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Single-Cell RNA Sequencing Unveils Macrophage Involvement in Aortic Valve Stenosis Progression

ABSTRACT: Introduction: Calcific aortic stenosis (AS) is an age-related progressive disease with increasing global prevalence. Although chronic inflammation is a key factor in its pathogenesis, the detailed immune cell profiles and their interactions with non-immune cells remain poorly understood. This study aimed to characterize the immune cell landscape in calcific AS at a single-cell level and evaluate the potential of anti-inflammatory therapy. Methods: Human aortic valve samples were obtained from four patients with non-calcified aortic regurgitation (AR) and 11 patients with AS undergoing surgical aortic valve replacement. Single-cell 3’ gene expression sequencing (scRNA-seq (3’)) was performed on CD45+ immune cells, while single-cell RNA sequencing Flex (scRNA-seq (Flex)) and bulk RNA sequencing were conducted on unsorted cells. Additionally, an anti-TNFα antibody experiment was performed in a murine AS model induced by aortic valve wire injury. Results: In myeloid cells, LYVE1 resident macrophages were significantly decreased, whereas classical monocytes expressing pro-inflammatory genes and C1Q macrophages were increased in AS valves compared to AR valves. These macrophages exhibited strong interactions with valve interstitial cells, particularly with chondrogenic subtypes expressing COMP and SPARC. Anti-TNFα treatment in the murine model significantly reduced aortic valve calcification without hematopoietic complications. Conclusions: This study is the first to integrate scRNA-seq (3’) and scRNA-seq (Flex) analyses of human aortic valves, revealing single cell-level characteristics of immune cells and their interactions with non-immune cells in calcific AS. These findings suggest that anti-inflammatory therapy could be a therapeutic target for calcific AS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291890 | GEO | 2026/03/01

REPOSITORIES: GEO

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Project description:Aims Calcific aortic valve disease (CAVD) is a significant cause of illness and death worldwide. The disease mechanism involves age-associated immuno-osteogenic processes but developmental origins and early disease mechanisms are not fully characterized. Identification of early predictive markers could help optimize therapy decisions and patient follow-up. Methods and Results RNA-sequencing was carried out on human fetal aortic valves at weeks 9, 13, and 22, and adult control, calcified bicuspid (BAV) and tricuspid aortic valves (TAV). K-means clustering was implemented to identify co-expressed gene patterns simultaneously up- and down-regulated over the different conditions. Canonical pathway analysis revealed a predominant immune-metabolic gene signature indicative of ongoing innate and adaptive immune responses, including lymphocyte T-cell metabolic adaptation. Specifically, cytokine and chemokine signalling, cellular migration and proliferation, were all increased in CAVD, while oxidative phosphorylation and protein translation were decreased. Discrete immune-metabolic gene signatures were present at foetal stages and adult controls, indicating that inflammation initiates as soon as the valves are formed and is maintained and amplified during post-natal life. Multiple pathways involved in cellular stress response and neurodegenerative disease were also aberrantly expressed, suggesting that chronic inflammation drives metabolic stress- and age-associated valve pathology in CAVD. Comparing the valve RNA-sequencing dataset with whole blood transcriptomes from asymptomatic individuals with early aortic valve calcification identified a gene signature including the CD28 pathway, highly predictive of patients with CAVD and healthy individuals with moderate levels of aortic valve calcification. Conclusion These data deepen and broaden our understanding of the molecular basis of CAVD, and identify a gene signature for the early detection of aortic valve calcification. Keywords Human foetal valve, CAVD, BAV, inflammation, biomarker, gene signature,PESA

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Single-Cell RNA Sequencing Unveils Macrophage Involvement in Aortic Valve Stenosis Progression

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