title: Activated platelets interfere with recruitment of mesenchymal stem cells to apoptotic cardiac cells via high mobility group box 1/Toll-like receptor 4-mediated down-regulation of hepatocyte growth factor receptor MET.
abstract: Recruitment of mesenchymal stem cells (MSC) following cardiac injury, such as myocardial infarction, plays a critical role in tissue repair and may contribute to myocardial recovery. However, the mechanisms that regulate migration of MSC to the site of tissue damage remain elusive. Here, we demonstrate in vitro that activated platelets substantially inhibit recruitment of MSC toward apoptotic cardiac myocytes and fibroblasts. The alarmin high mobility group box 1 (HMGB1) was released by platelets upon activation and mediated inhibition of the cell death-dependent migratory response through Toll-like receptor (TLR)-4 expressed on the MSC. Migration of MSC to apoptotic cardiac myocytes and fibroblasts was driven by hepatocyte growth factor (HGF), and platelet activation was followed by HMGB1/TLR-4-dependent down-regulation of HGF receptor MET on MSC, thereby impairing HGF-driven MSC recruitment. We identify a novel mechanism by which platelets, upon activation, interfere with MSC recruitment to apoptotic cardiac cells, a process that may be of particular relevance for myocardial repair and regeneration.
authors.affiliation: From the Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vogel
authors.affiliation: From the Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: From the Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Metzger
authors.affiliation: From the Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.affiliation: From the Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Geisler
authors.affiliation: From the Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Seizer
authors.affiliation: From the Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Müller
authors.affiliation: the Institute of Anatomy, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mack
authors.affiliation: the Department of Oncology, Haematology, Immunology, Rheumatology and Pulmonology, and Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schumann
authors.affiliation: the Department of Oncology, Haematology, Immunology, Rheumatology and Pulmonology, and Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Bühring
authors.affiliation: the Institute of Physiology, Eberhard Karls University, 72076 Tübingen, Germany and.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.affiliation: the Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Rüdiger V
authors.initials: RV
authors.lastname: Sorg
authors.affiliation: From the Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Langer
authors.affiliation: From the Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany. Electronic address: meinrad.gawaz@med.uni-tuebingen.de.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D015539:Platelet Activation / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics; D012038:Regeneration / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C066855:HGF protein, human; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: Cardiac Repair and Regeneration; Cell Migration; HMGB1; Mesenchymal Stem Cells; Myocardial Infarction; Platelets; Toll-like Receptors (TLR)