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.
Highlights
Cell-based therapy is a promising strategy for induction of therapeutic angiogenesis in ischemic tissues
Blood perfusion from post-operative days (POD) 7 to POD 28 was markedly increased in the group receiving preconditioned peripheral blood mononuclear cells (PBMNCs) with apelin-13 (H-PBMNC + apelin) among the PBMNC injection groups; blood perfusion in the H-PBMNC + apelin group recovered to the pre-operative state value at POD 28
We demonstrated that a triple combinatorial strategy using PBMNC transplantation, preconditioned hypoxic graft cells, and apelin-13 infusion is an effective therapeutic approach for severe peripheral ischemia
Summary
Cell-based therapy is a promising strategy for induction of therapeutic angiogenesis in ischemic tissues. Preclinical evidence supports the notion that combinatorial approaches using a cell-based therapy in parallel with gene therapy induces neovessel maturation and improved hindlimb function[19] These reports suggest that a combination treatment comprising a growth factor component is a potentially effective approach to enhance cell-based therapeutic angiogenesis in ischemic tissues. Combinatorial delivery of Ang-1 enhanced the therapeutic effects of a cell-based therapy using bone marrow-derived mononuclear cells in rabbit hindlimb ischemia models, and gene delivery of apelin in parallel with VEGF resulted in formation of well-developed vessels in ischemic mouse hindlimbs[19,22] These reports indicate that a strategy targeting vessel maturation is a promising approach to enhance therapeutic angiogenesis. A triple combinatorial strategy comprising hypoxic preconditioning of graft cells, cell transplantation, and apelin-mediated vessel maturation could be an effective method of improving ischemia in peripheral tissues
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