Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by progressive lung fibrosis. While considerable progress has been made towards characterizing the cell and molecular profiles of lung tissue in IPF and other fibrotic lung diseases, we lack sufficient context for how pulmonary fibrosis manifests across different diseases. Using spatial transcriptomics, we perform a comparative histopathology study of different fibrotic niches across different lung diseases and identify both shared and distinct combinations of fibrosis-associated features. Methods A tissue microarray of 2mm diameter punches was constructed from 48 lung tissues from 36 patients with fibrotic lung diseases including IPF, silicosis, langerhans cell histiocytosis and respiratory bronchiolitis, alongside disease-free controls. Spatial transcriptomics was performed with the Spatial Xenium Imager (10X Genomics), and subsequently analyzed in R using the package Seurat. Results Several previously described cell phenotypes associated with pulmonary fibrosis were observed across tissues from different diseases. These cell phenotypes include activated fibroblast (expressing COL10A1, COL11A1, MMP11, MM14, CTHRC1 and high levels of COL1A1 and COL3A1), profibrotic macrophage (CCL22, CCL24, CHI3L1, CHIT1 and high levels of SPP1) and aberrant basaloid cells (CDH2, EPHB2, CDKN2B, KRT17 and high levels of MMP7 and GDF15). In IPF, these cells converge in regions with classic histopathological presentations of fibroblast foci (Fig. A). Fibroblasts closest to Aberrant Basaloid cells express a more extreme fibrosis profile (COL10A1, COL11A1) compared to distal fibroblasts in the same foci, suggestive of a signaling response to Aberrant Basaloid cells. The same combination of cells are observed in epithelialized regions of fibrosis in end-stage silicosis (Figure Biii). In granulomatous fibrosis from the same tissue, profibrotic macrophages and stimulated fibroblasts interact without epithelial cells (Fig. Bi-ii); while fibroblasts in these niches show elevated levels of COL1A1 and COL3A1, they lack the extreme phenotype associated with proximity to Aberrant Basaloid cells (Fig. Bi-ii). Conclusions Though many cell phenotypes of pulmonary fibrosis are conserved across diseases, different combinations of these cells are associated with unique histological patterns in different diseases. By comparing niches comprised of different combinations of fibrosis-associated cell types, we deduce how each pro-fibrotic cell phenotype influences another and identify common denominators for therapeutic intervention across pulmonary fibrosis diseases. This abstract is funded by: None
Adams et al. (Fri,) studied this question.