In asthma, chronic inflammation and airway remodeling profoundly alter the epithelial landscape, characterized by a decrease in multiciliated cells and a hyperplasia of mucus-secreting goblet cells. Current therapeutics primarily target the interplay between immune and epithelial cells to mitigate these effects. However, the epithelial-intrinsic mechanisms driving airway remodeling remain underexplored.

To identify molecular regulators of airway remodeling, we reconstructed airway epithelia using basal cells from healthy or severe asthma donors. Using single-cell RNA sequencing and imaging, we analyzed differential cellular and molecular features at baseline, following asthma-related triggers and upon recovery.

At baseline, severe asthma epithelia exhibited hyperplasia of basal and club cells, along with an inflammatory gene expression signature suggesting a lasting memory of the inflammatory environment present in the patients? airways. IL-13 treatment induced similar remodeling across all donor-derived epithelia, marked by goblet cell hyperplasia and the generation of cells displaying a mucociliary identity. However, single-cell gene expression revealed a stronger response in severe asthma epithelia, suggesting increased sensitivity to cytokine exposure. Recovery potential was assessed following a 2-week period of IL-13 washout. While epithelia from both severe asthma and healthy donors showed comparable recovery capacities, lineage inference revealed that some severe asthma epithelial cells remained engaged into a secretory fate.

Overall, although severe asthma epithelia retain a persistent inflammatory gene expression program in vitro, their cellular plasticity enables apparent full recovery.