Spatially resolved deconvolution of the fibrotic niche in lung fibrosis

作者：Michael Eyres, Joseph A. Bell, Elizabeth R. Davies, Aurélie Fabre, Aiman Alzetani, Sanjay Jogai, Ben G. Marshall, David A. Johnston, Zijian Xu, Sophie Fletcher, Yihua Wang, Gayle Marshall, Donna E. Davies, Emily Offer, Mark G. Jones · 发表于：Cell Reports · 年份：2022 · DOI：10.1016/j.celrep.2022.111230 · 被引用次数：52 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Occupational and environmental lung diseases、Medical Imaging and Pathology Studies

A defining pathological feature of human lung fibrosis is localized tissue heterogeneity, which challenges the interpretation of transcriptomic studies that typically lose spatial information. Here we investigate spatial gene expression in diagnostic tissue using digital profiling technology. We identify distinct, region-specific gene expression signatures as well as shared gene signatures. By integration with single-cell data, we spatially map the cellular composition within and distant from the fibrotic niche, demonstrating discrete changes in homeostatic and pathologic cell populations even in morphologically preserved lung, while through ligand-receptor analysis, we investigate cellular cross-talk within the fibrotic niche. We confirm findings through bioinformatic, tissue, and in vitro analyses, identifying that loss of NFKB inhibitor zeta in alveolar epithelial cells dysregulates the TGFβ/IL-6 signaling axis, which may impair homeostatic responses to environmental stress. Thus, spatially resolved deconvolution advances understanding of cell composition and microenvironment in human lung fibrogenesis.