Multiscale Single-Cell Assessment of the Fibrotic Niche in Idiopathic Pulmonary Fibrosis
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Background
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease characterized by excessive extracellular matrix deposition within the lung. Recent advances in single-cell RNA sequencing have identified unique populations of epithelial cells lacking KRT5 while expressing KRT17; fibroblasts characterized by high collagen production, and the expression of CTHRC1; as well as a distinct subset of SPP1 positive macrophages. However, the precise interactions among these and potentially other cells that lead to the formation of fibrotic niche remain unclear.
Methods
Using spatial transcriptomics and Hyperion imaging mass cytometry we compared the cellular populations in formalin fixed paraffin embedded fibrotic lesions (n=9 patients) with control lung (n=9), and using CellChat we investigated the cellular interactions.
Results
Spatial transcriptomic analysis identified 180,067 cells which demonstrated three unique fibrotic niches enriched for KRT5-/KRT17+ epithelial cells, SPP1+ macrophages and collagen producing fibroblasts as well as a unique DCN+ expressing plasma B cell. Ligand receptor analysis inferred that most fibrotic cells interacted with ATII cells, with the exception of KRT5-/KRT17+ epithelial cells which interacted primarily with macrophages. Hyperion Mass Cytometry identified 55,979 cells, which identified similar cell populations clustered into two unique fibrotic niches: a stromal fibrotic niche characterized by CTHRC1+ fibroblasts interacting with fibrotic associated plasma cells, and a second niche containing KRT5-/KRT17+ cells and SPP1+ macrophages. This latter niche appeared likely to originate from the control bronchial niche with progressive loss of KRT5.
Conclusion
These findings describe the characteristics of the fibrotic niche, support the hypothesis that basal cells can also contribute to the origin of the fibrotic epithelium and describe a novel fibrotic plasma cell population, shedding light on the complex cellular dynamics within fibrotic human lung tissues.
