TY  - JOUR
AU  - Rakers, Cordula
AU  - Schleif, Melvin
AU  - Blank, Nelli
AU  - Matušková, Hana
AU  - Ulas, Thomas
AU  - Händler, Kristian
AU  - Torres, Santiago Valle
AU  - Schumacher, Toni
AU  - Tai, Khalid
AU  - Schultze, Joachim L
AU  - Jackson, Walker S
AU  - Petzold, Gabor Claus Julius Peter
TI  - Stroke target identification guided by astrocyte transcriptome analysis.
JO  - Glia
VL  - 67
IS  - 4
SN  - 0894-1491
CY  - Bognor Regis [u.a.]
PB  - Wiley-Liss
M1  - DZNE-2020-06832
SP  - 619-633
PY  - 2019
AB  - 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.
KW  - Animals
KW  - Astrocytes: metabolism
KW  - Computational Biology
KW  - Connexin 43: genetics
KW  - Connexin 43: metabolism
KW  - Disease Models, Animal
KW  - Female
KW  - Galectin 3: genetics
KW  - Galectin 3: metabolism
KW  - Gene Expression Profiling: methods
KW  - Gene Expression Regulation: genetics
KW  - Immunoprecipitation
KW  - Infarction, Middle Cerebral Artery: pathology
KW  - Infarction, Middle Cerebral Artery: physiopathology
KW  - Lipocalin-2: genetics
KW  - Lipocalin-2: metabolism
KW  - Luminescent Proteins: genetics
KW  - Luminescent Proteins: metabolism
KW  - Male
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Transgenic
KW  - Nerve Tissue Proteins: metabolism
KW  - Rhombencephalon: pathology
KW  - Rotarod Performance Test
KW  - STAT3 Transcription Factor: genetics
KW  - STAT3 Transcription Factor: metabolism
KW  - Connexin 43 (NLM Chemicals)
KW  - Galectin 3 (NLM Chemicals)
KW  - Lipocalin-2 (NLM Chemicals)
KW  - Luminescent Proteins (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
KW  - STAT3 Transcription Factor (NLM Chemicals)
KW  - Stat3 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30585358
DO  - DOI:10.1002/glia.23544
UR  - https://pub.dzne.de/record/140510
ER  -