Notch2 Is Required for Inflammatory Cytokine-Driven Goblet Cell Metaplasia in the Lung

The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia in vitro and in vivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases. [Display omitted] •Airway basal cells differentiate into goblet and ciliated cells in 3D cultures•Inflammatory cytokines bias airway basal cell fate to drive goblet cell metaplasia•Notch2 is a key node required for goblet cell metaplasia•Targeting Notch2 prevents goblet cell metaplasia, regardless of the stimulus Goblet cell metaplasia, resulting in excessive mucus production, is a hallmark of airway diseases. Here, Danahay et al. demonstrate that inhibition of Notch2 prevents goblet cell metaplasia in response to diverse stimuli in vitro and in vivo, validating Notch2 blockade as a therapeutic strategy for airway diseases.