Changes in gene expression that occur across the central nervous system (CNS) during neurological diseases do not address the heterogeneity of cell types from one CNS region to another and are complicated by alterations in cellular composition during disease. Multiple sclerosis (MS) is multifocal by definition. Here, a cell-specific and region-specific transcriptomics approach was used to determine gene expression changes in astrocytes in the most widely used MS model, experimental autoimmune encephalomyelitis (EAE). Astrocyte-specific RNAs from various neuroanatomic regions were attained using RiboTag technology. Sequencing and bioinformatics analyses showed that EAE-induced gene expression changes differed between neuroanatomic regions when comparing astrocytes from spinal cord, cerebellum, cerebral cortex, and hippocampus. The top gene pathways that were changed in astrocytes from spinal cord during chronic EAE involved decreases in expression of cholesterol synthesis genes while immune pathway gene expression in astrocytes was increased. Optic nerve from EAE and optic chiasm from MS also showed decreased cholesterol synthesis gene expression. The potential role of cholesterol synthesized by astrocytes during EAE and MS is discussed. Together, this provides proof-of-concept that a cell-specific and region-specific gene expression approach can provide potential treatment targets in distinct neuroanatomic regions during multifocal neurological diseases.

中文翻译：

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多发性硬化症模型中的细胞特异性和区域特异性转录组学：关注星形胶质细胞

在神经系统疾病期间，整个中枢神经系统 (CNS) 发生的基因表达变化并不能解决从一个 CNS 区域到另一个区域的细胞类型的异质性，并且由于疾病期间细胞组成的改变而变得复杂。根据定义，多发性硬化症 (MS) 是多灶性的。在这里，使用细胞特异性和区域特异性转录组学方法来确定最广泛使用的 MS 模型、实验性自身免疫性脑脊髓炎 (EAE) 中星形胶质细胞的基因表达变化。使用 RiboTag 技术获得来自不同神经解剖区域的星形胶质细胞特异性 RNA。测序和生物信息学分析表明，当比较来自脊髓、小脑、大脑皮层和海马的星形胶质细胞时，EAE 诱导的基因表达变化在神经解剖学区域之间存在差异。在慢性 EAE 期间，脊髓星形胶质细胞中发生变化的主要基因通路涉及胆固醇合成基因表达的减少，而星形胶质细胞中免疫通路基因表达的增加。EAE 的视神经和 MS 的视交叉也显示胆固醇合成基因表达降低。讨论了 EAE 和 MS 期间星形胶质细胞合成的胆固醇的潜在作用。总之，这提供了概念验证，即细胞特异性和区域特异性基因表达方法可以在多灶性神经系统疾病期间在不同的神经解剖区域提供潜在的治疗靶点。EAE 的视神经和 MS 的视交叉也显示胆固醇合成基因表达降低。讨论了 EAE 和 MS 期间星形胶质细胞合成的胆固醇的潜在作用。总之，这提供了概念验证，即细胞特异性和区域特异性基因表达方法可以在多灶性神经系统疾病期间在不同的神经解剖区域提供潜在的治疗靶点。EAE 的视神经和 MS 的视交叉也显示胆固醇合成基因表达降低。讨论了 EAE 和 MS 期间星形胶质细胞合成的胆固醇的潜在作用。总之，这提供了概念验证，即细胞特异性和区域特异性基因表达方法可以在多灶性神经系统疾病期间在不同的神经解剖区域提供潜在的治疗靶点。