Single-cell Profiling Reveals Cooperative Participation of <i> SPP1 ⁺ </i> Myeloid and <i> POSTN ⁺ </i> Fibroblast Subsets in Inflammation and Remodeling in Thoracic Aortic Aneurysm

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.