Human Immuno-Lung Organoid Model to Study Macrophage-Mediated Lung Cell Senescence Upon SARS-CoV-2 Infection [scRNA-seq]

In this study, we utilized spatial transcriptional assays (NanoString CosMx) to analyze both explant and autopsy samples from COVID and non-COVID-19 lungs, identifying activation of proinflammatory macrophages. We then created macrophage-alveolar and macrophage-airway organoid models, integrating hPSC-derived macrophages with alveolar or airway organoids, and discovered that proinflammatory macrophages induce lung cell senescence through via the THBS1-(ITGA3+ITGB1) pathway. This study not only establishes immune-lung organoid models for studying macrophage-mediated host damage but also highlights the previously unrecognized role of the THBS1-(ITGA3+ITGB1) pathway in lung cell senescence during infectious diseases. Overall design: scRNA-seq analysis identified increased senescence in lung cells, including AT2 cells, within immune-alveolar organoids upon SARS-CoV-2 infection. The increase of senescence in lung cells was further confirmed in alveolar organoids co-cultured with proinflammatory macrophages. CosMx analysis and immunostaining validated the upregulation of senescence in lung cells within lung explant samples.