Genomic Analysis of Reactive Astrogliosis

By Jennifer L Zamanian, Lijun Xu, L. Foo, Navid Nouri, Lu Zhou, R. Giffard, B. Barres. Journal of Neuroscience, 2012

2,121 citations recorded by the source corpus.

Reactive astrogliosis is characterized by a profound change in astrocyte phenotype in response to all CNS injuries and diseases. To better understand the reactive astrocyte state, we used Affymetrix GeneChip arrays to profile gene expression in populations of reactive astrocytes isolated at various time points after induction using two mouse injury models, ischemic stroke and neuroinflammation. We find reactive gliosis consists of a rapid, but quickly attenuated, induction of gene expression after insult and identify induced Lcn2 and Serpina3n as strong markers of reactive astrocytes. Strikingly, reactive astrocyte phenotype strongly depended on the type of inducing injury. Although there is a core set of genes that is upregulated in reactive astrocytes from both injury models, at least 50% of the altered gene expression is specific to a given injury type. Reactive astrocytes in ischemia exhibited a molecular phenotype that suggests that they may be beneficial or protective, whereas reactive astrocytes induced by LPS exhibited a phenotype that suggests that they may be detrimental. These findings demonstrate that, despite well established commonalities, astrocyte reactive gliosis is a highly heterogeneous state in which astrocyte activities are altered to respond to the specific injury. This raises the question of how many subtypes of reactive astrocytes exist. Our findings provide transcriptome databases for two subtypes of reactive astrocytes that will be highly useful in generating new and testable hypotheses of their function, as well as for providing new markers to detect different types of reactive astrocytes in human neurological diseases.

Subfields: Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/f82ba5687a7b1384fbd484dd0b980ef1250a87ff

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. M. Sofroniew
2. M. Pekna
3. B. Barres
4. M. Pekny
5. I. Galea
6. R. Daneman
7. C. Iadecola
8. N. J. Allen

In Neurology

1. M. Sofroniew
2. M. Pekny
3. M. Pekna
4. E. Hol
5. Alexei Verkhratsky
6. N. J. Allen
7. B. Barres
8. C. Iadecola

Citations in the corpus

• Astrocytes: a central element in neurological diseases (2016, background): “Large-scale gene expression evaluations also show that inflammatory mediators can drive astrocyte transcriptome profiles towards pro-inflammatory and potentially cytotoxic phenotypes [82, 262] that may be beneficial in”
• Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse (2015, positive): “Previous reports of mouse reactive astrocytes have described two distinct types of reactive phenotypes: a bacterial lipopolysaccharide (LPS)infection-induced ‘‘A1’’ phenotype and an ischemia-induced ‘‘A2’’ phenotype (Zamanian et al., 2012).”
• The Biology of Regeneration Failure and Success After Spinal Cord Injury. (2018, background): “(436) have found that 50% of the genes upregulated in reactive astrocytes were different between lipopolysaccharide (LPS)-evoked and ischemic injuries.”
• Immune responses to stroke: mechanisms, modulation, and therapeutic potential. (2020, background): “Astrocytes participate in the immune response to ischemia by upregulating proinflammatory genes and promoting neutrophil recruitment through C-X-C class chemokines (53, 54).”
• Astrocyte reactivity: Subtypes, states and functions in CNS innate immunity (2020, background): “For example, early transcriptome profiling studies identified an ‘A1’ molecular signature of 12 genes associated with a neurotoxic astrocyte subtype that emerged after exposure to specific cytokines secreted by microglia exposed to lipopolysaccharide (LPS), and an ‘A2’ molecular signature of 12 gene”
• Physiology of Astroglia. (2018, neutral): “The transcriptional profile of reactive astroglia was studied on FACS-isolated astrocytes from adult Aldh1l1-EGFP transgenic mice following brain injury (either ischemic stroke by MCAO causing cell death, or LPS injection causing neuroinflammation) (1933).”
• Astrocyte reactivity and reactive astrogliosis: costs and benefits. (2014, background): “Furthermore, the phenotype of reactive astrocytes depends to some degree on the type of insult as shown by the comparison of gene expression profiles of reactive astrocytes isolated from ischemic stroke and lipopolysaccharide (LPS)induced neuroinflammation (271).”
• New tools for studying microglia in the mouse and human CNS (2016, background): “To identify a microglia-specific marker, we generated a microglia-enriched gene expression profile of CD45 immunopanned brain leukocytes from adult mice (18).”