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Multimodal Single-Cell Transcriptomic and Chromatin Accessibility Profiling Reveals Monocyte-Derived Macrophage Dynamics Following Ischemic Stroke [scRNA-seq]

ABSTRACT: Ischemic stroke promotes monocyte recruitment to the injured brain and their differentiation into monocyte-derived macrophages (MDMs). These cells contribute to debris clearance but may also exacerbate neuroinflammation. However, the heterogeneity of macrophage subsets and the phenotypic transitions that shape MDM functional states during the subacute phase of stroke remain incompletely characterized. To address this, we first performed single-cell RNA sequencing (scRNA-seq) to define the transcriptional landscape of the mouse brain 48 hours after transient middle cerebral artery occlusion/reperfusion compared with sham controls. Reclustering of macrophage-lineage cells identified multiple monocyte-derived subsets, including a distinct Cd68hi/Ctsdhi MDM subset enriched for lysosomal and lipid-processing gene expression programs. Cell trajectory inference supported a transition from inflammatory infiltrates toward the Cd68hi/Ctsdhi state, accompanied by induction of transcriptomic networks that drive macrophage function to favor a clearance-competent phenotype in response to ischemic stroke. Complementary single-cell ATAC sequencing (scATAC-seq) demonstrated cell type-specific chromatin remodeling after stroke and revealed MDM subclusters with accessibility at key loci regulating lysosomal function and lipid metabolism. Together, our findings define a cellular and regulatory framework of the subacute post-stroke brain and identify a lysosome-enriched Cd68hi/Ctsdhi MDM trajectory, highlighting endolysosomal and lipid-processing programs during early stroke recovery.

ORGANISM(S): Mus musculus

PROVIDER: GSE326241 | GEO | 2026/05/15

REPOSITORIES: GEO

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Multimodal Single-Cell Transcriptomic and Chromatin Accessibility Profiling Reveals Monocyte-Derived Macrophage Dynamics Following Ischemic Stroke [scATAC-seq]

Project description:Ischemic stroke promotes monocyte recruitment to the injured brain and their differentiation into monocyte-derived macrophages (MDMs). These cells contribute to debris clearance but may also exacerbate neuroinflammation. However, the heterogeneity of macrophage subsets and the phenotypic transitions that shape MDM functional states during the subacute phase of stroke remain incompletely characterized. To address this, we first performed single-cell RNA sequencing (scRNA-seq) to define the transcriptional landscape of the mouse brain 48 hours after transient middle cerebral artery occlusion/reperfusion compared with sham controls. Reclustering of macrophage-lineage cells identified multiple monocyte-derived subsets, including a distinct Cd68hi/Ctsdhi MDM subset enriched for lysosomal and lipid-processing gene expression programs. Cell trajectory inference supported a transition from inflammatory infiltrates toward the Cd68hi/Ctsdhi state, accompanied by induction of transcriptomic networks that drive macrophage function to favor a clearance-competent phenotype in response to ischemic stroke. Complementary single-cell ATAC sequencing (scATAC-seq) demonstrated cell type-specific chromatin remodeling after stroke and revealed MDM subclusters with accessibility at key loci regulating lysosomal function and lipid metabolism. Together, our findings define a cellular and regulatory framework of the subacute post-stroke brain and identify a lysosome-enriched Cd68hi/Ctsdhi MDM trajectory, highlighting endolysosomal and lipid-processing programs during early stroke recovery.

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