Combinatorial Treatment with Apelin-13 Enhances the Therapeutic Efficacy of a Preconditioned Cell-Based Therapy for Peripheral Ischemia.
Combinatorial Treatment with Apelin-13 Enhances the Therapeutic Efficacy of a Preconditioned Cell-Based Therapy for Peripheral Ischemia.
复制标题
与APELIN-13联合治疗可以增强基于预处理细胞的外周缺血治疗的治疗功效。
DOI：
10.1038/srep19379
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发表时间：
2016-01-14
影响因子：
4.6
通讯作者：
Hamano K
中科院分区：
文献类型：
--
作者：
Samura M;Morikage N;Suehiro K;Tanaka Y;Nakamura T;Nishimoto A;Ueno K;Hosoyama T;Hamano K
外周血单核细胞(PBMNCs)低氧预处理可促进细胞移植后缺血组织的治疗性血管生成。然而，使用这种方法产生的新形成的血管还不成熟，不足以促进严重缺血后的功能恢复。在这项研究中，我们研究了血管成熟调节因子apelin-13是否可以有效地促进严重肢体缺血后的治疗性血管生成。低氧预适应的PBMNCs与apelin-13的联合治疗与包含每种因子的单一治疗相比，导致了缺血小鼠后肢的血液灌注量和血管反应性的增加。Apelin-13上调低氧外周血单个核细胞PDGFR-BB和转化生长因子-β1的表达，上调血管平滑肌细胞PDGFFR-β的表达。在PDGF-BB存在的情况下，apelin-13处理的VSMCs的增殖和迁移速度加快。有趣的是，APJ受体在外周血单核细胞中的表达在低氧下增加，但在常氧下不增加。此外，使用小鼠胸主动脉、低氧PBMNCs和apelin-13共同培养模型进行的体外血管生成试验表明，联合治疗可以招募壁细胞从主动脉环长出血管，从而促进新生血管的成熟。因此，联合注射低氧外周血单个核细胞和apelin-13可能是治疗严重缺血性疾病的有效策略。
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.