Spatial Transcriptomic Analysis Reveals HDAC Inhibition Modulates Microglial Dynamics to Protect Against Ischemic...

Area of Science:

• Neuroscience
• Immunology
• Epigenetics

Background:

• Ischemic stroke causes significant global disability.
• Microglia play dual roles in stroke, potentially exacerbating or protecting against injury.
• Epigenetic modulation of microglia in stroke is an underexplored therapeutic avenue.

Purpose of the Study:

• To characterize transcriptomic profiles and spatial distribution of microglia in the stroke brain after histone deacetylase inhibitor (HDACi) administration.
• To investigate if HDACi epigenetically modulates microglial activation and phenotype, shifting them towards neuroprotection and repair.
• To explore HDACi's potential in facilitating neuronal repair in the ischemic penumbra.

Main Methods:

• Rodent model of ischemic stroke.
• Spatial transcriptomics to analyze microglial gene expression.
• 3D morphometric reconstruction to assess microglial morphology and distribution.
• Administration of sodium butyrate as a histone deacetylase inhibitor (HDACi).

Main Results:

• HDACi significantly altered the microglial transcriptomic landscape, impacting neuroinflammation, neuroprotection, and phagocytosis pathways.
• HDACi induced a shift in microglial morphological phenotype towards reparative and neurotrophic profiles within the ischemic penumbra.
• These microglial changes were associated with enhanced neuronal survival and reduced neuroinflammation in specific stroke-affected brain regions.

Conclusions:

• HDACi epigenetically modulates microglial function, promoting a shift from a neurotoxic to a neuroprotective phenotype in ischemic stroke.
• The study elucidates mechanisms of HDACi action on microglia, suggesting therapeutic potential for stroke neuroprotection and rehabilitation.
• Findings propose HDACi as a potential therapeutic strategy for other neurodegenerative conditions involving microglia-mediated neuroinflammation.