Single cell reconstruction of human basal cell diversity in normal and IPF lung

Rationale Declining lung function in patients with interstitial lung disease is accompanied by epithelial remodeling and progressive scarring of the gas-exchange region. There is a need to better understand the contribution of basal cell hyperplasia and associated mucosecretory dysfunction to the development of idiopathic pulmonary fibrosis (IPF). Objectives We sought to decipher the transcriptome of freshly isolated epithelial cells from normal and IPF lung to discern disease-dependent changes within basal stem cells. Methods Single cell RNA sequencing was used to map epithelial cell types of the normal and IPF human airway. Organoid and ALI cultures were used to investigate functional properties of basal cell subtypes. Measurements and Main Results We found that basal cells included multipotent and secretory primed subsets in control adult lung tissue. Secretory primed basal cells include an overlapping molecular signature with basal cells obtained from distal lung tissue of IPF lungs. We confirmed that NOTCH2 maintains undifferentiated basal cells and restrict basal-to-ciliated differentiation, and present evidence that NOTCH3 functions to restrain secretory differentiation. Conclusions Basal cells are dynamically regulated in disease and are specifically biased towards expansion of the secretory primed basal cell subset in idiopathic pulmonary fibrosis. Modulation of basal cell plasticity may represent a relevant target for therapeutic intervention in IPF.