title: Human cardiac-derived adherent proliferating cells reduce murine acute Coxsackievirus B3-induced myocarditis.
abstract: BACKGROUND
  Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. We recently isolated and identified novel cardiac-derived cells from human cardiac biopsies: cardiac-derived adherent proliferating cells (CAPs). They have similarities with mesenchymal stromal cells, which are known for their anti-apoptotic and immunomodulatory properties. We explored whether CAPs application could be a novel strategy to improve acute Coxsackievirus B3 (CVB3)-induced myocarditis.
  
  
  RESULTS
  To evaluate the safety of our approach, we first analyzed the expression of the coxsackie- and adenovirus receptor (CAR) and the co-receptor CD55 on CAPs, which are both required for effective CVB3 infectivity. We could demonstrate that CAPs only minimally express both receptors, which translates to minimal CVB3 copy numbers, and without viral particle release after CVB3 infection. Co-culture of CAPs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis and viral progeny release. In addition, CAPs reduced CD4 and CD8 T cell proliferation. All CAPs-mediated protective effects were nitric oxide- and interleukin-10-dependent and required interferon-γ. In an acute murine model of CVB3-induced myocarditis, application of CAPs led to a decrease of cardiac apoptosis, cardiac CVB3 viral load and improved left ventricular contractility parameters. This was associated with a decline in cardiac mononuclear cell activity, an increase in T regulatory cells and T cell apoptosis, and an increase in left ventricular interleukin-10 and interferon-γ mRNA expression.
  
  
  CONCLUSIONS
  We conclude that CAPs are a unique type of cardiac-derived cells and promising tools to improve acute CVB3-induced myocarditis.
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Kapka
authors.initials: K
authors.lastname: Miteva
authors.forename: Marion
authors.initials: M
authors.lastname: Haag
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
authors.forename: Kostas
authors.initials: K
authors.lastname: Savvatis
authors.forename: Peter Moritz
authors.initials: PM
authors.lastname: Becher
authors.forename: Martina
authors.initials: M
authors.lastname: Seifert
authors.forename: Katrin
authors.initials: K
authors.lastname: Warstat
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Jochen
authors.initials: J
authors.lastname: Ringe
authors.forename: Michael
authors.initials: M
authors.lastname: Sittinger
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.forename: Sophie
authors.initials: S
authors.lastname: Van Linthout
mesh_terms: D000818:Animals; D017209:Apoptosis; D018958:CD55 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D049109:Cell Proliferation; D002470:Cell Survival; D017690:Cell Transplantation; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003384:Coxsackievirus Infections / Q000150:complications / Q000473:pathology* / Q000503:physiopathology / Q000821:virology*; D004770:Enterovirus / Q000502:physiology*; D006801:Humans; D056747:Immunomodulation; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology; D009205:Myocarditis / Q000150:complications / Q000473:pathology* / Q000503:physiopathology / Q000821:virology*; D009206:Myocardium / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D018958:CD55 Antigens; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma