Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction

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  • A Corrigendum to this article was published on 06 April 2016

Abstract

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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Figure 1: Bioinformatic secretome analysis and functional screens.
Figure 2: Mydgf protects cardiac myocytes from simulated ischemia and reperfusion injury.
Figure 3: Mydgf promotes endothelial cell proliferation.
Figure 4: MYDGF expression in the heart after MI (coronary artery ligation for 1 h followed by reperfusion).
Figure 5: Tissue repair and remodeling after MI (coronary artery ligation for 1 h followed by reperfusion) in Mydgf wild-type (WT) and knockout (KO) mice.
Figure 6: Mydgf protein therapy after MI (coronary artery ligation for 1 h followed by reperfusion in FVB/N mice).

Change history

  • 19 November 2015

    In the version of this article initially published, the article number in reference 13 is incorrectly stated as '100ra190' and should be '100ra90'. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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).

Author information

M.K.-K., M.R.R., S.K., T.B., A.P., F.P., L.C.N., T.K. and Y.W. designed and carried out experiments and analyzed the data. E.B. and I.R. carried out experiments. H.W.N., J.M., H.-J.S., A.I. and M.B. provided key reagents, tissue samples and experimental protocols. J.B. and A.G. supported the BOOST-2 trial. K.C.W. designed the study, supervised the experiments and wrote the manuscript.

Correspondence to Kai C Wollert.

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