Regionally diverse astrocyte subtypes and their heterogeneous response to EAE.

Malte Borggrewe,Erik W G M Boddeke,Ilia D Vainchtein,Nieske Brouwer,Susanne M Kooistra,Bart J L Eggen,Corien Grit,Jon D Laman,Evelyn M Wesseling

doi:10.1002/glia.23954

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).

Highlights

Astrocytes fulfil numerous essential functions in the central nervous system (CNS), including structural and metabolic support that shapeMalte Borggrewe and Corien Grit are shared first authors Susanne M
Dissecting the differences between hindbrain subtypes further, we found that genes enriched in GLASTneg compared to GLASTpos astrocytes were associated with “myelination” and “oligodendrocyte differentiation” (Figure 2(d) and Supplemental file Table S2)
Summarizing, our findings demonstrate that GLASTpos and GLASTneg astrocytes are transcriptionally distinct and partially overlap with subtypes identified in other studies, indicating that GLAST expression distinguishes distinct astrocyte subtypes

Summary

| INTRODUCTION

Astrocytes fulfil numerous essential functions in the central nervous system (CNS), including structural and metabolic support that shape. Astrocytes feature molecular and functional heterogeneity that is shaped by local environmental cues of different anatomical regions. Astrocyte subtypes found across anatomical regions exhibit functional differences in synaptogenesis support (John Lin et al, 2017). These subtypes are associated with glioma disease symptoms, suggesting differential contribution of astrocyte subtypes to CNS disease (John Lin et al, 2017). Spinal cord astrocytes are affected most by EAE compared to other anatomical regions, highlighting interregional heterogeneity in diseased states (Itoh et al, 2017). We delineated differential contribution of these astrocyte subtypes in EAE and generated a transcriptional blueprint of spinal cord and hindbrain astrocytes during the progression of disease

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION