Paracrine-acting proteins are emerging as a central mechanism by which bone marrow cell–based therapies improve tissue repair and heart function after myocardial infarction (MI). We carried out a bioinformatic secretome analysis in bone marrow cells from patients with acute MI to identify novel secreted proteins with therapeutic potential. Functional screens revealed a secreted protein encoded by an open reading frame on chromosome 19 (C19orf10) that promotes cardiac myocyte survival and angiogenesis. We show that bone marrow–derived monocytes and macrophages produce this protein endogenously to protect and repair the heart after MI, and we named it myeloid-derived growth factor (MYDGF). Whereas Mydgf-deficient mice develop larger infarct scars and more severe contractile dysfunction compared to wild-type mice, treatment with recombinant Mydgf reduces scar size and contractile dysfunction after MI. This study is the first to assign a biological function to MYDGF, and it may serve as a prototypical example for the development of protein-based therapies for ischemic tissue repair.
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Go, A.S. et al. Heart disease and stroke statistics 2013 update: a report from the American Heart Association. Circulation 127, e6–e245 (2013).
White, H.D. & Chew, D.P. Acute myocardial infarction. Lancet 372, 570–584 (2008).
Burns, R.J. et al. The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis. J. Am. Coll. Cardiol. 39, 30–36 (2002).
Kelle, S. et al. Prognostic value of myocardial infarct size and contractile reserve using magnetic resonance imaging. J. Am. Coll. Cardiol. 54, 1770–1777 (2009).
Velagaleti, R.S. et al. Long-term trends in the incidence of heart failure after myocardial infarction. Circulation 118, 2057–2062 (2008).
Wollert, K.C. & Drexler, H. Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nat. Rev. Cardiol. 7, 204–215 (2010).
Kamihata, H. et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 104, 1046–1052 (2001).
van der Bogt, K.E. et al. Comparison of different adult stem cell types for treatment of myocardial ischemia. Circulation 118, S121–S129 (2008).
Delewi, R. et al. Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis. Eur. Heart J. 35, 989–998 (2014).
Assmus, B. et al. Red blood cell contamination of the final cell product impairs the efficacy of autologous bone marrow mononuclear cell therapy. J. Am. Coll. Cardiol. 55, 1385–1394 (2010).
Seeger, F.H. et al. Heparin disrupts the CXCR4/SDF-1 axis and impairs the functional capacity of bone marrow-derived mononuclear cells used for cardiovascular repair. Circ. Res. 111, 854–862 (2012).
Dimmeler, S. & Leri, A. Aging and disease as modifiers of efficacy of cell therapy. Circ. Res. 102, 1319–1330 (2008).
Wang, X. et al. Donor myocardial infarction impairs the therapeutic potential of bone marrow cells by an interleukin-1-mediated inflammatory response. Sci. Transl. Med. 3, 100ra90 (2011).
Laflamme, M.A. & Murry, C.E. Heart regeneration. Nature 473, 326–335 (2011).
Gnecchi, M. et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat. Med. 11, 367–368 (2005).
Gnecchi, M., Zhang, Z., Ni, A. & Dzau, V.J. Paracrine mechanisms in adult stem cell signaling and therapy. Circ. Res. 103, 1204–1219 (2008).
Lee, R.H. et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5, 54–63 (2009).
Ranganath, S.H., Levy, O., Inamdar, M.S. & Karp, J.M. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10, 244–258 (2012).
Korf-Klingebiel, M. et al. Bone marrow cells are a rich source of growth factors and cytokines: implications for cell therapy trials after myocardial infarction. Eur. Heart J. 29, 2851–2858 (2008).
Korf-Klingebiel, M. et al. Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction. Circulation 123, 504–514 (2011).
Urbich, C. et al. Proteomic characterization of human early pro-angiogenic cells. J. Mol. Cell. Cardiol. 50, 333–336 (2011).
Wollert, K.C. et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364, 141–148 (2004).
Hofmann, M. et al. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 111, 2198–2202 (2005).
Petit, I., Jin, D. & Rafii, S. The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol. 28, 299–307 (2007).
Seeger, F.H. et al. CXCR4 expression determines functional activity of bone marrow-derived mononuclear cells for therapeutic neovascularization in acute ischemia. Arterioscler. Thromb. Vasc. Biol. 29, 1802–1809 (2009).
Shantsila, E., Tapp, L.D., Wrigley, B.J., Montoro-Garcia, S. & Lip, G.Y. CXCR4 positive and angiogenic monocytes in myocardial infarction. Thromb. Haemost. 109, 255–262 (2013).
Kempf, T. et al. The transforming growth factor-β superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ. Res. 98, 351–360 (2006).
Klausner, R.D., Donaldson, J.G. & Lippincott-Schwartz, J. Brefeldin A: insights into the control of membrane traffic and organelle structure. J. Cell Biol. 116, 1071–1080 (1992).
Alessi, D.R. et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15, 6541–6551 (1996).
Tait, S.W. & Green, D.R. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat. Rev. Mol. Cell Biol. 11, 621–632 (2010).
