Atherogenic Cytokines Regulate VEGF-A-Induced Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells into Endothelial Cells.
Atherogenic Cytokines Regulate VEGF-A-Induced Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells into Endothelial Cells.
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DOI：
10.1155/2015/498328
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发表时间：
2015
影响因子：
4.3
通讯作者：
Agrawal DK
中科院分区：
文献类型：
--
作者：
Ikhapoh IA;Pelham CJ;Agrawal DK
冠状动脉支架植入术或血管成形术经常导致长期内皮功能障碍或损失以及包括动脉血栓形成和心肌梗死的并发症。已经提出了基于干细胞的疗法来支持内皮再生。间充质干细胞（MSC）在VEGF-A存在下体外分化为内皮细胞（EC）。在介入部位应用VEGF-A和MSC衍生的EC是一项复杂的临床挑战。在这项研究中，我们研究了致动脉粥样硬化细胞因子（IL-6，TNF α和Ang II）对EC分化和功能的影响。从尤卡坦小型猪的骨髓中分离MSC（CD44+、CD73+、CD90+、CD14-和CD45-）。在含有VEGF-A（50 ng/mL）的分化培养基中培养的幼稚MSC表现出EC特异性标志物（vWF、PECAM-1和VE-钙粘蛋白）、VEGFR-2和Sox 18的表达增加，并增强了内皮管形成。IL-6或TNF α引起VEGF-A刺激的MSC中EC标志物表达的剂量依赖性衰减。与此相反，血管紧张素II增强EC标志物的表达在VEGF-A刺激的MSC。在VEGF-A和IL-6或TNF α中加入Ang II足以挽救EC表型。因此，Ang II促进而IL-6和TNF α抑制VEGF-A诱导的MSC向EC的分化。这些发现对于增加心脏血管分布和在介入后使冠状动脉再内皮化的治疗具有重要的临床意义。
Coronary artery stenting or angioplasty procedures frequently result in long-term endothelial dysfunction or loss and complications including arterial thrombosis and myocardial infarction. Stem cell-based therapies have been proposed to support endothelial regeneration. Mesenchymal stem cells (MSCs) differentiate into endothelial cells (ECs) in the presence of VEGF-A in vitro. Application of VEGF-A and MSC-derived ECs at the interventional site is a complex clinical challenge. In this study, we examined the effect of atherogenic cytokines (IL-6, TNFα, and Ang II) on EC differentiation and function. MSCs (CD44+, CD73+, CD90+, CD14−, and CD45−) were isolated from the bone marrow of Yucatan microswine. Naïve MSCs cultured in differentiation media containing VEGF-A (50 ng/mL) demonstrated increased expression of EC-specific markers (vWF, PECAM-1, and VE-cadherin), VEGFR-2 and Sox18, and enhanced endothelial tube formation. IL-6 or TNFα caused a dose-dependent attenuation of EC marker expression in VEGF-A-stimulated MSCs. In contrast, Ang II enhanced EC marker expression in VEGF-A-stimulated MSCs. Addition of Ang II to VEGF-A and IL-6 or TNFα was sufficient to rescue the EC phenotype. Thus, Ang II promotes but IL-6 and TNFα inhibit VEGF-A-induced differentiation of MSCs into ECs. These findings have important clinical implications for therapies intended to increase cardiac vascularity and reendothelialize coronary arteries following intervention.
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