title: Macrophage subpopulations are essential for infarct repair with and without stem cell therapy.
abstract: OBJECTIVE
  This study sought to investigate the hypothesis that the favorable effects of mesenchymal stromal cells (MSCs) on infarct repair are mediated by macrophages.
  
  
  BACKGROUND
  The favorable effects of MSC therapy in myocardial infarction (MI) are complex and not fully understood.
  
  
  METHODS
  We induced MI in mice and allocated them to bone marrow MSCs, mononuclear cells, or saline injection into the infarct, with and without early (4 h before MI) and late (3 days after MI) macrophage depletion. We then analyzed macrophage phenotype in the infarcted heart by flow cytometry and macrophage secretome in vitro. Left ventricular remodeling and global and regional function were assessed by echocardiography and speckle-tracking based strain imaging.
  
  
  RESULTS
  The MSC therapy significantly increased the percentage of reparative M2 macrophages (F4/80(+)CD206(+)) in the infarcted myocardium, compared with mononuclear- and saline-treated hearts, 3 and 4 days after MI. Macrophage cytokine secretion, relevant to infarct healing and repair, was significantly increased after MSC therapy, or incubation with MSCs or MSC supernatant. Significantly, with and without MSC therapy, transient macrophage depletion increased mortality 30 days after MI. Furthermore, early macrophage depletion produced the greatest negative effect on infarct size and left ventricular remodeling and function, as well as a significant incidence of left ventricular thrombus formation. These deleterious effects were attenuated with macrophage restoration and MSC therapy.
  
  
  CONCLUSIONS
  Some of the protective effects of MSCs on infarct repair are mediated by macrophages, which are essential for early healing and repair. Thus, targeting macrophages could be a novel strategy to improve infarct healing and repair.
authors: Neufeld Cardiac Research Institute, Tel Aviv University, Sheba Center for Regenerative Medicine, Stem Cells, and Tissue Engineering, and Tamman Cardiovascular Research Institute, Tel Aviv, Israel.
authors: Tamar
authors: T
authors: Ben-Mordechai
authors: Radka
authors: R
authors: Holbova
authors: Natalie
authors: N
authors: Landa-Rouben
authors: Tamar
authors: T
authors: Harel-Adar
authors: Micha S
authors: MS
authors: Feinberg
authors: Ihab
authors: I
authors: Abd Elrahman
authors: Galia
authors: G
authors: Blum
authors: Fred H
authors: FH
authors: Epstein
authors: Zmira
authors: Z
authors: Silman
authors: Smadar
authors: S
authors: Cohen
authors: Jonathan
authors: J
authors: Leor
mesh_terms: D000818:Animals; D005260:Female; D006321:Heart / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D009203:Myocardial Infarction / Q000276:immunology* / Q000628:therapy*; D012038:Regeneration / Q000276:immunology*
keywords: AMI; BM; CL; IL; LV; MNC; MSC; TNF; acute myocardial infarction; bone marrow; clodronate liposomes; inflammation; interleukin; left ventricle; macrophage; mesenchymal stroma cell; mesenchymal stromal cells; mononuclear cell; myocardial infarction; remodeling; tumor necrosis factor