Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration
Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration
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DOI：
10.1186/s12974-020-01898-y
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发表时间：
2020-07-31
影响因子：
9.3
通讯作者：
Serrano-Pozo, Alberto
中科院分区：
文献类型：
--
作者：
Das, Sudeshna;Li, Zhaozhi;Serrano-Pozo, Alberto
在小鼠和人类中，急性中枢神经系统损伤和慢性神经退行性疾病中的神经元损伤总是伴随着星形胶质细胞反应。然而，中枢神经系统急性与慢性损伤的性质是否以及如何影响星形胶质细胞的反应，以及这些小鼠模型中星形胶质细胞转录组的变化是否忠实地再现了人类疾病中的星形胶质细胞反应仍有待阐明。我们假设，星形胶质细胞启动不同的转录组程序，以响应急性与慢性侮辱，除了共享的“泛损伤”的签名共同的两种类型的条件，并调查这些小鼠星形胶质细胞的签名在人类神经退行性疾病的转录组学研究中的存在。方法我们对来自急性损伤（n= 6）和慢性神经退行性变（n= 9）小鼠模型的15个已发表的星形胶质细胞转录组数据集进行了荟萃分析，并识别了泛损伤、急性和慢性特征，其中包括上调（UP）和下调（Down）基因。接下来，我们在来自各种人类神经退行性疾病的7个转录组数据集中研究了这些特征。结果在小鼠模型中，每个标签的UP/DOWN基因数量在全损伤中为64/21，在急性损伤中为109/79，而在慢性神经变性中仅为13/27。泛损伤UP特征由星形胶质细胞反应的经典细胞骨架标志（GfapandVim）加上细胞外基质（即，Cd 44，Lgals 1，Lgals 3，Timp 1）和免疫应答（即，C3、Serping1、Fas、Stat1、Stat2、Stat3）。急性损伤-UP签名富含蛋白质合成和降解（泛素-蛋白酶体和自噬系统），细胞内运输和抗氧化防御基因，而急性损伤-DOWN签名包括调节染色质结构和转录活性的基因，其中许多是转录抑制因子。慢性神经退行性变-UP特征进一步富集星形胶质细胞分泌的细胞外基质蛋白（Lama 4、Cyr 61、Thbs 4），而DOWN特征包括相关基因如Agl（糖原分解）、S1 pr 1（免疫调节）和Sod 2（抗氧化剂）。只有泛损伤-UP小鼠特征清楚地存在于一些人类神经退行性转录组数据集中。结论急性和慢性中枢神经系统损伤导致不同的星形胶质细胞基因表达程序超出其共同的星形胶质细胞反应签名。然而，在将星形胶质细胞转录组学的发现从小鼠模型外推到人类疾病时应谨慎。
Background Neuronal damage in acute CNS injuries and chronic neurodegenerative diseases is invariably accompanied by an astrocyte reaction in both mice and humans. However, whether and how the nature of the CNS insult-acute versus chronic-influences the astrocyte response, and whether astrocyte transcriptomic changes in these mouse models faithfully recapitulate the astrocyte reaction in human diseases remains to be elucidated. We hypothesized that astrocytes set off different transcriptomic programs in response to acute versus chronic insults, besides a shared "pan-injury" signature common to both types of conditions, and investigated the presence of these mouse astrocyte signatures in transcriptomic studies from human neurodegenerative diseases. Methods We performed a meta-analysis of 15 published astrocyte transcriptomic datasets from mouse models of acute injury (n= 6) and chronic neurodegeneration (n= 9) and identified pan-injury, acute, and chronic signatures, with both upregulated (UP) and downregulated (DOWN) genes. Next, we investigated these signatures in 7 transcriptomic datasets from various human neurodegenerative diseases. Results In mouse models, the number of UP/DOWN genes per signature was 64/21 for pan-injury and 109/79 for acute injury, whereas only 13/27 for chronic neurodegeneration. The pan-injury-UP signature was represented by the classic cytoskeletal hallmarks of astrocyte reaction (GfapandVim), plus extracellular matrix (i.e.,Cd44,Lgals1, Lgals3, Timp1), and immune response (i.e.,C3, Serping1, Fas, Stat1, Stat2, Stat3). The acute injury-UP signature was enriched in protein synthesis and degradation (both ubiquitin-proteasome and autophagy systems), intracellular trafficking, and anti-oxidant defense genes, whereas the acute injury-DOWN signature included genes that regulate chromatin structure and transcriptional activity, many of which are transcriptional repressors. The chronic neurodegeneration-UP signature was further enriched in astrocyte-secreted extracellular matrix proteins (Lama4,Cyr61,Thbs4), while the DOWN signature included relevant genes such asAgl(glycogenolysis),S1pr1(immune modulation), andSod2(anti-oxidant). Only the pan-injury-UP mouse signature was clearly present in some human neurodegenerative transcriptomic datasets. Conclusions Acute and chronic CNS injuries lead to distinct astrocyte gene expression programs beyond their common astrocyte reaction signature. However, caution should be taken when extrapolating astrocyte transcriptomic findings from mouse models to human diseases.