Transcriptomic, Specific Marker, and Pathway Analysis of Smooth Muscle Cell Foam Cells Compared to Macrophage Foam Cells in Human Atherosclerosis
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BACKGROUND
Smooth muscle cells (SMCs) comprise the majority of cells in human atherosclerotic lesions and are thought to be a major source of cholesterol-overloaded foam cells in human and mouse atheromas. However, the transcriptomic profile, specific markers, and biologic itinerary of SMC foam cells relative to macrophage foam cells remain poorly defined.
METHODS
Single-cell RNA sequencing (scRNA-seq) was performed on fresh coronary artery segments from heart transplant recipients with early- to intermediate-stage atherosclerosis. Gene expression in a putative SMC foam cell cluster was compared with cultured SMCs loaded with aggregated low-density lipoprotein (agLDL) or cholesterol–methyl-β-cyclodextrin (Chol-MβCD). Candidate markers distinguishing SMC from macrophage foam cells were validated using additional publicly-available scRNA-seq datasets, Xenium spatial transcriptomics, and immunofluorescence microscopy of human coronary atheromas. Pathway analysis was performed using Gene Set Enrichment Analysis Hallmark gene sets.
RESULTS
A distinct SMC foam cell cluster derived from fibromyocytes (“lipomyocytes”) was identified using markers induced by in vitro cholesterol loading. agLDL loading reproduced the lipomyocyte transcriptional profile, whereas Chol-MβCD induced an inflammatory phenotype colocalizing with macrophages rather than lipomyocytes. Lipomyocytes highly expressed SERPINE1 , encoding plasminogen activator inhibitor-1 (PAI-1), and CFH , encoding complement factor H, which were validated in human coronary lesions by spatial transcriptomics and immunofluorescence microscopy. Compared with macrophage foam cells, lipomyocytes demonstrated distinct pathway activation, including enrichment of extracellular matrix, coagulation and angiogenesis pathways.
CONCLUSIONS
SMC foam cells, or lipomyocytes, represent a distinct foam cell phenotype with unique markers and biologic programs that differ from macrophage foam cells during atherosclerotic plaque development.
Clinical Perspective
What Is New?
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Smooth muscle cell (SMC) foam cells, or lipomyocytes, arise from fibromyocytes and exhibit a transcriptomic profile that is markedly distinct from that of macrophage foam cells.
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In vitro loading of SMCs with aggregated LDL recapitulates the gene expression profile of SMC foam cells in human coronary atheromas, whereas loading with cyclodextrin-bound cholesterol does not.
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Plasminogen activator inhibitor 1 (PAI-1, encoded by SERPINE1 ) and Complement Factor H are specific markers of SMC foam cells and are not expressed by macrophage foam cells.
What Are the Clinical Implications?
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SMCs contribute a substantial proportion, and potentially the majority, of foam cells in atherosclerotic lesions.
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Defining the biological trajectory of SMC foam cells within plaques is critical for understanding their roles in plaque progression, rupture and thrombosis, and for establishing their relevance as a distinct therapeutic target to reduce major cardiovascular events.
