Spatially resolved deconvolution of the fibrotic niche in lung fibrosis
Spatially resolved deconvolution of the fibrotic niche in lung fibrosis
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.
CP: molecular biology, alveolar epithelial cell homeostasis, cellular deconvolution, fibrosis, lung, spatial transcriptomics
Eyres, Michael
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Bell, Joseph A.
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Davies, Elizabeth R.
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Fabre, Aurelie
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Alzetani, Aiman
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Jogai, Sanjay
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Marshall, Ben G.
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Johnston, David. A.
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Xu, Zijian
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Fletcher, Sophie V.
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Wang, Yihua
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Marshall, Gayle
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Davies, Donna E.
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Offer, Emily
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Jones, Mark G.
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16 August 2022
Eyres, Michael
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Bell, Joseph A.
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Davies, Elizabeth R.
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Fabre, Aurelie
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Alzetani, Aiman
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Jogai, Sanjay
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Marshall, Ben G.
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Johnston, David. A.
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Xu, Zijian
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Fletcher, Sophie V.
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Wang, Yihua
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Marshall, Gayle
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Davies, Donna E.
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Offer, Emily
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Jones, Mark G.
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Eyres, Michael, Bell, Joseph A. and Davies, Elizabeth R.
,
et al.
(2022)
Spatially resolved deconvolution of the fibrotic niche in lung fibrosis.
Cell Reports, 40 (7), [111230].
(doi:10.1016/j.celrep.2022.111230).
Abstract
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.
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Accepted/In Press date: 26 July 2022
e-pub ahead of print date: 16 August 2022
Published date: 16 August 2022
Additional Information:
Funding Information: supported by NC3Rs (NC/V002384/1), the Medical Research Council (MR/S025480/1), the Wellcome Trust (100638/Z/12/Z), an Academy of Medical Sciences/the Wellcome Trust Springboard Award (SBF002\1038), and the AAIR Charity. Infrastructure support was provided by the National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Centre. Graphical abstract was created with BioRender.com. We thank the staff of the NIHR Wellcome Trust Southampton Clinical Research Facility, the Biomedical Imaging Unit, and the Histochemistry Research Unit. We thank Julian Downward (Francis Crick Institute, UK) for providing human ATII cells. M.E. J.B. D.E.D. G.M. E.O. and M.G.J. conceived and designed the study. M.E. J.B. and E.R.D. performed all experiments and data analysis. D.J. supported confocal imaging studies. Y.W. and Z.X. supported in vitro studies. A.F. performed pathology review and interpretation. S.J. S.V.F. A.A. and B.M. performed tissue collection. All authors read and approved the manuscript. D.E.D. is co-founder of, shareholder in, and consultant to Synairgen Research Ltd. D.E.D. M.G.J. and Y.W. acknowledge grants from Boehringer Ingelheim.
Funding Information: supported by NC3Rs (NC/V002384/1), the Medical Research Council (MR/S025480/1), the Wellcome Trust (100638/Z/12/Z), an Academy of Medical Sciences /the Wellcome Trust Springboard Award (SBF002\1038), and the AAIR Charity . Infrastructure support was provided by the National Institute for Health Research ( NIHR ) Southampton Respiratory Biomedical Research Centre . Graphical abstract was created with BioRender.com . We thank the staff of the NIHR Wellcome Trust Southampton Clinical Research Facility, the Biomedical Imaging Unit, and the Histochemistry Research Unit. We thank Julian Downward (Francis Crick Institute, UK) for providing human ATII cells.
Funding Information: D.E.D. is co-founder of, shareholder in, and consultant to Synairgen Research Ltd. D.E.D., M.G.J., and Y.W. acknowledge grants from Boehringer Ingelheim.
Keywords:
CP: molecular biology, alveolar epithelial cell homeostasis, cellular deconvolution, fibrosis, lung, spatial transcriptomics
Identifiers
Local EPrints ID: 468826
URI: http://eprints.soton.ac.uk/id/eprint/468826
ISSN: 2211-1247
PURE UUID: f9529d0e-4aa0-4154-bfcf-9261323facb3
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Date deposited: 26 Aug 2022 16:44
Last modified: 21 Sep 2024 04:01
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Contributors
Author:
Michael Eyres
Author:
Joseph A. Bell
Author:
Aurelie Fabre
Author:
Aiman Alzetani
Author:
Sanjay Jogai
Author:
David. A. Johnston
Author:
Sophie V. Fletcher
Author:
Gayle Marshall
Author:
Emily Offer
Corporate Author: et al.
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