Spatiotemporal transcriptome analysis reveals that conversion of IKFZ1-mediated microglia underlies a therapy for intracerebral hemorrhage

Abstract Intracerebral hemorrhage (ICH) is a type of stroke with high morbidity and mortality. Activation of microglia in response to ICH can lead to neuroinflammation, which can further exacerbate brain damage and neuronal death. By integration of single-cell RNA sequencing (scRNA-seq) and spatial transcriptome (ST) technologies in rat ICH model, we demonstrated that a microglia subtype (MIkzf1) with strong expression of Ikzf1 exhibits a stage-specific response to ICH around the damaged region. MIkzf1 expressed neuroinflammatory factors and markedly drove neuronal damage by accelerated pyroptosis. By downregulation of Ikzf1, MIkzf1 can be converted to promoting neuronal remodeling microglia subtype MPtn (high expression of Ptn), a neurite growth-promoting subtype, accompanied by the improved ICH outcome. Thus, Ikzf1 is an important promoter of pathogenic microglia MIkzf1 in ICH and suppressing Ikzf1 can reverse MIkzf1 to the repair subtype MPtn. These findings underscore the potential role of Ikzf1 as a new therapeutic target for ICH.