title: Combinatorial Treatment with Apelin-13 Enhances the Therapeutic Efficacy of a Preconditioned Cell-Based Therapy for Peripheral Ischemia.
abstract: Hypoxic pretreatment of peripheral blood mononuclear cells (PBMNCs) enhances therapeutic angiogenesis in ischemic tissues after cell transplantation. However, newly formed vessels generated using this approach are immature and insufficient for promoting functional recovery from severe ischemia. In this study, we examined whether apelin-13, a regulator of vessel maturation, could be an effective promoter of therapeutic angiogenesis, following severe limb ischemia. Combinatorial treatment of hypoxic preconditioned PBMNCs with apelin-13 resulted in increased blood perfusion and vascular reactivity in ischemic mouse hindlimbs compared with a monotherapy comprising each factor. Apelin-13 upregulated expression of PDGF-BB and TGF-β1 in hypoxic PBMNCs, as well as that of PDGFR-β in vascular smooth muscle cells (VSMCs). Proliferation and migration of VSMCs treated with apelin-13 was accelerated in the presence of PDGF-BB. Interestingly, expression of an apelin receptor, APJ, in PBMNC was increased under hypoxia but not under normoxia. In addition, an in vitro angiogenesis assay using a co-culture model comprising mouse thoracic aorta, hypoxic PBMNCs, and apelin-13 demonstrated that combinatorial treatment recruited mural cells to sprouted vessel outgrowths from the aortic ring, thereby promoting neovessel maturation. Thus, combinatorial injection of hypoxic PBMNCs and apelin-13 could be an effective therapeutic strategy for patients with severe ischemic diseases.
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Samura
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Morikage
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Suehiro
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.
authors.forename: Tamami
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Nishimoto
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.|Center for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ueno
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.|Center for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Hosoyama
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-0836, Japan.
authors.forename: Kimikazu
authors.initials: K
authors.lastname: Hamano
mesh_terms: D000818:Animals; D000075244:Apelin Receptors; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017690:Cell Transplantation; D064987:Cell- and Tissue-Based Therapy; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D015870:Gene Expression; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D000860:Hypoxia; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology* / Q000628:therapy; D019194:Ischemic Preconditioning; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism
chemical_list: D000075244:Apelin Receptors; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; C495199:apelin-13 peptide