Regionally diverse astrocyte subtypes and their heterogeneous response to EAE

Abstract

Astrocytes fulfil many functions in the central nervous system (CNS), including contribution to the blood brain barrier, synapse formation, and trophic support. In addition, they can mount an inflammatory response and are heterogeneous in morphology and function. To extensively characterize astrocyte subtypes, we FACS‐isolated and gene expression profiled distinct astrocyte subtypes from three central nervous system regions; forebrain, hindbrain and spinal cord. Astrocyte subpopulations were separated based on GLAST/SLC1A3 and ACSA‐2/ATP1B2 cell surface expression. The local brain environment proved key in establishing different transcriptional programs in astrocyte subtypes. Transcriptional differences between subtypes were also apparent in experimental autoimmune encephalomyelitis (EAE) mice, where these astrocyte subtypes showed distinct responses. While gene expression signatures associated with blood–brain barrier maintenance were lost, signatures involved in neuroinflammation and neurotoxicity were increased in spinal cord astrocytes, especially during acute disease stages. In chronic stages of EAE, this reactive astrocyte signature was slightly decreased, while obtaining a more proliferative profile, which might be relevant for glia scar formation and tissue regeneration. Morphological heterogeneity of astrocytes previously indicated the presence of astrocyte subtypes, and here we show diversity based on transcriptome variation associated with brain regions and differential responsiveness to a neuroinflammatory insult (EAE).

Single‐Cell Transcriptomics‐Based Study of Transcriptional Regulatory Features in the Mouse Brain Vasculature

“…The expression of BSG in endothelial cells has been found to be positively correlated with age in humans, which may explain the increased risk of cardiovascular disease with advancing age [19]. Atp1b2 was found to be associated with changes in the microenvironment within the brain, and we hypothesize that the expression of fibroblasts may affect the microenvironment within the brain [20,21]. The main marker genes for oligodendrocytes in the present study were Mbp and Cldn11.…”

Epigenetic control of region‐specific transcriptional programs in mouse cerebellar and cortical astrocytes

“…A widely discussed hypothesis suggests that functional properties of regional astrocytes are mainly determined by the distinct neuronal environments, implying an instructive, and neuronal activity dependent mechanism. However, recent bulk and single cell RNA-Seq data indicate that the molecular properties of astrocytes strongly follow region-and layer-specific cues (Batiuk et al, 2020;Bayraktar et al, 2020;Boisvert et al, 2018;Borggrewe et al, 2020;Chai et al, 2017;Itoh et al, 2018;Lin et al, 2017;Morel et al, 2017;Zeisel et al, 2018).…”

“…However, in the past decade the functional diversity of astrocytes in distinct brain regions became evident (reviewed by Murai, 2017 andClarke, Taha, Tyzack, &Patani, 2021). It was demonstrated that gene expression changed gradually along the dorsoventral as well as the rostrocaudal axis of the brain (Borggrewe et al, 2020;Morel et al, 2017). Moreover, striatal and hippocampal astrocytes have specialized properties like altered morphology, electrophysiology, and Ca 2+ -signaling within neural circuits (Chai et al, 2017).…”

Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice

“…This is supported by the observation that statin-mediated inhibition of cholesterol synthesis blocks remyelination (Miron et al, 2009). However, astrocytes, which provide cholesterol in the healthy brain, fail as a local cholesterol source in myelin disease as they strongly downregulate its synthesis both in mouse models (Berghoff et al, 2021;Borggrewe et al, 2021;Itoh et al, 2018) and MS lesions (this study). We hypothesize that chronic myelin disease depletes neuronal and oligodendroglial cholesterol levels, which triggers cell-autonomous cholesterol synthesis by feedback regulation.…”