The University of Southampton
University of Southampton Institutional Repository

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
Bell, Joseph
68ba55a7-95b8-4a5a-a9f2-f90afea18b11
Eyres, Michael
caa1bc6a-9373-4f2c-874f-822f0b5d2ebf
Davies, Elizabeth
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Fabre, Aurelie
69bec59e-56b8-4a0e-be2f-f36222fe1344
Alzetani, Aiman
04d65796-5c8e-4c5b-aeeb-ea093c118f03
Jogai, Sanjay
18c2f36b-4572-46d5-b17d-a6d2cdaa916c
Marshall, Benjamin
9abf382c-977f-459c-9b91-5ed8cbf2284f
Johnston, DA
b41163c9-b9d2-425c-af99-2a357204014e
Xu, Zijian
052c41eb-6256-4ed8-94a4-ab0dfe0f87b1
Fletcher, Sophie V.
29363f9b-517e-4303-9cdf-941461520fa5
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Marshall, Gayle
9929ff17-9d6d-46f3-a8c4-1df450d48778
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Offer, Emily
7eb13084-7518-495a-b231-4acdb99ff9e4
Jones, Mark
a6fd492e-058e-4e84-a486-34c6035429c1
Bell, Joseph
68ba55a7-95b8-4a5a-a9f2-f90afea18b11
Eyres, Michael
caa1bc6a-9373-4f2c-874f-822f0b5d2ebf
Davies, Elizabeth
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Fabre, Aurelie
69bec59e-56b8-4a0e-be2f-f36222fe1344
Alzetani, Aiman
04d65796-5c8e-4c5b-aeeb-ea093c118f03
Jogai, Sanjay
18c2f36b-4572-46d5-b17d-a6d2cdaa916c
Marshall, Benjamin
9abf382c-977f-459c-9b91-5ed8cbf2284f
Johnston, DA
b41163c9-b9d2-425c-af99-2a357204014e
Xu, Zijian
052c41eb-6256-4ed8-94a4-ab0dfe0f87b1
Fletcher, Sophie V.
29363f9b-517e-4303-9cdf-941461520fa5
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Marshall, Gayle
9929ff17-9d6d-46f3-a8c4-1df450d48778
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Offer, Emily
7eb13084-7518-495a-b231-4acdb99ff9e4
Jones, Mark
a6fd492e-058e-4e84-a486-34c6035429c1

Bell, Joseph, Eyres, Michael, Davies, Elizabeth, Fabre, Aurelie, Alzetani, Aiman, Jogai, Sanjay, Marshall, Benjamin, Johnston, DA, Xu, Zijian, Fletcher, Sophie V., Wang, Yihua, Marshall, Gayle, Davies, Donna, Offer, Emily and Jones, Mark (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.

Text
DSPaccepted - Accepted Manuscript
Download (167kB)
Text
1-s2.0-S2211124722010476-main - Version of Record
Available under License Creative Commons Attribution.
Download (8MB)

More information

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. Publisher Copyright: © 2022 The Author(s)
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 Davies: ORCID iD orcid.org/0000-0002-8629-8324
ORCID for DA Johnston: ORCID iD orcid.org/0000-0001-6703-6014
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Mark Jones: ORCID iD orcid.org/0000-0001-6308-6014

Catalogue record

Date deposited: 26 Aug 2022 16:44
Last modified: 17 Nov 2022 05:02

Export record

Altmetrics

Contributors

Author: Joseph Bell
Author: Michael Eyres
Author: Aurelie Fabre
Author: Aiman Alzetani
Author: Sanjay Jogai
Author: DA Johnston ORCID iD
Author: Zijian Xu
Author: Sophie V. Fletcher
Author: Yihua Wang ORCID iD
Author: Gayle Marshall
Author: Donna Davies ORCID iD
Author: Emily Offer
Author: Mark Jones ORCID iD

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×