Stroke target identification guided by astrocyte transcriptome analysis

Abstract

Astrocytes support normal brain function, but may also contribute to neurodegeneration when they become reactive under pathological conditions such as stroke. However, the molecular underpinnings of this context‐dependent interplay between beneficial and detrimental properties in reactive astrogliosis have remained incompletely understood. Therefore, using the RiboTag technique, we immunopurified translating mRNAs specifically from astrocytes 72\u2009hr after transient middle cerebral artery occlusion in mice (tMCAO), thereby generating a stroke‐specific astroglial translatome database. We found that compared to control brains, reactive astrocytes after tMCAO show an enrichment of transcripts linked to the A2 phenotype, which has been associated with neuroprotection. However, we found that astrocytes also upregulate a large number of potentially neurotoxic genes. In total, we identified the differential expression of 1,003 genes and 38 transcription factors, of which Stat3, Sp1, and Spi1 were the most prominent. To further explore the effects of Stat3‐mediated pathways on stroke pathogenesis, we subjected mice with an astrocyte‐specific conditional deletion of Stat3 to tMCAO, and found that these mice have reduced stroke volume and improved motor outcome 72\u2009hr after focal ischemia. Taken together, our study extends the emerging database of novel astrocyte‐specific targets for stroke therapy, and supports the role of astrocytes as critical safeguards of brain function in health and disease.