Neuroinflammatory astrocyte subtypes in the mouse brain

• Published in: Nature neuroscience Vol. 24; no. 10; pp. 1475 - 1487
• Main Authors: Hasel, Philip, Rose, Indigo V. L., Sadick, Jessica S., Kim, Rachel D., Liddelow, Shane A.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-10-2021; Nature Publishing Group
• Subjects: 631/378/2596; 631/378/2596/1308; Alzheimer's disease; Analysis; Animal Genetics and Genomics; Animals; Antigens; Astrocytes; Astrocytes - pathology; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain - pathology; Brain injury; Cell walls; Cells, Cultured; Cytokines; Encephalitis - chemically induced; Encephalitis - pathology; Endotoxins; Female; Gene expression; Gene Expression Profiling; Gene sequencing; Health aspects; Heterogeneity; Hybridization; Identification and classification; In Situ Hybridization; Inflammation; Interferons - pharmacology; Lipopolysaccharides; Male; Metabolites; Mice; Neurobiology; Neurodegenerative diseases; Neurophysiology; Neurosciences; Physiological aspects; Rats; Rats, Sprague-Dawley; Resource; Rodents; Sequence Analysis, RNA; Transcriptome; Transcriptomes; Transcriptomics; United States
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-021-00905-6

Astrocytes undergo an inflammatory transition after infections, acute injuries and chronic neurodegenerative diseases. How this transition is affected by time and sex, its heterogeneity at the single-cell level and how sub-states are spatially distributed in the brain remains unclear. In this study, we investigated transcriptome changes of mouse cortical astrocytes after an acute inflammatory stimulus using the bacterial cell wall endotoxin lipopolysaccharide. We identified fast transcriptomic changes in astrocytes occurring within hours that drastically change over time. By sequencing ~80,000 astrocytes at single-cell resolution, we show that inflammation causes a widespread response with subtypes of astrocytes undergoing distinct inflammatory transitions with defined transcriptomic profiles. We also attribute key sub-states of inflammation-induced reactive astrocytes to specific brain regions using spatial transcriptomics and in situ hybridization. Together, our datasets provide a powerful resource for profiling astrocyte heterogeneity and will be useful for understanding the biological importance of regionally constrained reactive astrocyte sub-states.
Using single-cell RNA sequencing and spatial transcriptomics, Hasel et al. uncover complex reactive astrocyte subtypes that occupy distinct areas of the brain. They find two super-responders expressing unique genes in strategic locations in the brain.