Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713, AV, Groningen, the Netherlands.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
J Neuroinflammation. 2020 Dec 11;17(1):373. doi: 10.1186/s12974-020-02045-3.
Multiple sclerosis (MS) is an inflammation-mediated demyelinating disease of the central nervous system that eventually results in secondary axonal degeneration due to remyelination failure. Successful remyelination is orchestrated by astrocytes (ASTRs) and requires sequential activation, recruitment, and maturation of oligodendrocyte progenitor cells (OPCs). In both MS and experimental models, remyelination is more robust in grey matter (GM) than white matter (WM), which is likely related to local differences between GM and WM lesions. Here, we investigated whether adult gmASTRs and wmASTRs per se and in response to MS relevant Toll-like receptor (TLR) activation differently modulate myelination.
Differences in modulation of myelination between adult gmASTRs and wmASTRs were examined using an in vitro myelinating system that relies on a feeding layer of ASTRs. Transcriptional profiling and weighted gene co-expression network analysis were used to analyze differentially expressed genes and gene networks. Potential differential modulation of OPC proliferation and maturation by untreated adult gmASTRs and wmASTRs and in response to TLR3 and TLR4 agonists were assessed.
Our data reveal that adult wmASTRs are less supportive to in vitro myelination than gmASTRs. WmASTRs more abundantly express reactive ASTR genes and genes of a neurotoxic subtype of ASTRs, while gmASTRs have more neuro-reparative transcripts. We identified a gene network module containing cholesterol biosynthesis enzyme genes that positively correlated with gmASTRs, and a network module containing extracellular matrix-related genes that positively correlated with wmASTRs. Adult wmASTRs and gmASTRs responding to TLR3 agonist Poly(I:C) distinctly modulate OPC behavior, while exposure to TLR4 agonist LPS of both gmASTRs and wmASTRs results in a prominent decrease in myelin membrane formation.
Primary adult gmASTRs and wmASTRs are heterogeneous at the transcriptional level, differed in their support of in vitro myelination, and their pre-existing phenotype determined TLR3 agonist responses. These findings point to a role of ASTR heterogeneity in regional differences in remyelination efficiency between GM and WM lesions.
多发性硬化症（MS）是一种中枢神经系统的炎症性脱髓鞘疾病，最终会因髓鞘再生失败而导致继发性轴突变性。成功的髓鞘再生是由星形胶质细胞（ASTRs）协调的，需要少突胶质前体细胞（OPCs）的顺序激活、募集和成熟。在 MS 和实验模型中，灰质（GM）中的髓鞘再生比白质（WM）更为活跃，这可能与 GM 和 WM 病变之间的局部差异有关。在这里，我们研究了成年 GM-ASTR 和 WM-ASTR 本身以及对 MS 相关 Toll 样受体（TLR）激活的反应是否会不同地调节髓鞘形成。
使用依赖于 ASTR 饲养层的体外髓鞘形成系统，研究了成年 GM-ASTR 和 WM-ASTR 之间髓鞘形成调节的差异。采用转录谱分析和加权基因共表达网络分析，分析差异表达基因和基因网络。评估未经处理的成年 GM-ASTR 和 WM-ASTR 以及 TLR3 和 TLR4 激动剂对 OPC 增殖和成熟的潜在差异调节作用。
我们的数据表明，成年 WM-ASTR 对体外髓鞘形成的支持作用不如 GM-ASTR。WM-ASTR 更丰富地表达反应性 ASTR 基因和 ASTR 神经毒性亚型的基因，而 GM-ASTR 则具有更多的神经修复转录本。我们确定了一个包含胆固醇生物合成酶基因的基因网络模块，该模块与 GM-ASTR 呈正相关，以及一个包含细胞外基质相关基因的网络模块，该模块与 WM-ASTR 呈正相关。成年 GM-ASTR 和 WM-ASTR 对 TLR3 激动剂 Poly(I:C)的反应明显调节 OPC 行为，而 TLR4 激动剂 LPS 对 GM-ASTR 和 WM-ASTR 的暴露则导致髓鞘膜形成明显减少。
成年 GM-ASTR 和 WM-ASTR 在转录水平上存在异质性，在体外支持髓鞘形成的能力上存在差异，其预先存在的表型决定了 TLR3 激动剂的反应。这些发现表明 ASTR 异质性在 GM 和 WM 病变之间髓鞘再生效率的区域差异中起作用。
