Abstract Background and aims Immune responses are central but incompletely understood drivers of human ischemic stroke pathology. Limited access to human tissue and reliance on rodent models have constrained the identification of human-specific cellular programs. Methods We generated an integrated spatiotemporal atlas of the post-stroke immune response using postmortem human brain tissue, combining immunohistochemistry, single-nucleus RNA sequencing, and spatial transcriptomics, with validation in the murine MCAO model. Results The immune response followed a stereotyped sequence, characterized by rapid neutrophil infiltration into the infarct core, delayed T cell entry, and progressive accumulation of activated microglia/macrophages, defining an “inflammatory penumbra” at the infarct border. Single-nucleus profiling resolved 19 transcriptionally distinct cell populations and revealed a temporal cascade of early neuronal loss, subsequent oligodendrocyte and astrocyte decline, and late dominance of infiltrating myeloid cells. Stroke-associated myeloid cells (SAMCs) expanded between days 5–15, exhibited proliferative and lipid-clearance signatures, localized to degenerating neurons and oligodendrocytes, and were activated via APP-CD74 signaling. Fibroblasts dynamically reprogrammed toward wound-healing and matrix-remodeling states, while endothelial cells underwent endothelial-to-mesenchymal transition (EndMT), which was modulated by neutrophils and T cells in the MCAO model. Conclusions SAMCs and EndMT represent conserved, temporally regulated hallmarks of the human post-stroke response. This study establishes a translational framework for dissecting human-specific immune mechanisms in stroke and highlights potential cellular targets for therapeutic intervention. Conflict of interest nothing to disclose
Strecker et al. (Fri,) studied this question.
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