gene.com/OligoLandscape/) will be important to understand disease progression and develop therapeutic interventions.
少突胶质细胞功能障碍与神经退行性疾病的发病机制有关，因此了解少突胶质细胞的激活状态将有助于揭示疾病进程。我们通过对阿尔茨海默病 (AD) 和多发性硬化症 (MS) 的小鼠模型的单细胞 RNA 测序 (RNA-seq) ，鉴定出三种不同的少突胶质细胞激活状态：DA1（与免疫原性基因相关）、DA2（与影响存活的基因相关）和 IFN（与干扰素反应基因相关）。在杯状朊病毒模型中对疾病相关的少突胶质细胞 (DAO) 的空间分析表明，DA1 和 DA2 在脱髓鞘期间在病变区域之外建立，并且 DA1 在髓鞘再生期间重新填充病变。对人类单核 RNA-seq 数据集的独立荟萃分析表明，MS 少突胶质细胞的转录反应与小鼠模型具有相似的特征。相比之下，在人类 AD 中观察到的少突胶质细胞激活特征与在小鼠中观察到的特征有很大的不同。这个少突胶质细胞激活状态目录（http://research-pub.gene.com/OligoLandscape/）对于了解疾病进展和开发治疗干预措施将非常重要。
