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 hr 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 hr 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.

Foreign body responses in central nervous system mimic natural wound responses and alter biomaterial functions

“…Additionally, we identified a possible conserved function for galectin-3 in isolating foreign bodies from parenchymal neural tissue regardless of the severity of the FBR, with its expression occurring rapidly following hydrogel injection and present only in cells forming the materialtissue interface, regardless of cell type (inflammatory cells, stromal cells or astrocytes). Galectin-3 is known to be associated with fibrosis and wound healing in various tissue injuries including kidney, liver and heart [44] and is significantly upregulated in macrophages/microglia and reactive astrocytes after various traumatic CNS injuries [42,[45][46][47]. Here we identify galectin-3 to also be an important constituent of CNS FBRs to materials.…”

Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration

“…Dataset category (acute injury versus neurodegeneration), mouse model, mouse age and sex, CNS region, method of astrocyte isolation, GEO accession number, and literature reference for these datasets can be found in Table 1. Mouse acute injury datasets (n = 6) included LPS-induced sepsis (n = 1) [1], MCAO stroke (n = 2) [1,12], SCI (n = 2) [13,14], and acute toxic parkinsonism (MPTP, n = 1) [15]. For one of the stroke studies [1], only the dataset from 3 days after MCAO was analyzed, because gene expression changes were maximum 3 days and attenuated by 7 days after MCAO surgery.…”

Vagus nerve stimulation reduces spreading depolarization burden and cortical infarct volume in a rat model of stroke

“…MCAO was performed as previously described [12,16]. Briefly, the animal was placed on its back and an incision was made above the thyroid gland.…”