Abstract
Thoracic aortic aneurysm (TAA) is a life-threatening condition characterized by aortic dilation, inflammation, and extracellular matrix degradation. Despite advances in surgical management, effective pharmacological therapies are still lacking, largely due to an incomplete understanding of the cellular mechanisms driving disease progression. Although recent single-cell RNA sequencing (scRNA-seq) studies have revealed diverse cell types in TAA, the intercellular communication driving pathological remodeling is still poorly defined. Here, we performed integrated scRNA-seq analysis of human TAA (n = 8) and healthy aorta (n = 8) to construct a comprehensive cellular landscape. We identified a disease-associated crosstalk between SPP1 (+) myeloid cells and POSTN (+) fibroblasts, mediated by SPP1 and MK signaling. These two cell subsets were enriched in TAA and co-activated TNF-α signaling via NF-κB and epithelial mesenchymal transition (EMT) pathways, thereby promoting inflammation and ECM remodeling. Cell-cell communication analysis further uncovered upregulated interactions involving SPP1-integrin (e.g., ITGAV/ITGA8/ITGA5+ITGB1) and MDK receptors (SDC4/SDC2/NCL/LRP1/ITGA4/ITGA6+ITGB1) in TAA. These computational findings were further supported by multiplex immunofluorescence and spatial transcriptomics analyses. By integrating key genes and signaling pathways, we identified hub genes and their associated transcription factors, whose regulatory activity was further supported by transcription factor regulon analysis. Our findings highlight the crucial role of myeloid-fibroblast interactions in driving TAA pathogenesis and identify potential therapeutic targets.