A single-cell and spatial transcriptomic atlas of human tuberculous constrictive pericardium

<h4>Background</h4>Tuberculous pericarditis (TP) can progress to tuberculous constrictive pericarditis (TB-CP), a life-threatening fibrotic syndrome. However, the cellular architecture and intercellular circuits that link granulomatous inflammation to pericardial fibrosis remain poorly defined.<h4>Methods</h4>We performed single-cell RNA sequencing (scRNA-seq) on 81,634 cells from surgically resected pericardium of six patients with TB-CP and three normal controls. Ligand-receptor and trajectory analyses were integrated with spatial transcriptomics, histology, immunohistochemistry, and multiplex immunofluorescence to map cell states, signalling pathways, and immune-stromal niches in situ.<h4>Findings</h4>We generated an integrated single-cell and spatial atlas of the human pericardium in TB-CP, delineating 14 major cell types and heterogeneous transcriptional programmes associated with granuloma formation, vascular remodelling, and fibrotic activation. Spatial mapping revealed MMP9⁺ macrophage-rich granulomatous cores surrounded by infiltrating CCL19⁺ fibroblasts and T cells. In parallel, S100A4⁺ endothelial cells displayed endothelial-to-mesenchymal transition-like programmes and trajectories converging on ACTA2⁺ myofibroblasts, supported by immune cell-derived TGF-β and VEGF signalling. Ligand-receptor analysis and spatial co-localisation suggested macrophages may act as hubs that couple immune activation to endothelial reprogramming, fibroblast activation, and T-cell recruitment within fibrotic lesions.<h4>Interpretation</h4>This human atlas defines the cellular landscape and key intercellular circuits underlying the immunopathogenesis of TB-CP. Our findings show that a spatially organised immune-endothelial-fibroblast network is associated with pericardial fibrosis and nominate VEGF/TGF-β pathways and associated cell states as potential biomarkers and therapeutic targets.<h4>Funding</h4>National Natural Science Foundation of China (82270486 to F.X.); Science and Technology Bureau of Sichuan Province (2021YFS0051, 2024YFFK0209 to Y.W.; 2024NSFC0646 to F.X.).