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Hoeft, K.* ; Schaefer, G.J.L.* ; Kim, H.* ; Schumacher, D.* ; Bleckwehl, T.* ; Long, Q.* ; Klinkhammer, B.M.* ; Peisker, F.* ; Koch, L.* ; Nagai, J.* ; Halder, M.* ; Ziegler, S.* ; Liehn, E.* ; Kuppe, C.* ; Kranz, J.* ; Menzel, S.* ; Costa, I.* ; Wahida, A. ; Boor, P.* ; Schneider, R.K.* ; Hayat, S.* ; Kramann, R.*

Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner.

Cell Rep. 42:112131 (2023)
Publ. Version/Full Text DOI PMC
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Fibrosis represents the common end stage of chronic organ injury independent of the initial insult, destroying tissue architecture and driving organ failure. Here we discover a population of profibrotic macrophages marked by expression of Spp1, Fn1, and Arg1 (termed Spp1 macrophages), which expands after organ injury. Using an unbiased approach, we identify the chemokine (C-X-C motif) ligand 4 (CXCL4) to be among the top upregulated genes during profibrotic Spp1 macrophage differentiation. In vitro and in vivo studies show that loss of Cxcl4 abrogates profibrotic Spp1 macrophage differentiation and ameliorates fibrosis after both heart and kidney injury. Moreover, we find that platelets, the most abundant source of CXCL4 in vivo, drive profibrotic Spp1 macrophage differentiation. Single nuclear RNA sequencing with ligand-receptor interaction analysis reveals that macrophages orchestrate fibroblast activation via Spp1, Fn1, and Sema3 crosstalk. Finally, we confirm that Spp1 macrophages expand in both human chronic kidney disease and heart failure.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cp: Immunology ; Cxcl4 ; Pf4 ; Spp1 ; Spp1 Macrophages ; Chronic Kidney Disease ; Fibrosis ; Heart Failure ; Innate Immunity ; Myocardial Infarction ; Platelets; Macrophages; Reveals; Kidney; Cells; Recovery; Distinct; Injury; Progression; Mechanisms; Spectrum
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 42, Issue: 2, Pages: , Article Number: 112131 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506900-001
Grants RWTH Aachen University START grant
German Society of Internal Medicine
German Society for Cardiology
German Research Foundation
European Research Council
BMBF Consortia FibroMap
German Research Foundation (DFG)
RWTH Aachen University Clinician Scientist grants
European Research Council (ERC) under the European Union
European Research Council (ERC)
BMBF Consortia FibroMap and CureFib
ERC Starting grant deFIBER
ERC-StG
DOI 10.1016/j.celrep.2023.112131
WOS ID 000948740100001
Scopus ID 85148349091
PubMed ID 36807143
Erfassungsdatum 2023-02-23
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