A07

Cell-specific activation of Wnt signaling in healing after myocardial infarction

Funding period: 2021-2029

Project Leaders

Prof. Dr. med. Florian Leuschner

Project Leader A07

Abstract

Wnt signaling orchestrates both reparative and maladaptive processes after myocardial infarction (MI) and during heart failure. This project aims to map Wnt ligand secretion after MI and to assess their specific roles in cardiac healing and remodeling. Using cell type-specific in vivo secretome profiling, we will determine which and how Wnt ligands are released by cardiomyocytes and macrophages after MI and upon pharmacological inhibition. Next, we will validate the presence of vesicle-bound and freely circulating Wnt ligands in a patient cohort experiencing acute coronary ischemia. Finally, we will dissect the mechanistic and functional effects of MI-associated Wnts using CRISPRi and pharmacological inhibition in living human cardiac tissue slices.

Project-related Publications

Spatial multiomics of acute myocardial infarction reveals immune cell infiltration through the endocardium

Wünnemann F, Sicklinger F, Bestak K, Nimo J, Thiemann T, Amrute JM, Nordbeck M, Hartmann N, Ibarra-Arellano MA, Tanevski J, Chazotte M, Heine C, Frey N, Lavine KJ, Coscia F, Saez-Rodriguez J, Leuschner F, Schapiro D. Nat Cardiovasc Res. 2025 Oct;4(10):1345-1362. doi: 10.1038/s44161-025-00717-y. Epub 2025 Oct 3.

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CXCL4-Induced PBMCs Modulate Vascular Extracellular Matrix via Wnt5a-Dependent Matrix Metalloproteinase-7 and Calcifying Extracellular Vesicle Release

Krohn JB, Sprehe LK, Sicklinger F, Kawohl J, Hess C, Spieler A, Dihlmann S, Eis L, Gleissner CA, Katus HA, Frey N, Leuschner F. Arterioscler Thromb Vasc Biol. 2025 Oct;45(10):1799-1817.

doi: 10.1161/ATVBAHA.124.322067. Epub 2025 Aug 21.

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Blockade of Wnt Secretion Attenuates Myocardial Ischemia-Reperfusion Injury by Modulating the Inflammatory Response

Meyer IS, Li X, Meyer C, Voloshanenko O, Pohl S, Boutros M, Katus HA, Frey N, Leuschner F. Int J Mol Sci. 2022 Oct 14;23(20):12252. doi: 10.3390/ijms232012252.

PMID: 36293109

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A Minimal-Invasive Approach for Standardized Induction of Myocardial Infarction in Mice

Sicklinger F, Zhang Y, Lavine KJ, Simon N, Bucher V, Jugold M, Lehmann L, Konstandin MH, Katus HA, Leuschner F. Circ Res. 2020 Oct 9;127(9):1214-1216. doi: 10.1161/CIRCRESAHA.120.317794. Epub 2020 Aug 28. PMID: 32854590

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Secretome Analysis of Cardiomyocytes Identifies PCSK6 (Proprotein Convertase Subtilisin/Kexin Type 6) as a Novel Player in Cardiac Remodeling After Myocardial Infarction

Kuhn TC, Knobel J, Burkert-Rettenmaier S, Li X, Meyer IS, Jungmann A, Sicklinger F, Backs J, Lasitschka F, Müller OJ, Katus HA, Krijgsveld J*, Leuschner F*. Circulation. 2020 May 19;141(20):1628-1644. doi: 10.1161/CIRCULATIONAHA.119.044914. Epub 2020 Feb 26. *Joint senior authors.

PMID: 32100557

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Novel functions of macrophages in the heart: insights into electrical conduction, stress, and diastolic dysfunction

Leuschner F, Nahrendorf M. Eur Heart J. 2020 Mar 1;41(9):989-994. doi: 10.1093/eurheartj/ehz159. PMID: 30945736

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The role of Wnt signaling in the healing myocardium: a focus on cell specificity

Meyer IS, Leuschner F. Basic Res Cardiol. 2018 Oct 16;113(6):44. doi: 10.1007/s00395-018-0705-y. PMID: 30327885

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Silencing the CSF-1 Axis Using Nanoparticle Encapsulated siRNA Mitigates Viral and Autoimmune Myocarditis

Meyer IS, Goetzke CC, Kespohl M, Sauter M, Heuser A, Eckstein V, Vornlocher HP, Anderson DG, Haas J, Meder B, Katus HA, Klingel K, Beling A, Leuschner F. Front Immunol. 2018 Oct 8;9:2303. doi: 10.3389/fimmu.2018.02303. eCollection 2018. PMID: 30349538

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The cardiac microenvironment uses non-canonical WNT signaling to activate monocytes after myocardial infarction

Meyer IS, Jungmann A, Dieterich C, Zhang M, Lasitschka F, Werkmeister S, Haas J, Müller OJ, Boutros M, Nahrendorf M, Katus HA, Hardt SE, Leuschner F. EMBO Mol Med. 2017 Sep;9(9):1279-1293. doi: 10.15252/emmm.201707565. PMID: 28774883

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Silencing of CCR2 in myocarditis

Leuschner F, Courties G, Dutta P, Mortensen LJ, Gorbatov R, Sena B, Novobrantseva TI, Borodovsky A, Fitzgerald K, Koteliansky V, Iwamoto Y, Bohlender M, Meyer S, Lasitschka F, Meder B, Katus HA, Lin C, Libby P, Swirski FK, Anderson DG, Weissleder R, Nahrendorf M. Eur Heart J. 2015 Jun 14;36(23):1478-88. doi: 10.1093/eurheartj/ehu225. Epub 2014 Jun 20. PMID: 24950695

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Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis

Leuschner F, Rauch PJ, Ueno T, Gorbatov R, Marinelli B, Lee WW, Dutta P, Wei Y, Robbins C, Iwamoto Y, Sena B, Chudnovskiy A, Panizzi P, Keliher E, Higgins JM, Libby P, Moskowitz MA, Pittet MJ, Swirski FK, Weissleder R, Nahrendorf M. J Exp Med. 2012 Jan 16;209(1):123-37. doi: 10.1084/jem.20111009. Epub 2012 Jan 2. PMID: 22213805

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Therapeutic siRNA silencing in inflammatory monocytes in mice

Leuschner F, Dutta P, Gorbatov R, Novobrantseva TI, Donahoe JS, Courties G, Lee KM, Kim JI, Markmann JF, Marinelli B, Panizzi P, Lee WW, Iwamoto Y, Milstein S, Epstein-Barash H, Cantley W, Wong J, Cortez-Retamozo V, Newton A, Love K, Libby P, Pittet MJ, Swirski FK, Koteliansky V, Langer R, Weissleder R, Anderson DG, Nahrendorf M. Nat Biotechnol. 2011 Oct 9;29(11):1005-10. doi: 10.1038/nbt.1989. PMID: 21983520

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