Mapping spatially resolved transcriptomes in human and mouse pulmonary fibrosis

Nat Genet. 2024 Aug;56(8):1725-1736. doi: 10.1038/s41588-024-01819-2. Epub 2024 Jul 1.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and poor translatability of available preclinical models. Here we generated spatially resolved transcriptome maps of human IPF (n = 4) and bleomycin-induced mouse pulmonary fibrosis (n = 6) to address these limitations. We uncovered distinct fibrotic niches in the IPF lung, characterized by aberrant alveolar epithelial cells in a microenvironment dominated by transforming growth factor beta signaling alongside predicted regulators, such as TP53 and APOE. We also identified a clear divergence between the arrested alveolar regeneration in the IPF fibrotic niches and the active tissue repair in the acutely fibrotic mouse lung. Our study offers in-depth insights into the IPF transcriptional landscape and proposes alveolar regeneration as a promising therapeutic strategy for IPF.

MeSH terms

  • Alveolar Epithelial Cells / metabolism
  • Animals
  • Apolipoproteins E / genetics
  • Bleomycin* / toxicity
  • Disease Models, Animal
  • Gene Expression Profiling
  • Humans
  • Idiopathic Pulmonary Fibrosis* / genetics
  • Idiopathic Pulmonary Fibrosis* / pathology
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Regeneration / genetics
  • Signal Transduction / genetics
  • Transcriptome*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Bleomycin
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Apolipoproteins E