Human organoids reveal inflammation-mediated effects on alveolar epithelial regeneration

Chronic obstructive pulmonary disease (COPD) is marked by inflammation and emphysema, the progressive destruction of alveolar tissue. To date, there are no therapies that effectively regenerate alveolar epithelium. This study aimed to improve our understanding of how an inflammatory environment impacts alveolar regeneration, guiding new treatment approaches for COPD patients. We developed a primary adult human organoid model that is feeder- and serum-free, enabling long-term expansion and maturation of alveolar type 2 (AT2) cells, and differentiation to alveolar type 1 (AT1) cells. Our defined culturing conditions allow for precise pathway manipulation. To model the regenerative response of alveolar cells in a pro-inflammatory environment, we exposed the organoids to cytokines elevated in COPD. Notably, we found that interferon-γ (IFN-γ) had distinct effects on AT1 and AT2 cells. IFN-γ is a key cytokine released during infections and known for its cytotoxic effects on epithelial cells. While we confirmed its cytotoxic effect on AT1 cells, we found that it enhanced the growth of AT2 cells. Both effects could be rescued by inhibiting Janus kinase 1/2 downstream of the IFN-γ receptor. Further pathway analysis revealed that AT2 cells, but not AT1 cells, upregulate apoptosis inhibitors upon IFN-γ treatment, suggesting a mechanism by which AT2 cells might evade the cytotoxic effects of IFN-γ. These findings highlight the importance of understanding the nuanced effects of pro-inflammatory cytokines on alveolar regeneration. Our organoid model provides a new platform for mechanistic studies in human cells, aiming to identify treatments that prevent alveolar destruction and enhance alveolar regeneration.