Sustaining microglial reparative function enhances stroke recovery | Nature
Subjects
- Molecularly targeted therapy
- Neuroimmunology
- Stroke
Abstract
Neurological symptoms after brain injury can remain as lifelong detrimental sequelae because most of the spontaneous recovery response disappears within a few months after the injury1,2. Microglia have an essential role in this process; however, the cellular and molecular mechanisms that diminish spontaneous functional recovery in the brain remain unclear. Here using cellular fate analysis, we show that reparative microglia persist in the brain after a stroke even after losing their beneficial functions. In these cells, ZFP384 is identified as a pivotal transcriptional regulator that diminishes the expression of genes associated with the recovery phase, turning them into dysfunctional microglia that lose their reparative functions. Mechanistically, ZFP384 diminishes the YY1-mediated chromatin interaction necessary to induce the expression of these genes in microglia. The use of antisense oligonucleotides that target Zfp384 can sustain the broad range of neural repair effects of microglia and enhance recovery after stroke, even in the chronic phase of ischaemic stroke. Thus, therapeutics that prevent the loss of reparative immunity—the beneficial restorative functions of immune cells—can prolong functional recovery in the brain.
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Fig. 1: Microglia remain in the brain even after losing recovery-phase-associated gene expression.The alternative text for this image may have been generated using AI.
Fig. 2: ZFP384 diminishes the expression of recovery-phase-associated genes in microglia.The alternative text for this image may have been generated using AI.
Fig. 3: ASO-Zfp384 prolongs microglial reparative function to sustain stroke recovery.The alternative text for this image may have been generated using AI.
Fig. 4: ASO-Zfp384 promotes broad-range neural repair in the chronic phase after stroke.The alternative text for this image may have been generated using AI.
Fig. 5: ZFP384 disrupts YY1-mediated recovery-phase-associated gene expression in microglia.The alternative text for this image may have been generated using AI.
Fig. 6: ZFP384 expression is inversely correlated with IGF1 expression in the peri-infarct region of the brain after stroke in humans.The alternative text for this image may have been generated using AI.
Data availability
The next-generation sequencing data have been deposited into the Gene Expression Omnibus under accession numbers GSE319235 (ATAC–seq), GSE319237 (bulk RNA-seq), GSE319238 (scRNA-seq), GSE319239 (CUT&Tag) and GSE319240 (HiChIP). Source data are provided with this paper.
Code availability
No custom code was developed for this study. All analyses were performed using publicly available software packages as described in the Methods.
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