Extracellular Matrix Protein 1 as a Mediator of Inflammation-Induced Fibrosis After Myocardial Infarction

Hardy, S; Patrick, R; Liesinger, L; Pöttler, M; Rech, L; Gindlhuber, J; Mabotuwana, N; Ashour, D; Stangl, V; Bigland, M; Murtha, L; Starkey, M; Scherr, D; Hansbro, P; Höfler, G; Ramos, G; Cochain, C

Extracellular Matrix Protein 1 as a Mediator of Inflammation-Induced Fibrosis After Myocardial Infarction

Hardy, S Patrick, R Liesinger, L Pöttler, M Rech, L Gindlhuber, J Mabotuwana, N Ashour, D Stangl, V Bigland, M Murtha, L Starkey, M Scherr, D Hansbro, P

Höfler, G Ramos, G Cochain, C

Permalink

Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Heart Lung and Circulation, 2022, 31, (S3), pp. 311-311
Issue Date:: 2022

Closed Access

	Filename	Description	Size
	PIIS1443950622008150.pdf	Published version	73.58 kB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Hardy, S
dc.contributor.author	Patrick, R
dc.contributor.author	Liesinger, L
dc.contributor.author	Pöttler, M
dc.contributor.author	Rech, L
dc.contributor.author	Gindlhuber, J
dc.contributor.author	Mabotuwana, N
dc.contributor.author	Ashour, D
dc.contributor.author	Stangl, V
dc.contributor.author	Bigland, M
dc.contributor.author	Murtha, L
dc.contributor.author	Starkey, M
dc.contributor.author	Scherr, D
dc.contributor.author	Hansbro, P https://orcid.org/0000-0002-4741-3035
dc.contributor.author	Höfler, G
dc.contributor.author	Ramos, G
dc.contributor.author	Cochain, C
dc.date.accessioned	2023-04-19T20:48:34Z
dc.date.available	2023-04-19T20:48:34Z
dc.date.issued	2022
dc.identifier.citation	Heart Lung and Circulation, 2022, 31, (S3), pp. 311-311
dc.identifier.issn	1443-9506
dc.identifier.uri	http://hdl.handle.net/10453/169987
dc.description.abstract	Background Fibrosis is a hallmark of heart disease, particularly following myocardial infarction (MI) and in heart failure. We previously identified a key role for extracellular matrix protein (ECM1) in wound healing post-MI but the cellular origin and mechanism of ECM1 remained elusive. Here, we investigate the spatiotemporal cellular origin of ECM1 in healthy and diseased human and mouse hearts, and ECM1 dependent human cardiac fibroblast (HuCFb) signalling mechanisms. Methods ECM1 specific analysis of existing single-cell/-nuclei RNA sequencing data was conducted. ECM1 expression was assessed in non-failing (NF), ischaemic (ICM) and dilated (DCM) failing human heart tissue via immunoblotting (n=8), immunohistochemistry (ICM; n=8, NF; n=4) and mRNA in-situ hybridisation (n=3). HuCFbs were treated with recombinant ECM1 and assessed via phosphoproteomics (n=6), wound healing assay (n=4), MTT assay (n=8), qPCR (n=6). Results ECM1 originates from fibroblasts, macrophages/monocytes (MΦ/Mo), and pericytes/vascular cells in uninjured human and mouse hearts. In mouse hearts post-MI, ECM1 originates predominantly from M1MΦ/Mo at day-3, and myofibroblasts and M2MΦ’s at day-7, and expression correlated with cell-cell communication, collagen organisation, inflammation, adhesion, and migration. Fittingly, ECM1 expression was upregulated in human ICM (p=0.048) and DCM (p=0.027), localised interstitially to fibrotic, inflammatory, and peri-vascular areas. In vitro, ECM1 inhibited HuCFb migration (p=0.044) and CCL2 mRNA expression, and stimulated inflammatory (IL-6, IL-1β), fibrotic (TGF-β1, Col1a2), and non-canonical Wnt5a mRNA expression (p<0.05). Phosphoproteomics showed ECM1 stimulates HuCFb Rho protein, cell-cell adhesion, and chemotactic signalling pathways. Conclusions ECM1 may represent a novel mechanism in facilitating inflammation-fibrosis crosstalk post-MI, and a potential therapeutic target.
dc.language	en
dc.publisher	Elsevier
dc.relation.ispartof	Heart Lung and Circulation
dc.relation.isbasedon	10.1016/j.hlc.2022.06.539
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1102 Cardiorespiratory Medicine and Haematology, 1117 Public Health and Health Services
dc.subject.classification	Cardiovascular System & Hematology
dc.title	Extracellular Matrix Protein 1 as a Mediator of Inflammation-Induced Fibrosis After Myocardial Infarction
dc.type	Journal Article
utslib.citation.volume	31
utslib.for	1102 Cardiorespiratory Medicine and Haematology
utslib.for	1117 Public Health and Health Services
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2023-04-19T20:48:33Z
pubs.issue	S3
pubs.publication-status	Published
pubs.volume	31
utslib.citation.issue	S3

Abstract:

Background Fibrosis is a hallmark of heart disease, particularly following myocardial infarction (MI) and in heart failure. We previously identified a key role for extracellular matrix protein (ECM1) in wound healing post-MI but the cellular origin and mechanism of ECM1 remained elusive. Here, we investigate the spatiotemporal cellular origin of ECM1 in healthy and diseased human and mouse hearts, and ECM1 dependent human cardiac fibroblast (HuCFb) signalling mechanisms. Methods ECM1 specific analysis of existing single-cell/-nuclei RNA sequencing data was conducted. ECM1 expression was assessed in non-failing (NF), ischaemic (ICM) and dilated (DCM) failing human heart tissue via immunoblotting (n=8), immunohistochemistry (ICM; n=8, NF; n=4) and mRNA in-situ hybridisation (n=3). HuCFbs were treated with recombinant ECM1 and assessed via phosphoproteomics (n=6), wound healing assay (n=4), MTT assay (n=8), qPCR (n=6). Results ECM1 originates from fibroblasts, macrophages/monocytes (MΦ/Mo), and pericytes/vascular cells in uninjured human and mouse hearts. In mouse hearts post-MI, ECM1 originates predominantly from M1MΦ/Mo at day-3, and myofibroblasts and M2MΦ’s at day-7, and expression correlated with cell-cell communication, collagen organisation, inflammation, adhesion, and migration. Fittingly, ECM1 expression was upregulated in human ICM (p=0.048) and DCM (p=0.027), localised interstitially to fibrotic, inflammatory, and peri-vascular areas. In vitro, ECM1 inhibited HuCFb migration (p=0.044) and CCL2 mRNA expression, and stimulated inflammatory (IL-6, IL-1β), fibrotic (TGF-β1, Col1a2), and non-canonical Wnt5a mRNA expression (p<0.05). Phosphoproteomics showed ECM1 stimulates HuCFb Rho protein, cell-cell adhesion, and chemotactic signalling pathways. Conclusions ECM1 may represent a novel mechanism in facilitating inflammation-fibrosis crosstalk post-MI, and a potential therapeutic target.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/169987