Mesenchymal stem cells as vehicles for targeted delivery of anti-angiogenic protein to solid tumors
Mesenchymal stem cells as vehicles for targeted delivery of anti-angiogenic protein to solid tumors
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DOI：
10.1002/jgm.1552
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发表时间：
2011-03-01
影响因子：
3.5
通讯作者：
Wu, Jian
中科院分区：
文献类型：
--
作者：
Ghaedi, Mahboobe;Soleimani, Masoud;Wu, Jian
抑制肿瘤诱导的血管生成可能会限制肿瘤的生长和转移。血管生成抑制剂的长期全身递送与毒性以及其他严重的副作用有关。利用细胞作为基因治疗的载体来传递治疗分子被认为是一种有效的方法。间充质干细胞（MSCs）表现出向癌症组织的趋向性，可以作为细胞传递载体和局部抗血管生成药物的生产者。方法在本研究中，我们试图评估转基因α 1-抗胰蛋白酶（AAT）在慢病毒转导的人间充质干细胞中的产生及其对人脐带静脉内皮细胞（HUVEC）的细胞毒性。通过酶联免疫吸附法测定这些效应细胞分泌的蛋白质。通过凋亡实验评估过表达人AAT基因的hMSCs对HUVEC的细胞毒性。结果慢病毒转导的hMSCs产生功能性AAT，对HUVEC表现出比未转导的hMSCs更高的细胞毒性。此外，与未转导的hMSCs相比，转导的hMSCs分泌的AAT显著抑制了HUVEC的增殖。本研究首次证实转基因hMSCs释放了大量功能性的AAT，对HUVEC具有明显的细胞毒性。结论：hMSC可作为治疗性蛋白靶向递送到肿瘤部位的有效平台。版权所有：John Wiley & Sons， Ltd。
Background Inhibition of tumor-induced angiogenesis may restrict tumor growth and metastasis. Long-term systemic delivery of angiogenic inhibitors is associated with toxicity, as well as other severe side-effects. The utility of cells as vehicles for gene therapy to deliver therapeutic molecules has been suggested to represent an efficient approach. Mesenchymal stem cells (MSCs) exhibit a tropism to cancer tissue, and may serve as a cellular delivery vehicle and a local producer of anti-angiogenic agents.Methods In the present study, we attempted to assess production of the transgene, alpha 1-antitrypsin (AAT), in lentivirus-transduced human MSCs and its cytotoxicity against human umbilical cord vein endothelial cells (HUVEC). The secreted protein from these effector cells was determined by an enzyme-linked immunosorbent assay. The cytotoxicity of hMSCs that overexpress the human AAT gene against HUVEC was evaluated with an apoptotic assay.Results Lentivirus-transduced hMSCs produced functional AAT and displayed much higher cytotoxicity against HUVEC than untransduced hMSCs. Moreover, AAT secreted from transduced hMSCs significantly inhibited HUVEC proliferation compared to untransduced hMSCs. The data obtained demonstrate for the first time that genetically modified hMSCs released abundant and functional AAT that caused obvious cytotoxicity to HUVEC.Conclusions hMSC may serve as an effective platform for the targeted delivery of therapeutic proteins to cancer sites. Copyright (C) 2011 John Wiley & Sons, Ltd.