Aims: Severe coronavirus disease 2019 (COVID-19) is characterized by marked heterogeneity in lung pathology, including diffuse alveolar damage, inflammation, and fibrosis. However, how spatially organized cellular interactions contribute to these divergent pathological outcomes remains incompletely understood. We aimed to define the spatial organization of cellular microenvironments in severe COVID-19 lungs and identify niche-specific cellular interactions associated with distinct histopathological states.

Methods: We applied imaging-based single-cell spatial transcriptomics to post-mortem lung tissues from patients with severe COVID-19 and control subjects, enabling high-resolution mapping of cellular composition, spatial neighborhoods, and predicted ligand-receptor interactions within intact tissue architecture.

Results: Analysis of 76,973 cells identified 20 distinct cell populations and revealed marked heterogeneity between COVID-19 samples, corresponding to different histopathological states. Spatial niche analysis identified discrete macrophage-associated microenvironments. Fibrotic niches were enriched in chitinase 3-like 1 (CHI3L1)/matrix metalloproteinase 9 (MMP9^hi) macrophages spatially associated with collagen type I alpha 1 chain (COL1A1⁺) fibroblasts and basal cells. Ligand-receptor inference predicted macrophage-derived transforming growth factor beta (TGF-β) and galectin-3 signaling as drivers of pathogenic fibroblast activation and extracellular matrix remodeling. In contrast, alveolar niches contained secreted phosphoprotein 1 (SPP1^hi) macrophages exposed to epithelial-derived cues, including WNT ligands and granulocyte-macrophage colony-stimulating factor (GM-CSF), consistent with differentiation toward an alveolar macrophage-like state.

Conclusion: Severe COVID-19 lungs are organized into distinct spatial niches associated with divergent immunopathological trajectories. Imaging-based spatial transcriptomics provides a platform to link histopathological states with localized cellular interactions and macrophage-driven tissue remodeling programs.

The aorta is increasingly recognized as an immunologically active organ, with studies reporting both resident and recruited myeloid cells throughout its anatomical range. Substantial evidence from experimental and clinical studies suggests that both adaptive and innate immune cells contribute to the pathogenesis of major aortic diseases. This review aims to present the current understanding of myeloid cell biology in the aorta, structured along both anatomical and disease-specific dimensions. We recapitulate the anatomy of the aorta, with an emphasis on the regional immune heterogeneity that underlies segment-specific disease susceptibility. We discuss the role of myeloid cells in prenatal aortic development and their contributions to hematopoietic stem cell emergence within the aorta-gonad-mesonephros region and to cardiac valve morphogenesis, followed by an overview of myeloid populations found in the healthy adult aorta. Subsequent sections address myeloid involvement in congenital aortic disease, calcific aortic valve stenosis, aortic dissection, and aortic aneurysm. Across these pathological states, studies have reported on mechanisms involving myeloid cells. The review concludes with an evaluation of myeloid-targeted therapeutic strategies, discussing lessons from clinical trials and the rationale for emerging inflammasome inhibitors, cytokine blockade, macrophage-targeting approaches, and biomarker studies. In summary, the available evidence suggests that myeloid cells may be involved in aortic pathology across the full anatomical and clinical spectrum, and their convergent inflammatory mechanisms may represent a potential therapeutic opportunity in aortic disease.