Project A07

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

Project leader: Florian Leuschner

Abstract

Myocardial injury elicits a sterile immune response that impacts healing and subsequent ventricular function. Monocytes are key players in this inflammatory process. While our understanding of systemic activation of monocytes following cardiac injury has substantially grown in recent years, little is known about the impact of the cardiac microenvironment on these accumulating leukocytes. We have recently identified a novel role for Wnt signaling in local activation of monocytes and described cardiomyocyte-secreted Wnt-Inhibitory Factor 1 (WIF1) as a crucial modulator of this process. In ongoing work, we evaluate the effect of WIF1- administration and monocyte-specific inhibition of non-canonical Wnt signaling on healing after myocardial infarction. In order to further elucidate the impact of Wnt proteins secreted from cardiomyocytes we analyze small molecule mediated inhibition of Wnt secretion and transgenic mice with an inducible cardiomyocytespecific deletion of Evi/Wls, a cargo-receptor essential for the secretion of Wnt molecules. In an envisioned continuation of this funded research grant project (LE2530/7-1), we aim to (1) elucidate the mechanistic involvement of two Wnt related molecules in MI healing and (2) define Wnt signaling after MI in a cell-specific and time-resolved manner. For aim (1), we will focus on the Wnt receptor ROR2 and its role for monocyte/macrophage activation after myocardial injury. Secondly, we will evaluate the mechanism of the Wnt modulator FAM129B in this context. Our own unpublished work suggests a key regulatory role for FAM129B for inflammatory activation of monocytes/ macrophages. With the use of established FAM129bfloxx Cx3CR1-cre mice as well as FAM129bflox x VE-cad-CreERT2, we will evaluate its contribution in the context of cardiac injury. Analyses of the molecular mechanism of FAM129B with its interaction partners will give further insides in the - so far unknown - underlying function of the protein within the Wnt signaling pathway. For aim (2), we plan to define cell-specific secretion of Wnt proteins and Wnt modulators from cardiac cells (cardiomyocytes, fibroblasts, and endothelial cells) upon hypoxia in vitro. Established single cell sequencing and spatial transcriptomics of murine hearts after MI will complement and allow integration of information on cell-specific cardiac Wnt activation. These findings will then be corroborated in established transgenic mouse lines. Taken together, the goal of these investigations is to advance our understanding of cell-specific Wnt signaling during adverse cardiac remodeling and to identify novel targets for the modulation of myeloid cell activation during sterile inflammation.

Project-related publications

  • Kuhn, T.C., J. Knobel, S. Burkert-Rettenmaier, X. Li, I.S. Meyer, A. Jungmann, F. Sicklinger, J. Backs, F. Lasitschka, O.J. Müller, H.A. Katus, J. Krijgsveld, and F. Leuschner. 2020. Secretome Analysis of Cardiomyocytes Identifies PCSK6 (Proprotein Convertase Subtilisin/Kexin Type 6) as a Novel Player in Cardiac Remodeling After Myocardial Infarction. Circulation. 141:1628-1644. PMID: 32100557
  • Sicklinger, F., Y. Zhang, K.J. Lavine, N. Simon, V. Bucher, M. Jugold, L. Lehmann, M.H. Konstandin, H.A. Katus, and F. Leuschner. 2020. A Minimal-Invasive Approach for Standardized Induction of Myocardial Infarction in Mice. Circ Res. 127:1214-1216. PMID: 32854590
  • Leuschner, F., and M. Nahrendorf. 2020. Novel functions of macrophages in the heart: insights into electrical conduction, stress, and diastolic dysfunction. Eur Heart J. 41:989-994. PMID: 30945736
  • Meyer, I.S., C.C. Goetzke, M. Kespohl, M. Sauter, A. Heuser, V. Eckstein, H.P. Vornlocher, D.G. Anderson, J. Haas, B. Meder, H.A. Katus, K. Klingel, A. Beling, and F. Leuschner. 2018. Silencing the CSF-1 Axis Using Nanoparticle Encapsulated siRNA Mitigates Viral and Autoimmune Myocarditis. Front Immunol. 9:2303. PMID: 30349538
  • Meyer, I.S., and F. Leuschner. 2018. The role of Wnt signaling in the healing myocardium: a focus on cell specificity. Basic Res Cardiol. 113:44.
  • Meyer, I.S., A. Jungmann, C. Dieterich, M. Zhang, F. Lasitschka, S. Werkmeister, J. Haas, O.J. Müller, M. Boutros, M. Nahrendorf, H.A. Katus, S.E. Hardt, and F. Leuschner. 2017. The cardiac microenvironment uses non-canonical WNT signaling to activate monocytes after myocardial infarction. EMBO Mol Med. 9:1279-1293. PMID: 28774883
  • Leuschner, F., G. Courties, P. Dutta, L.J. Mortensen, R. Gorbatov, B. Sena, T.I. Novobrantseva, A. Borodovsky, K. Fitzgerald, V. Koteliansky, Y. Iwamoto, M. Bohlender, S. Meyer, F. Lasitschka, B. Meder, H.A. Katus, C. Lin, P. Libby, F.K. Swirski, D.G. Anderson, R. Weissleder, and M. Nahrendorf. 2015. Silencing of CCR2 in myocarditis. Eur Heart J. 36:1478-1488. PMID: 24950695
  • Leuschner, F., P.J. Rauch, T. Ueno, R. Gorbatov, B. Marinelli, W.W. Lee, P. Dutta, Y. Wei, C. Robbins, Y. Iwamoto, B. Sena, A. Chudnovskiy, P. Panizzi, E. Keliher, J.M. Higgins, P. Libby, M.A. Moskowitz, M.J. Pittet, F.K. Swirski, R. Weissleder, and M. Nahrendorf. 2012. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J Exp Med. 209:123-137. PMID: 22213805
  • Leuschner, F., P. Dutta, R. Gorbatov, T.I. Novobrantseva, J.S. Donahoe, G. Courties, K.M. Lee, J.I. Kim, J.F. Markmann, B. Marinelli, P. Panizzi, W.W. Lee, Y. Iwamoto, S. Milstein, H. Epstein-Barash, W. Cantley, J. Wong, V. Cortez-Retamozo, A. Newton, K. Love, P. Libby, M.J. Pittet, F.K. Swirski, V. Koteliansky, R. Langer, R. Weissleder, D.G. Anderson, and M. Nahrendorf. 2011. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol. 29:1005-1010. PMID: 21983520