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Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis [Xenium]

ABSTRACT: Pulmonary fibrosis (PF) is a chronic, progressive condition that represents the end-stage of many interstitial lung diseases (ILDs). Single-cell transcriptomic studies have revealed disease-emergent epithelial, fibroblast, and macrophage cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using image-based spatial transcriptomics to profile gene expression changes in-situ across 28 lung samples from control and PF lungs, we characterized the expression of 343 genes in over 1 million nuclei at subcellular resolution. Using both cell-based and cell-agnostic approaches, we observed a diversity of distinct molecularly-defined spatial niches in control and PF lungs. Overlaying these computationally-defined niches with disease-associated histopathologic features, we identified novel patterns of dysregulation in alveoli informed by spatial context. We computationally segmented individual air spaces and using cell composition, we ordered airspaces from homeostatic to most dysregulated. Using this ordering we identified a series of stepwise molecular changes associated with progressive distal lung remodeling. Together, these results advance our understanding of the molecular programs underlying progressive PF.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250346 | GEO | 2024/06/04

REPOSITORIES: GEO

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Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis [Visium]

Project description:Pulmonary fibrosis (PF) is a chronic, progressive condition that represents the end-stage of many interstitial lung diseases (ILDs). Single-cell transcriptomic studies have revealed disease-emergent epithelial, fibroblast, and macrophage cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using image-based spatial transcriptomics to profile gene expression changes in-situ across 28 lung samples from control and PF lungs, we characterized the expression of 343 genes in over 1 million nuclei at subcellular resolution. Using both cell-based and cell-agnostic approaches, we observed a diversity of distinct molecularly-defined spatial niches in control and PF lungs. Overlaying these computationally-defined niches with disease-associated histopathologic features, we identified novel patterns of dysregulation in alveoli informed by spatial context. We computationally segmented individual air spaces and using cell composition, we ordered airspaces from homeostatic to most dysregulated. Using this ordering we identified a series of stepwise molecular changes associated with progressive distal lung remodeling. Together, these results advance our understanding of the molecular programs underlying progressive PF.

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