A unique cell population expressing the Epithelial-Mesenchymal Transition-transcription factor Snail moderates microglial and astrocyte injury responses.
Cheryl Clarkson-ParedesMolly T KarlAnastas PopratiloffRobert H MillerPublished in: PNAS nexus (2023)
Insults to the central nervous system (CNS) elicit common glial responses including microglial activation evidenced by functional, morphological, and phenotypic changes, as well as astrocyte reactions including hypertrophy, altered process orientation, and changes in gene expression and function. However, the cellular and molecular mechanisms that initiate and modulate such glial response are less well-defined. Here we show that an adult cortical lesion generates a population of ultrastructurally unique microglial-like cells that express Epithelial-Mesenchymal Transcription factors including Snail. Knockdown of Snail with antisense oligonucleotides results in a postinjury increase in activated microglial cells, elevation in astrocyte reactivity with increased expression of C3 and phagocytosis, disruption of astrocyte junctions and neurovascular structure, increases in neuronal cell death, and reduction in cortical synapses. These changes were associated with alterations in pro-inflammatory cytokine expression. By contrast, overexpression of Snail through microglia-targeted an adeno-associated virus (AAV) improved many of the injury characteristics. Together, our results suggest that the coordination of glial responses to CNS injury is partly mediated by epithelial-mesenchymal transition-factors (EMT-Fsl).
Keyphrases
- epithelial mesenchymal transition
- neuropathic pain
- transcription factor
- inflammatory response
- transforming growth factor
- spinal cord
- gene expression
- lipopolysaccharide induced
- cell death
- spinal cord injury
- signaling pathway
- poor prognosis
- lps induced
- cell cycle arrest
- induced apoptosis
- blood brain barrier
- dna binding
- single cell
- binding protein
- stem cells
- cancer therapy
- gene therapy
- magnetic resonance
- cell therapy
- drug delivery
- oxidative stress
- magnetic resonance imaging
- genome wide identification
- pi k akt
- cerebrospinal fluid
- nucleic acid