Transcriptional heterogeneity between primary adult grey and white matter astrocytes underlie differences in modulation of in vitro myelination

ABSTRACT: Background: Multiple sclerosis (MS) is an inflammation-mediated demyelinating disease of the central nervous system, which 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) that is likely related to local differences between GM and WM lesions. Here, we investigated whether adult gmASTRs and wmASTRs differently modulate myelination. Methods: Differences in modulation of myelination between adult gmASTRs and wmASTRs were examined using in vitro myelinating cultures that rely 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 adult gmASTRs and wmASTRs, in response to Toll-like receptor (TLR) 3 and TLR4 agonists, were assessed. Results: 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. 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, are identified. Adult wmASTRs and gmASTRs responding to TLR3 agonist Poly(I:C) differently modulate OPC behavior, while LPS treatment of both gmASTRs and wmASTRs results in a prominent decrease in myelin membrane formation. Conclusions: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE155866 | GEO | 2020/12/21

REPOSITORIES: GEO