title: Mesenchymal stem cells improve murine acute coxsackievirus B3-induced myocarditis.
abstract: OBJECTIVE
  Coxsackievirus B3 (CVB3)-induced myocarditis, initially considered a sole immune-mediated disease, also results from a direct CVB3-mediated injury of the cardiomyocytes. Mesenchymal stem cells (MSCs) have, besides immunomodulatory, also anti-apoptotic features. In view of clinical translation, we first analysed whether MSCs can be infected by CVB3. Next, we explored whether and how MSCs could reduce the direct CVB3-mediated cardiomyocyte injury and viral progeny release, in vitro, in the absence of immune cells. Finally, we investigated whether MSC application could improve murine acute CVB3-induced myocarditis.
  
  
  RESULTS
  Phase contrast pictures and MTS viability assay demonstrated that MSCs did not suffer from CVB3 infection 4-12-24-48 h after CVB3 infection. Coxsackievirus B3 RNA copy number decreased in this time frame, suggesting that no CVB3 replication took place. Co-culture of MSCs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis, oxidative stress, intracellular viral particle production, and viral progeny release in a nitric oxide (NO)-dependent manner. Moreover, MSCs required priming via interferon-γ (IFN-γ) to exert their protective effects. In vivo, MSC application improved the contractility and relaxation parameters in CVB3-induced myocarditis, which was paralleled with a reduction in cardiac apoptosis, cardiomyocyte damage, left ventricular tumour necrosis factor-α mRNA expression, and cardiac mononuclear cell activation. Mesenchymal stem cells reduced the CVB3-induced CD4- and CD8- T cell activation in an NO-dependent way and required IFN-γ priming.
  
  
  CONCLUSIONS
  We conclude that MSCs improve murine acute CVB3-induced myocarditis via their anti-apoptotic and immunomodulatory properties, which occur in an NO-dependent manner and require priming via IFN-γ.
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité-University Medicine Berlin, Campus Virchow, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Van Linthout
authors.forename: K
authors.initials: K
authors.lastname: Savvatis
authors.forename: K
authors.initials: K
authors.lastname: Miteva
authors.forename: J
authors.initials: J
authors.lastname: Peng
authors.forename: J
authors.initials: J
authors.lastname: Ringe
authors.forename: K
authors.initials: K
authors.lastname: Warstat
authors.forename: C
authors.initials: C
authors.lastname: Schmidt-Lucke
authors.forename: M
authors.initials: M
authors.lastname: Sittinger
authors.forename: H-P
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: C
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003384:Coxsackievirus Infections; D029822:Enterovirus B, Human / Q000254:growth & development; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000503:physiopathology / Q000628:therapy* / Q000821:virology; D009569:Nitric Oxide / Q000096:biosynthesis; D016276:Ventricular Function / Q000502:physiology; D014779:Virus Replication / Q000502:physiology
chemical_list: D009569:Nitric Oxide; D007371:Interferon-gamma