Alveolar type 2 cell senescence is a critical mechanism involved in the lack of repair during emphysema

<bold>Introduction:</bold> During emphysema, which is characterized by alveolar destruction, cell senescence is emerging as a critical mechanism involved in the lack of repair. <bold>Aim:</bold> To define how senescence impacts the properties of epithelial alveolar progenitor cells (AT2s) during the repair process in emphysema. <bold>Methods:</bold> Alveolar organoids were formed with proliferative lung epithelial H441 cells combined with an increasing number of H441 senescent cells and fibroblast (MRC5). In parallel, we sorted SPiDER-β-gal positive and negative human primary AT2 cells (hAT2s) and tested their ability to form alveolospheres (n=2 lung biopsies). Alveolar organoids were also obtained from mice epithelial cells (EpCAM+) isolated from elastase-induced emphysema and control mice and treated with the senolytics Dasatinib + Quercetin (D+Q). Finally, mice were treated with D+Q between 21 to 90 days after elastase instillation. <bold>Results:</bold> The addition of H441 senescent cells decreased the H441 cells’ capacity to form organoids and reduced their size. SPiDER β-gal positive hAT2s formed lower and smaller alveolospheres than SPiDER β-gal negative hAT2s. Similarly, organoids from elastase EpCAM+ cells were fewer and smaller than those from control mice. Supplementation of organoids medium with D+Q decreases β-gal staining and increases the number and size of these organoids. <italic>In vivo</italic>, D+Q reduced emphysema in a curative manner. <bold>Conclusion:</bold> This study highlights the altered properties of AT2 progenitor cells in emphysema, suggesting a potentially deleterious role of senescent AT2 cells in disease progression and the interest in targeting these cells to improve emphysema outcomes.