Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome pulmonary fibrosis.

Abstract

Hermansky-Pudlak syndrome (HPS) is a genetic disorder associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. Unifying mechanisms of AT2 cell dysfunction in genetic and sporadic fibrotic lung diseases remain unknown. Incorporating AT2 cell lineage tracing in HPS mice, we observed a progressive decline in AT2 cell numbers with aging and aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. HPS AT2 cell proliferation was impaired ex vivo and in vivo , suggesting an intrinsic progenitor defect. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and cellular senescence. Through lineage tracing and organoid modeling, we demonstrated that HPS AT2 cells were primed to persist in a Krt8 + reprogrammed transitional state, mediated by p53 activity. These findings suggest that pulmonary fibrosis in HPS may be driven by AT2 cell progenitor dysfunction in the setting of p53-mediated senescence, highlighting a novel potential therapeutic target in HPS and suggesting unifying mechanisms underlying HPS and other forms of pulmonary fibrosis.