Conditioned medium derived from mesenchymal stem cells overexpressing HPV16 E6E7 dramatically improves ischemic limb
Conditioned medium derived from mesenchymal stem cells overexpressing HPV16 E6E7 dramatically improves ischemic limb
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DOI：
10.1016/j.yjmcc.2014.04.012
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发表时间：
2014-07-01
影响因子：
5
通讯作者：
Hung, Shih-Chieh
中科院分区：
文献类型：
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作者：
Chang, Ming-Chau;Tsao, Ching-Hua;Hung, Shih-Chieh
间充质干细胞（MSC）已被证明可以分泌血管生成所需的细胞因子和生长因子。先前，我们证明了表达HPV 16 E6 E7 mRNA的MSC（E6 E7-MSC）增加了寿命和分化潜力，并且在没有肿瘤转化的情况下维持。E6 E7-MSC是否是增强血管生成的分子来源尚不清楚。我们证明，E6 E7-MSC衍生的条件培养基（E6 E7-CM）增强内皮细胞迁移和管形成相比，原代MSC衍生的条件培养基（primary-CM）。此外，E6 E7-MSC增加AKT活化并增强白细胞介素-1 β（IL-1 β）和血管内皮生长因子A（VEGFA）的释放。用针对IL-1 β或VEGFA的抗体中和E6 E7-CM消除了其增强内皮迁移和管形成的作用。添加IL-1 β和VEGFA的Primary-CM增强了其增加内皮迁移和管形成的能力。E6 E7-CM显示出增加改善小鼠肢体缺血模型中的血液灌注的能力。组织学分析显示，与初级CM相比，E6 E7-CM抑制肌肉损失或纤维化并增加内皮细胞计数。类似地，E6 E7-CM在改善缺血肢体中的灌注的作用也由IL-1 β或VEGFA水平的增加贡献。这些结果表明，E6 E7-MSC通过Ala活化增加分泌血管生成因子的能力，并且E6 E7-CM在IL-1 β和VEGFA水平上丰富，从而增加改善小鼠肢体缺血模型中的血液灌注和防止肌肉损失或纤维化的能力。(C)2014爱思唯尔有限公司版权所有。
Mesenchymal stem cells (MSCs) have been shown to secrete cytokines and growth factors required for angiogenesis. Previously, we demonstrated that MSCs expressing HPV16 E6E7 mRNA (E6E7-MSCs) increase life span and differentiation potential and maintain without neoplastic transformation. Whether E6E7-MSCs are sources of molecules for enhancing angiogenesis is unknown. We demonstrated that E6E7-MSC-derived conditioned medium (E6E7-CM) enhanced endothelial cell migration and tube formation compared to primary MSC-derived conditioned medium (primary-CM). Moreover, E6E7-MSCs increased AKT activation and enhanced the release of Interleukin-1 beta (IL-1 beta) and vascular endothelial growth factor A (VEGFA). Neutralization of E6E7-CM with antibodies against IL-1 beta or VEGFA abrogated its effect in enhancing endothelial migration and tube formation. Primary-CM, added with IL-1 beta and VEGFA, enhanced its ability to increase endothelial migration and tube formation. E6E7-CM was shown to increase the ability to improve blood perfusion in a mouse limb ischemia model. Histological analysis revealed that E6E7-CM prohibited muscle loss or fibrosis and increased endothelial cell counts compared to primary-CM. Similarly, the effects of E6E7-CM in improving perfusion in ischemic limb were also contributed by the increase of IL-1 beta or VEGFA levels. These results suggest that E6E7-MSCs increase the ability to secrete angiogenic factors via Ala activation, and E6E7-CM is abundant in IL-1 beta and VEGFA levels and thereby increases the ability to improve blood perfusion and prohibit muscle loss or fibrosis in a mouse limb ischemia model. (C) 2014 Elsevier Ltd. All rights reserved.