title: Erythropoietin priming improves the vasculogenic potential of G-CSF mobilized human peripheral blood mononuclear cells.
abstract: OBJECTIVE
  From our previous clinical trials, intracoronary infusion of granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells ((mob)PBMCs) proved to be effective in improving myocardial contractility and reducing infarct volume in acute myocardial infarction. We tested the effect of priming (mob)PBMCs with erythropoietin (EPO) to augment its therapeutic efficacy.
  
  
  RESULTS
  (mob)PBMCs were obtained from healthy volunteers after a 3-day subcutaneous injection of G-CSF (10 μg/kg). About 40% of (mob)PBMCs were EPO receptor (EPOR) (+) and responded to 6 h EPO-priming (10 IU/mL) by increasing the expression of vasculogenic factors (i.e. IL8, IL10, bFGF, PDGF, MMP9) and adhesion molecules (i.e. integrin αV, β1, β2, β8) through the JAK2 and Akt pathway. These responses were also observed in PBMCs from elderly patients with coronary disease. The conditioned media from EPO-primed (mob)PBMCs contained various cytokines such as IL8, IL10, TNFα, and PDGF, which enhanced the migration and tube formation capability of endothelial cells. EPO-primed (mob)PBMCs also showed increased adhesion on endothelial cells or fibronectin. Augmented vasculogenic potential of EPO-primed (mob)PBMCs was confirmed in a Matrigel plug assay, ischaemic hindlimb, and myocardial infarction models of athymic nude mice. There were two action mechanisms: (i) cellular effects confirmed by direct incorporation of human (mob)PBSCs into mouse vasculature and (ii) indirect humoral effects confirmed by the therapeutic effect of the supernatant of EPO-primed (mob)PBMCs.
  
  
  CONCLUSIONS
  Brief ex vivo EPO-priming is a novel method to augment the vasculogenic potential of human (mob)PBMCs, which would help to achieve better results after intracoronary infusion in myocardial infarction patients.
authors.affiliation: Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu, Seoul 110-744, Korea National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Jeehoon
authors.initials: J
authors.lastname: Kang
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Yun
authors.affiliation: Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu, Seoul 110-744, Korea National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Hur
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Kang
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Choi
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Ko
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu, Seoul 110-744, Korea Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: In-Chang
authors.initials: IC
authors.lastname: Hwang
authors.affiliation: Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu, Seoul 110-744, Korea Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.affiliation: Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu, Seoul 110-744, Korea National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea hyosoo@snu.ac.kr.
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000097:blood; D017077:Culture Media, Conditioned / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006614:Hindlimb; D006801:Humans; D007279:Injections, Subcutaneous; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D053614:Janus Kinase 2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D008297:Male; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000098:blood supply*; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D036102:Peripheral Blood Stem Cell Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D042501:Angiogenic Proteins; D015815:Cell Adhesion Molecules; D017077:Culture Media, Conditioned; D016207:Cytokines; D011994:Recombinant Proteins; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt
keywords: Erythropoietin; G-CSF mobilized peripheral blood mononuclear cells; Myocardial infarction; Priming; Vasculogenesis