Schust, J., Sperl, B., Hollis, A., Mayer, T.U. & Berg, T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem. Biol. 13, 1235–1242 (2006).
Klein, E.A. & Assoian, R.K. Transcriptional regulation of the cyclin D1 gene at a glance. J. Cell Sci. 121, 3853–3857 (2008).
van den Borne, S.W. et al. Mouse strain determines the outcome of wound healing after myocardial infarction. Cardiovasc. Res. 84, 273–282 (2009).
Roubille, F. et al. Delayed postconditioning in the mouse heart in vivo. Circulation 124, 1330–1336 (2011).
Jay, S.M. & Lee, R.T. Protein engineering for cardiovascular therapeutics: untapped potential for cardiac repair. Circ. Res. 113, 933–943 (2013).
Grimmond, S.M. et al. The mouse secretome: functional classification of the proteins secreted into the extracellular environment. Genome Res. 13, 1350–1359 (2003).
Tulin, E.E. et al. SF20/IL-25, a novel bone marrow stroma-derived growth factor that binds to mouse thymic shared antigen-1 and supports lymphoid cell proliferation. J. Immunol. 167, 6338–6347 (2001); retraction 170, 1593 (2003).
Tulin, E.E. et al. Letter of retraction. J. Immunol. 170, 1593 (2003).
Wang, P. et al. Profiling of the secreted proteins during 3T3–L1 adipocyte differentiation leads to the identification of novel adipokines. Cell. Mol. Life Sci. 61, 2405–2417 (2004).
Weiler, T. et al. The identification and characterization of a novel protein, c19orf10, in the synovium. Arthritis Res. Ther. 9, R30 (2007).
Bailey, M.J. et al. Extracellular proteomes of M-CSF (CSF-1) and GM-CSF-dependent macrophages. Immunol. Cell Biol. 89, 283–293 (2011).
Petersen, T.N., Brunak, S., von Heijne, G. & Nielsen, H. SignalP 4.0: discriminating signal peptides from transmembrane regions. Nat. Methods 8, 785–786 (2011).
Wen, Z., Zhong, Z. & Darnell, J.E. Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82, 241–250 (1995).
Decker, T. & Kovarik, P. Serine phosphorylation of STATs. Oncogene 19, 2628–2637 (2000).
Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007).
Swirski, F.K. & Nahrendorf, M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 339, 161–166 (2013).
Swirski, F.K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009).
Leuschner, F. et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J. Exp. Med. 209, 123–137 (2012).
Hilgendorf, I. et al. Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ. Res. 114, 1611–1622 (2014).
Heusch, G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet 381, 166–175 (2013).
Antrobus, R. & Borner, G.H. Improved elution conditions for native co-immunoprecipitation. PLoS ONE 6, e18218 (2011).
Emanuelsson, O., Brunak, S., von Heijne, G. & Nielsen, H. Locating proteins in the cell using TargetP, SignalP and related tools. Nat. Protoc. 2, 953–971 (2007).
Pitulescu, M.E., Schmidt, I., Benedito, R. & Adams, R.H. Inducible gene targeting in the neonatal vasculature and analysis of retinal angiogenesis in mice. Nat. Protoc. 5, 1518–1534 (2010).
Lim, Y.C. & Luscinskas, F.W. Isolation and culture of murine heart and lung endothelial cells for in vitro model systems. Methods Mol. Biol. 341, 141–154 (2006).
Picotti, P. & Aebersold, R. Selected reaction monitoring-based proteomics: workflows, potential, pitfalls and future directions. Nat. Methods 9, 555–566 (2012).
We thank the late H. Drexler for his advice during the early stages of this project. We acknowledge L. Arseniev and his team at the Cellular Therapy Center at Hannover Medical School for preparing nucleated bone marrow cells, O. Kustikova from the Institute of Experimental Hematology at Hannover Medical School for helping with the bone marrow transplantations, M. Ballmaier from the FACS core facility and C. Falk from the Institute of Transplant Immunology at Hannover Medical School for supporting us with cell sorting, R. Geffers from the Helmholtz Center for Infection Research (Braunschweig, Germany) for performing the microarray analyses and R. Patten from Tufts New England Medical Center (Boston, MA) for providing Akt1 adenoviruses. We are indebted to our colleagues who recruited patients into the BOOST-2 trial: G. Meyer, J. Pirr and B. Ritter, Hannover Medical School; C. Tschöpe and H. Schultheiß, Charité Berlin; J. Müller-Ehmsen and E. Erdmann, University of Cologne; K. Empen and S. Felix, University of Greifswald; A. May and M. Gawaz, University of Tübingen (all in Germany). The BOOST-2 trial was supported by the German Research Foundation (Programm Klinische Studien) and by the Alfried Krupp von Bohlen und Halbach-Stiftung. K.C.W. was supported by the German Research Foundation (WO 552/9-1, WO 552/10-1, Excellence Cluster REBIRTH-2).
The authors declare no competing financial interests.
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Korf-Klingebiel, M., Reboll, M., Klede, S. et al. Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction. Nat Med 21, 140–149 (2015). https://doi.org/10.1038/nm.3778
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