title: Tumor necrosis factor-α-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis.
abstract: Mesenchymal stem cells (MSCs) accelerate regeneration of ischemic or injured tissues by stimulation of angiogenesis through a paracrine mechanism. Tumor necrosis factor-α (TNF-α)-activated MSCs secrete pro-angiogenic cytokines, including IL-6 and IL-8. In the present study, using an ischemic hindlimb animal model, we explored the role of IL-6 and IL-8 in the paracrine stimulation of angiogenesis and tissue regeneration by TNF-α-activated MSCs. Intramuscular injection of conditioned medium derived from TNF-α-treated MSCs (TNF-α CM) into the ischemic hindlimb resulted in attenuated severe limb loss and stimulated blood perfusion and angiogenesis in the ischemic limb. Immunodepletion of IL-6 and IL-8 resulted in attenuated TNF-α CM-stimulated tissue repair, blood perfusion, and angiogenesis. In addition, TNF-α CM induced migration of human cord blood-derived endothelial progenitor cells (EPCs) through IL-6- and IL-8-dependent mechanisms in vitro. Intramuscular injection of TNF-α CM into the ischemic limb led to augmented homing of tail vein-injected EPCs into the ischemic limb in vivo and immunodepletion of IL-6 or IL-8 from TNF-α CM attenuated TNF-α CM-stimulated homing of EPCs. In addition, intramuscular injection of recombinant IL-6 and IL-8 proteins resulted in increased homing of intravenously transplanted EPCs into the ischemic limb and improved blood perfusion in vivo. These results suggest that TNF-α CM stimulates angiogenesis and tissue repair through an increase in homing of EPCs through paracrine mechanisms involving IL-6 and IL-8.
authors: Medical Research Center for Ischemic Tissue Regeneration, School of Medicine, Pusan National University, Yangsan, Republic of Korea; Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Yang Woo
authors: YW
authors: Kwon
authors: Soon Chul
authors: SC
authors: Heo
authors: Geun Ok
authors: GO
authors: Jeong
authors: Jung Won
authors: JW
authors: Yoon
authors: Won Min
authors: WM
authors: Mo
authors: Mi Jeong
authors: MJ
authors: Lee
authors: Il-Ho
authors: IH
authors: Jang
authors: Sang Mo
authors: SM
authors: Kwon
authors: Jung Sub
authors: JS
authors: Lee
authors: Jae Ho
authors: JH
authors: Kim
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006614:Hindlimb / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000172:deficiency / Q000276:immunology; D016209:Interleukin-8 / Q000172:deficiency / Q000276:immunology; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D018919:Neovascularization, Physiologic; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014945:Wound Healing
chemical_list: D017077:Culture Media, Conditioned; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha
keywords: Angiogenesis; EPCs; Endothelial progenitor cells; Ischemia; MSCs; Mesenchymal stem cells; TNF-α; TNF-α CM; Tumor necrosis factor-α; conditioned medium derived from TNF-α-treated MSCs; endothelial progenitor cells; hASCs; human adipose tissue-derived MSCs; mesenchymal stem cells; tumor necrosis factor-α