Conservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes

Alvaro G Alvarado,Xia Yang,Daniel H Geschwind,Ye Zhang,William G Pembroke,Lin Pan,Steven A Goldman,Ina B Wanner,Yen-Wei Chen,Jiwen Li,Michael C Condro,Harley I Kornblum,Jessica E Rexach,Linsey Stiles,Mineli Harteni,Angela Y Chen,Marlesa I Godoy

doi:10.1038/s41467-021-24232-3

Abstract

Astrocytes play important roles in neurological disorders such as stroke, injury, and neurodegeneration. Most knowledge on astrocyte biology is based on studies of mouse models and the similarities and differences between human and mouse astrocytes are insufficiently characterized, presenting a barrier in translational research. Based on analyses of acutely purified astrocytes, serum-free cultures of primary astrocytes, and xenografted chimeric mice, we find extensive conservation in astrocytic gene expression between human and mouse samples. However, the genes involved in defense response and metabolism show species-specific differences. Human astrocytes exhibit greater susceptibility to oxidative stress than mouse astrocytes, due to differences in mitochondrial physiology and detoxification pathways. In addition, we find that mouse but not human astrocytes activate a molecular program for neural repair under hypoxia, whereas human but not mouse astrocytes activate the antigen presentation pathway under inflammatory conditions. Here, we show species-dependent properties of astrocytes, which can be informative for improving translation from mouse models to humans.

Highlights

Astrocytes play important roles in neurological disorders such as stroke, injury, and neurodegeneration
We found that the genes expressed at higher levels by mouse compared to human astrocytes were enriched in multiple gene ontology (GO) terms associated with metabolism (Fig. 1i and Supplementary Data 3)
When we examined the extent to which hypoxia-induced genes are shared between human and mouse astrocytes, we found that 3.4% of (11 out of 322) genes downregulated in human astrocytes were downregulated in mouse astrocytes and 5.3% of (7 out of 132) genes upregulated in human astrocytes were upregulated in mouse astrocytes, demonstrating partial conservation of hypoxic responses between human and mouse (Fig. 6d, e; upregulated overlap: 13.8-fold higher than expected by chance; p = 3.65e−07; downregulated overlap: 6.0-fold higher than expected by chance; p = 7.50e-07; false discovery rate (FDR) < 0.05; fold change > 1.5; average RPKM > 1; overlap: genes meeting all three criteria in both species; see Supplementary Fig. 14)

Summary

Introduction

Astrocytes play important roles in neurological disorders such as stroke, injury, and neurodegeneration. Mouse models of ischemic stroke can often achieve full functional recovery[5], whereas human patients frequently have irreversible functional deficits These limitations represent a key barrier in translational research, as over 90% of neurological drug candidates with promising animal data failing in human clinical trials[6]. We identified striking differences in the cell survival, mitochondrial physiology, and molecular responses of human and mouse astrocytes under oxidative stress, hypoxia, inflammatory cytokine treatment, and simulated viral infections. These findings reveal important mechanistic differences between human and mouse astrocytes and provide insight into how mouse models of neurodegeneration and stroke can be improved to achieve better translation to humans

Methods

Results

Conclusion