Identification of profibrotic cells in the Idiopathic Pulmonary Fibrosis (IPF) lung

Rationale: Idiopathic Pulmonary Fibrosis (IPF) is a lethal disease with a mechanism of onset and progression that is not fully understood. Past genomic studies, focused on fibrotic lungs, provided valuable insights of its pathophysiology, but an important unanswered question remains: what are the cellular and molecular changes in the histologically normal looking parts of IPF lungs? The answer may help understand the early disease stages and unveil biological pathways that precede and likely lead to the histological changes in IPF. Methods: We reanalyzed our published single cell expression data from healthy controls and IPF patients (Morse et al, 2019, ERJ) . We used Seurat to identify cell types and perform all analyses. Results: We identified 20 cell types and further focused on 4 fibroblast sub-clusters. Two of the sub-clusters were significantly enriched for cells originating from the IPF lungs. Analysis of differentially expressed genes in each cluster identified unique expression profiles for IPF/control states. Interestingly, IPF upper non-fibrotic and lower fibrotic lobes didn’t show significant differences in these profiles. This result shows that fibroblast types such as myofibroblasts which have been associated with the IPF state, are present in parts of the lung that are histologically non-fibrotic. We also found an enrichment in multiple copper-binding proteins supporting the role of metal copper in IPF pathogenesis. Conclusion: We showed histologically normal tissue in IPF lungs is a profibrotic environment representing an earlier stage where many disease-associated cellular alterations have not yet occurred. This establishes a more appropriate environment to study early interventions.