Systems level identification of a matrisome-associated macrophage polarization state in multi-organ fibrosis
- SingHealth Duke-NUS Academic Medical Centre, Singapore
Abstract
Tissue fibrosis affects multiple organs and involves a master-regulatory role of macrophages which respond to an initial inflammatory insult common in all forms of fibrosis. The recently unravelled multi-organ heterogeneity of macrophages in healthy and fibrotic human disease suggests that macrophages expressing osteopontin (SPP1), associate with lung and liver fibrosis. However, the conservation of this SPP1+ macrophage population across different tissues, and its specificity to fibrotic diseases with different etiologies remain unclear. Integrating 15 single cell RNA-sequencing datasets to profile 235,930 tissue macrophages from healthy and fibrotic heart, lung, liver, kidney, skin and endometrium, we extended the association of SPP1+ macrophages with fibrosis to all these tissues. We also identified a subpopulation expressing matrisome-associated genes (e.g., matrix metalloproteinases and their tissue inhibitors), functionally enriched for ECM remodelling and cell metabolism, representative of a matrisome-associated macrophage (MAM) polarization state within SPP1+ macrophages. Importantly, the MAM polarization state follows a differentiation trajectory from SPP1+ macrophages and is associated with a core set of regulon activity. SPP1+ macrophages without the MAM polarization state (SPP1+MAM-) show a positive association with ageing lung in mice and humans. These results suggest an advanced and conserved polarization state of SPP1+ macrophages in fibrotic tissues resulting from prolonged inflammatory cues within each tissue microenvironment.
Data availability
The current manuscript is a computational study where we meta-analyze previously published data. No new primary datasets have been generated in this manuscript.The code used in the study is publicly available at https://github.com/the-ouyang-lab/mam-reproducibility.See also MethodsThe processed Seurat object for each of the six tissues and SPP1 macrophages can be downloaded at https://zenodo.org/record/8266711 (See also Methods)DATA SET information: Details on previously published datasets are provided and described in Table 1 within the manuscript.
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liver single cell dataNCBI Gene Expression Omnibus, GSE136103.
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lung single cell dataNCBI Gene Expression Omnibus, GSE134692.
Article and author information
Author details
Funding
Ministry of Education - Singapore (T2EP30221-0013)
- Enrico Petretto
Ministry of Education - Singapore (2022-MOET1-0003)
- Jacques Behmoaras
National Medical Research Council (OFLCG22may-0011)
- Enrico Petretto
- Jacques Behmoaras
National Medical Research Council (MOH-OFYIRG21nov-0004)
- John F Ouyang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Charles Farber, University of Virginia, United States
Version history
- Received: December 12, 2022
- Accepted: September 13, 2023
- Accepted Manuscript published: September 14, 2023 (version 1)
Copyright
© 2023, Ouyang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Systems level identification of a matrisome-associated macrophage polarization state in multi-organ fibrosis
eLife 12:e85530.
https://doi.org/10.7554/eLife.85530
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