Spatial transcriptomics reveals altered communities and drivers of aberrant epithelia and pro-fibrotic fibroblasts in interstitial lung diseases

Interstitial lung diseases (ILD) are characterized by fibrotic scarring of the distal lung parenchyma with remarkably unfavorable prognosis. Here we generated a comprehensive portrait of diverse cell types in distal lung and investigated how their spatial organization is altered in fibrosis. Through in-depth analyses, we find that cells native to normal parenchyma are supplanted by ectopic cells in ILD tissues. Integration with histopathology reveals the transformation to fibrotic parenchyma is accompanied by decellularization and immune cell depletion. We identified a co-localized pathogenic niche constituting aberrant transitional epithelial cells and pro-fibrotic fibroblasts concentrated in areas of heightened fibrotic activity. Modeling the maladaptive differentiation of alveolar type II cells into aberrant transitional cells using organoids implicates required signals from all three pro-inflammatory ligands, TGF-beta, IL1beta and TNF-alfa for their induction. We also discovered a novel pericyte supporting the alveolar capillaries. Collectively, these insights broaden our understanding of fibrotic interstitial lung diseases.