Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models

• DOI: 10.1126/scitranslmed.adk8623
• Publication Date: 2025-01-08T18:58:20Z
• Authors: A. Scott McCall; Sergey Gutor; Hari Tanjore; Ankita Burman; Taylor Sherrill; Micah Chapman; Carla L. Calvi; David Han; Jane Camarata; Raphael P. Hunt; David Nichols; Nicholas E. Banovich; William E. Lawson; Jason J. Gokey; Jonathan A. Kropski; Timothy S. Blackwell
• Keywords: Hypoxia; Hypoxia-Inducible Factors

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result accumulation of profibrotic intermediate/transitional “aberrant” cell states. The mechanisms leading to the emergence persistence aberrant populations distal remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF mouse model repeated injury, we identified persistent activation hypoxia-inducible factor (HIF) signaling these cells. Using genetic lineage-tracing strategies together scRNA-seq, found that disease-emergent cells predominantly arose airway-derived ( Scgb1a1-CreER –traced) progenitors exhibited transcriptional programs Hif2a activation. In mice treated intratracheal bleomycin, deletion Epas1 (Hif2a) but not Hif1a , progenitors, or administration small-molecule HIF2 inhibitor PT-2385, using both prevention rescue approaches, attenuated experimental fibrosis, reduced appearance cells, promoted repair. organoids, pharmacologic inhibition Hif2 differentiation progenitors. addition, treatment human organoids PT-2385 increased colony-forming efficiency, enhanced protein markers type 2 maturation, prevented Together, studies showed drives after targeted may represent an effective therapeutic strategy promote functional other diseases.