title: Intravenously Delivered Mesenchymal Stem Cells: Systemic Anti-Inflammatory Effects Improve Left Ventricular Dysfunction in Acute Myocardial Infarction and Ischemic Cardiomyopathy.
abstract: BACKGROUND
  Virtually all mesenchymal stem cell (MSC) studies assume that therapeutic effects accrue from local myocardial effects of engrafted MSCs. Because few intravenously administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm.
  
  
  OBJECTIVE
  To test whether intravenously administered MSCs reduce left ventricular (LV) dysfunction both post-acute myocardial infarction and in ischemic cardiomyopathy and that these effects are caused, at least partly, by systemic anti-inflammatory activities.
  
  
  RESULTS
  Mice underwent 45 minutes of left anterior descending artery occlusion. Human MSCs, grown chronically at 5% O2, were administered intravenously. LV function was assessed by serial echocardiography, 2,3,5-triphenyltetrazolium chloride staining determined infarct size, and fluorescence-activated cell sorting assessed cell composition. Fluorescent and radiolabeled MSCs (1×106) were injected 24 hours post-myocardial infarction and homed to regions of myocardial injury; however, the myocardium contained only a small proportion of total MSCs. Mice received 2×106MSCs or saline intravenously 24 hours post-myocardial infarction (n=16 per group). At day 21, we harvested blood and spleens for fluorescence-activated cell sorting and hearts for 2,3,5-triphenyltetrazolium chloride staining. Adverse LV remodeling and deteriorating LV ejection fraction occurred in control mice with large infarcts (≥25% LV). Intravenous MSCs eliminated the progressive deterioration in LV end-diastolic volume and LV end-systolic volume. MSCs significantly decreased natural killer cells in the heart and spleen and neutrophils in the heart. Specific natural killer cell depletion 24 hours pre-acute myocardial infarction significantly improved infarct size, LV ejection fraction, and adverse LV remodeling, changes associated with decreased neutrophils in the heart. In an ischemic cardiomyopathy model, mice 4 weeks post-myocardial infarction were randomized to tail-vein injection of 2×106MSCs, with injection repeated at week 3 (n=16) versus PBS control (n=16). MSCs significantly increased LV ejection fraction and decreased LV end-systolic volume.
  
  
  CONCLUSIONS
  Intravenously administered MSCs for acute myocardial infarction attenuate the progressive deterioration in LV function and adverse remodeling in mice with large infarcts, and in ischemic cardiomyopathy, they improve LV function, effects apparently modulated in part by systemic anti-inflammatory activities.
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: Dror
authors.initials: D
authors.lastname: Luger
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lipinski
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: Peter C
authors.initials: PC
authors.lastname: Westman
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: David K
authors.initials: DK
authors.lastname: Glover
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: Julien
authors.initials: J
authors.lastname: Dimastromatteo
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: Juan C
authors.initials: JC
authors.lastname: Frias
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Albelda
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: Sergey
authors.initials: S
authors.lastname: Sikora
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: Alex
authors.initials: A
authors.lastname: Kharazi
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: Grigory
authors.initials: G
authors.lastname: Vertelov
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.).
authors.forename: Ron
authors.initials: R
authors.lastname: Waksman
authors.affiliation: From the MedStar Washington Hospital Center, Washington, DC (D.L., M.J.L., P.C.W., R.W., S.E.E.); University of Virginia, Charlottesville (D.K.G., J.D.); Universidad CEU Cardenal Herrera, Valencia, Spain (J.C.F.); GIBI230, Grupo de Investigación Biomédica en Imagen, IIS La Fe, Valencia, Spain (M.T.A.); and CardioCell Inc, San Diego, CA (S.S., A.K., G.V.). stephen.epstein@medstar.net.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Epstein
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D009202:Cardiomyopathies / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000276:immunology; D051379:Mice; D009203:Myocardial Infarction / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D017202:Myocardial Ischemia / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*
keywords: cardiomyopathies; inflammation; killer cells, natural; myocardial infarction; stem cells