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Spatially resolved deconvolution of the fibrotic niche in lung fibrosis

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
2211-1247
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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et al.
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).

Record type: Article

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
ORCID for Elizabeth R. Davies: ORCID iD orcid.org/0000-0002-8629-8324
ORCID for David. A. Johnston: ORCID iD orcid.org/0000-0001-6703-6014
ORCID for Sophie V. Fletcher: ORCID iD orcid.org/0000-0002-5633-905X
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648
ORCID for Donna E. Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Mark G. Jones: ORCID iD orcid.org/0000-0001-6308-6014

Catalogue record

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: Ben G. Marshall
Author: David. A. Johnston ORCID iD
Author: Zijian Xu
Author: Sophie V. Fletcher ORCID iD
Author: Yihua Wang ORCID iD
Author: Gayle Marshall
Author: Donna E. Davies ORCID iD
Author: Emily Offer
Author: Mark G. Jones ORCID iD
Corporate Author: et al.

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