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Cardiomyocyte-derived CXCL12 is not involved in cardiogenesis but plays a crucial role in myocardial infarction

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Abstract

The chemokine CXCL12/SDF-1 is crucial for heart development and affects cardiac repair processes due to its ability to attract leukocytes and stem cells to injured myocardium. However, there is a great controversy whether CXCL12 is beneficial or detrimental after myocardial infarction (MI). The divergence in the reported CXCL12 actions may be due to the cellular source and time of release of the chemokine after MI. This study was designed to evaluate the role of cardiomyocyte-derived CXCL12 for cardiogenesis and heart repair after MI. We generated two rodent models each targeting CXCL12 in only one cardiac cell type: cardiomyocyte-specific CXCL12-overexpressing transgenic (Tg) rats and CXCL12 conditional knockout (cKO) mice. Animals of both models did not show any signs of cardiac abnormalities under baseline conditions. After induction of MI, cKO mice displayed preserved cardiac function and remodeling. Moreover, fibrosis was less pronounced in the hearts of cKO mice after MI. Accordingly, CXCL12 Tg rats revealed impaired cardiac function post-MI accompanied by enhanced fibrosis. Furthermore, we observed decreased numbers of infiltrating Th1 cells in the hearts of cKO mice. Collectively, our findings demonstrate that cardiomyocyte-derived CXCL12 is not involved in cardiac development but has adverse effects on the heart after injury via promotion of inflammation and fibrosis.

Key messages

• CXCL12 in cardiomyocytes is not involved in cardiac development.

• CXCL12 deficiency in cardiomyocytes improves outcome of myocardial infarction.

• CXCL12 overexpression in cardiomyocytes worsens outcome of myocardial infarction.

• CXCL12 increases fibrosis and invasion of Th1 cells in the heart after infarction.

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Acknowledgments

Tanja Schalow, Ariane Giese, Sabine Grüger, Astrid Schiche, Sina Wohlfart, Martin Taube, Stefanie Schelenz, Babette Dieringer, and Petra Domaing provided excellent technical assistance. This work has been supported by the Berlin-Brandenburg School for Regenerative Therapies (BSRT) Graduate School 203 through a fellowship to SM and by the German Center for Cardiovascular Research (DZHK).

Author information

Author notes

  1. Santhosh K. Ghadge

    Present address: Universitätsklinik Innsbruck Kardiologisches Labor/ Abtlg 1-G3-024, Anichstr. 35, 6020, Innsbruck, Austria

  2. Johan Duchene

    Present address: Institut für Prophylaxe & Epidemiologie der Kreislaufkrankheiten Klinikum der Universität München (KUM), Pettenkoferstrasse 9, 80336, München, Germany

  3. Cemil Özcelik

    Present address: Medizinische Klinik I, Klinikum Vest GmbH, Knappschaftskrankenhaus Recklinghausen, Dorstener Str. 151, D-45657, Recklinghausen, Germany

Authors and Affiliations

  1. Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany

    Silke Mühlstedt, Santhosh K. Ghadge, Johan Duchene, Fatimunnisa Qadri, Anne Järve, Larisa Vilianovich, Elena Popova, Andreas Pohlmann, Thoralf Niendorf & Michael Bader

  2. Berlin Institute of Health, Berlin, Germany

    Silke Mühlstedt & Michael Bader

  3. Faculty of Mathematics and Natural Sciences I, Humboldt-University Berlin, Berlin, Germany

    Silke Mühlstedt

  4. Department of Biology, Chemistry and Pharmacy, Free University Berlin, Berlin, Germany

    Santhosh K. Ghadge

  5. DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany

    Thoralf Niendorf & Michael Bader

  6. Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Philipp Boyé & Cemil Özcelik

  7. Charité Medical Faculty, Berlin, Germany

    Michael Bader

  8. Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

    Michael Bader

  9. Institute for Biology, University of Lübeck, Lübeck, Germany

    Michael Bader

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  1. Silke Mühlstedt
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  2. Santhosh K. Ghadge
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  4. Fatimunnisa Qadri
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  12. Michael Bader
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Correspondence to Michael Bader.

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Silke Mühlstedt and Santhosh K. Ghadge contributed equally to this work.

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Mühlstedt, S., Ghadge, S.K., Duchene, J. et al. Cardiomyocyte-derived CXCL12 is not involved in cardiogenesis but plays a crucial role in myocardial infarction. J Mol Med 94, 1005–1014 (2016). https://doi.org/10.1007/s00109-016-1432-1

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  • DOI: https://doi.org/10.1007/s00109-016-1432-1

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