Prostaglandin E Positively Modulates Endothelial Progenitor Cell Homeostasis: An Advanced Treatment Modality for Autologous Cell Therapy
Prostaglandin E Positively Modulates Endothelial Progenitor Cell Homeostasis: An Advanced Treatment Modality for Autologous Cell Therapy
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DOI：
10.1159/000189794
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发表时间：
2009-01-01
影响因子：
1.7
通讯作者：
Heeschen, Christopher
中科院分区：
文献类型：
--
作者：
Herrler, Tanja;Leicht, Simon F.;Heeschen, Christopher
目的：内皮祖细胞（endothelial progenitor cells， EPC）的动员及其在出生后新生血管形成中的功能受到严格调控。为了确定新的EPC稳态调节剂，我们筛选了具有生物活性的前列腺素E化合物，以研究它们对EPC产生、运输和功能的影响。方法和结果：我们发现EPC是前列腺素e2 （pge2）的丰富来源，以自动和旁分泌的方式刺激其数量和功能。通过选择性环氧化酶-2抑制在体内阻断pge2的产生，实际上消除了缺血诱导的EPC动员，表明其在组织缺血后EPC稳态中的关键作用。相反，用临床批准的pge1类似物前列地尔体外治疗分离的EPC可增强EPC数量和功能。这些作用是由趋化因子受体CXCR4的表达增加介导的，并依赖于一氧化氮合酶活性。最重要的是，通过激光多普勒分析、运动应激测试和免疫组织化学评估，体外pge1预处理分离的EPC可显著增强其在小鼠后肢缺血模型中的新生血管能力。结论：PGE在EPC稳态调节中的保守作用表明，在分离祖细胞中体外调节前列腺素通路可能是一种新的、安全的促进细胞治疗的策略。版权所有(C) 2009 S. Karger AG，巴塞尔
Aims: The mobilization of endothelial progenitor cells (EPC) and their functioning in postnatal neovascularization are tightly regulated. To identify new modulators of EPC homeostasis, we screened biologically active prostaglandin E compounds for their effects on EPC production, trafficking and function. Methods and Results: We found that EPC are a rich source for prostaglandin E 2 (PGE 2), stimulating their number and function in an auto- and paracrine manner. In vivo blockade of PGE 2 production by selective cyclooxygenase-2 inhibition virtually abrogated ischemia-induced EPC mobilization demonstrating its crucial role in EPC homeostasis following tissue ischemia. Conversely, ex vivo treatment of isolated EPC with the clinically approved PGE 1 analogue alprostadil enhanced EPC number and function. These effects were mediated by increased expression of the chemokine receptor CXCR4 and were dependent on nitric oxide synthase activity. Most importantly, ex vivo PGE 1 pretreatment of isolated EPC significantly enhanced their neovascularization capacity in a murine model of hind limb ischemia as assessed by laser Doppler analysis, exercise stress test and immunohistochemistry. Conclusions: The conserved role for PGE in the regulation of EPC homeostasis suggests that ex vivo modulation of the prostaglandin pathway in isolated progenitor cells may represent a novel and safe strategy to facilitate cell-based therapies. Copyright (C) 2009 S. Karger AG, Basel