title: Cardiomyocyte-derived CXCL12 is not involved in cardiogenesis but plays a crucial role in myocardial infarction.
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.
  
  
  
  • 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.
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.|Berlin Institute of Health, Berlin, Germany.|Faculty of Mathematics and Natural Sciences I, Humboldt-University Berlin, Berlin, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Mühlstedt
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.|Department of Biology, Chemistry and Pharmacy, Free University Berlin, Berlin, Germany.|Universitätsklinik Innsbruck Kardiologisches Labor/ Abtlg 1-G3-024, Anichstr. 35, 6020, Innsbruck, Austria.
authors.forename: Santhosh K
authors.initials: SK
authors.lastname: Ghadge
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.|Institut für Prophylaxe & Epidemiologie der Kreislaufkrankheiten Klinikum der Universität München (KUM), Pettenkoferstrasse 9, 80336, München, Germany.
authors.forename: Johan
authors.initials: J
authors.lastname: Duchene
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Järve
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.
authors.forename: Larisa
authors.initials: L
authors.lastname: Vilianovich
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Popova
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pohlmann
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.|DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
authors.forename: Thoralf
authors.initials: T
authors.lastname: Niendorf
authors.affiliation: Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Boyé
authors.affiliation: Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Medizinische Klinik I, Klinikum Vest GmbH, Knappschaftskrankenhaus Recklinghausen, Dorstener Str. 151, D-45657, Recklinghausen, Germany.
authors.forename: Cemil
authors.initials: C
authors.lastname: Özcelik
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany. mbader@mdc-berlin.de.|Berlin Institute of Health, Berlin, Germany. mbader@mdc-berlin.de.|DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany. mbader@mdc-berlin.de.|Charité Medical Faculty, Berlin, Germany. mbader@mdc-berlin.de.|Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. mbader@mdc-berlin.de.|Institute for Biology, University of Lübeck, Lübeck, Germany. mbader@mdc-berlin.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
mesh_terms: D000818:Animals; D001706:Biopsy; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D038081:Organogenesis / Q000235:genetics*; D011379:Prognosis; D051381:Rats; D055647:Rats, Transgenic; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D054377:Chemokine CXCL12
keywords: CXCL12; Fibrosis; Hypertrophy; Inflammation; Myocardial infarction