Single-cell spatial transcriptomic analyses of severe Covid-19 lungs identifies disease-associated spatial niches

Here, we applied imaging-based single-cell spatial transcriptomics to post-mortem lung samples from severe COVID-19 patients and controls. We identified distinct cellular niches associated with specific histopathological states, including fibrotic and alveolar remodeling regions.

Fibrotic niches were enriched in CHI3L1/MMP9hi macrophages spatially associated with COL1A1+ fibroblasts and predicted to drive pathogenic fibroblast reprogramming through Tgf-β and galectin-3 signaling. In contrast, alveolar niches contained SPP1hi macrophages exposed to epithelial-derived cues, including WNT ligands and GM-CSF, consistent with differentiation toward an alveolar macrophage-like state. These findings reveal that severe COVID-19 lungs are organized into discrete, macrophage-centered microenvironments that differentially regulate tissue remodeling, providing a spatial framework to understand divergent immunopathological trajectories.