A human organoid model of alveolar regeneration reveals distinct epithelial responses to interferon-gamma

Chronic obstructive pulmonary disease (COPD) is characterized by inflammation and emphysema, leading to progressive alveolar destruction. Currently, no therapies effectively regenerate the alveolar epithelium. Here, we developed and characterized a feeder- and serum-free primary adult human organoid model to investigate how inflammatory conditions influence alveolar regeneration. Using Wnt activation and heregulin-β, we achieved long-term expansion of progenitor cells, while AT2 maturation protocols enhanced surfactant production, including the formation of tubular myelin. Introducing a LATS inhibitor to the expansion conditions induced an AT1 differentiation program without eliminating AT2 cells. Single-cell RNA-sequencing revealed multipotent progenitor-like populations, reflecting a state of heightened plasticity associated with regeneration. To model the effects of inflammation, we exposed these organoids to cytokines elevated in COPD. Notably, interferon-gamma (IFN-γ) exerted distinct effects on AT1 and AT2 cells: while it was cytotoxic to AT1 cells, it promoted growth in regenerating AT2 cells in a dose- and time-dependent manner. These findings underscore the nuanced influence of pro-inflammatory cytokines on alveolar regeneration. Our organoid model provides a reductionist platform for mechanistic studies in human cells, aiming to identify therapies that prevent alveolar destruction and improve alveolar regeneration in COPD