Whole-transcriptome single-cell spatial landscape of instability in human carotid atherosclerosis

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ID: 334096
2026
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Abstract
AIMS: Carotid atherosclerotic plaque instability is a major cause of ischemic stroke. While current clinical guidelines for carotid endarterectomy rely primarily on stenosis severity and patient symptomatology, unstable plaques can cause strokes even with low to moderate stenosis, suggesting that factors beyond plaque stenosis may drive its instability. This study aimed to characterize the cellular and spatial features of plaque instability at both single-cell and subcellular resolution. METHODS AND RESULTS: single-cell RNA sequencing (scRNA-seq) was performed on carotid endarterectomy samples from patients with clinically and histologically classified stable or unstable plaques, consisting of more than 53,000 cells. Vascular smooth muscle cells (VSMCs), macrophages, and T-lymphocytes accounted for ∼85% of plaque-resident cells, with unstable plaques showing increased abundance of inflammatory synthetic VSMCs, GZMK+ cytotoxic T-lymphocytes, and antigen-presenting macrophages. In contrast, stable plaques were enriched in contractile and fibroblast-like VSMCs, alongside MRC1+ resident-like macrophages. To then spatially map these populations, CosMx™ high-plex spatial transcriptomics was integrated utilizing the unprecedented whole-transcriptome (∼18,934 targets) Human Discovery RNA panel. This revealed a distinct spatially disorganized plaque architecture in unstable plaques, characterized by infiltration of inflammatory synthetic VSMCs and effector T-lymphocytes distributed across both the fibrotic cap and lipid core, alongside distinct multicellular microenvironments enriched for adaptive immune engagement. This was in contrast to stable plaques, which exhibited more structured, macrophage-dominant spatial microenvironments and neighborhoods. We lastly profiled ∼90,000 paired peripheral blood mononuclear cells (PBMCs) to assess the plaque macroenvironment. PBMCs surrounding unstable plaques displayed exclusive enrichment of CD14+CD16+ intermediate monocytes and effector T-lymphocytes, which were depleted surrounding stable plaques. Ligand-receptor interaction analyses within CCL and CXCL-mediated pathways revealed enhanced immune-stromal signaling between PBMC-derived monocytes and plaque-resident VSMCs in the unstable plaque group, with coordinated chemokine-driven interactions indicating a shift toward VSMC- and T-lymphocyte mediated recruitment of circulating immune cells. CONCLUSIONS: These results demonstrate that carotid plaque instability is driven by spatially coordinated expansion of inflammatory VSMCs and effector immune cells within the plaque and from the circulation, with a shift from predominantly innate immune-dominant characteristics in stable plaques toward adaptive immune-enriched responses in unstable conditions. This integrated single-cell and spatial transcriptomic approach refines an integrated immune-stromal framework linking local plaque remodeling with systemic immune activation, highlighting key tissue-resident and circulating contributors to instability and establishing a foundation for mechanism-informed diagnostics and targeted therapeutic strategies beyond stenosis severity.
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Authors Jae Hyun Byun, Yiming Cao, Ashot S. Harutyunyan, Spyros Oikonomopoulos, Jiannis Ragoussis, John P. Veinot, Helena Papacostas Quintanilla, Stella Styliani Daskalopoulou
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Journal cardiovascular research
Year 2026
DOI
10.1093/cvr/cvag253
URL
https://academic.oup.com/cardiovascres/advance-article-pdf/doi/10.1093/cvr/cvag253/72518148/cvag253.pdf
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