混合杆状病毒-腺相关病毒载体功能化针对下咽癌的人骨髓间充质干细胞。,Stem Cells and Development

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混合杆状病毒-腺相关病毒载体功能化针对下咽癌的人骨髓间充质干细胞。
Stem Cells and Development ( IF 2.5 ) Pub Date : 2019-03-11 , DOI: 10.1089/scd.2018.0252
Jun Wang _{1,

2} , Liying Zhu ₃ , Xinwei Chen ₁ , Ruofei Huang ₁ , Shili Wang ₂ , Pin Dong ₁

Affiliation

下咽喉癌是常见的头颈部恶性肿瘤，预后很差。在印度，治愈性患者的中位生存时间为17.2个月。然而，基于细胞的基因治疗有望改善患者的预后。在这项研究中，我们调查了人类骨髓间充质干细胞（BMSCs）是否具有下咽癌的潜在归巢能力。为了通过报告基因成像监测BMSC移植治疗的效率，我们使用了一种混合杆状病毒载体，该载体包含在巨细胞病毒启动子控制下的Luc-P2A-eGFP融合体或碘化钠转运体（NIS）序列。为了提高转染效率，杆状病毒载体（Bac-CMV-Luc-P2A-eGFP-ITR和Bac-CMV-NIS-ITR）的两侧是反向末端重复序列（ITR），这是腺相关病毒的关键要素。Bac-CMV-Luc-P2A-eGFP-ITR在骨髓间充质干细胞中的感染效率高达92.84±1.14％，在感染400次时没有明显的毒性作用。此外，Bac-CMV-NIS-ITR感染的BMSCs显示出高效率的放射性碘（125I）吸收；这些高摄取水平维持至少2小时。Transwell迁移分析进一步证明了BMSC在体外对下咽癌细胞（FaDu细胞）的趋化性。将萤火虫荧光素酶报告基因或NIS修饰的BMSCs注射入咽下癌的裸鼠中，并通过生物发光成像和微单光子发射计算机断层成像技术成功跟踪了BMSCs的定位变化。这些数据表明，骨髓间充质干细胞作为下咽癌基因治疗的有希望的靶向递送载体的潜在用途。重要的是，骨髓间充质干细胞可能代表着一种有希望的靶向载体，用于一般肿瘤放射性核素治疗。

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Human Bone Marrow Mesenchymal Stem Cells Functionalized by Hybrid Baculovirus-Adeno-Associated Viral Vectors for Targeting Hypopharyngeal Carcinoma.

Hypopharyngeal carcinoma is a common malignant tumor of the head and neck with a very poor prognosis; the median survival time for curatively treated patients was 17.2 months in India. However, cell-based gene therapy holds promise to improve patient outcomes. In this study, we investigated whether human bone marrow mesenchymal stem cells (BMSCs) possess potential homing capacity for hypopharyngeal carcinoma. To monitor the efficiency of BMSC transplantation therapy through reporter gene imaging, we employed a hybrid baculovirus vector containing the Luc-P2A-eGFP fusion or sodium iodide symporter (NIS) sequence under the control of the cytomegalovirus promoter. To enhance the transfection efficiency, baculovirus vectors (Bac-CMV-Luc-P2A-eGFP-ITR and Bac-CMV-NIS-ITR) were flanked by inverted terminal repeats (ITRs), which are key elements of adeno-associated viruses. The infection efficiency of Bac-CMV-Luc-P2A-eGFP-ITR in BMSCs was as high as 92.84 ± 1.14% with no obvious toxic effects at a multiplicity of infection of 400. Moreover, Bac-CMV-NIS-ITR-infected BMSCs showed highly efficient radioactive iodide (125I) uptake; these high uptake levels were maintained for at least 2 h. Transwell migration assays further demonstrated the chemotaxis of BMSCs to hypopharyngeal carcinoma cells (FaDu cells) in vitro. BMSCs modified by firefly luciferase report gene or NIS were injected into nude mice with hypopharyngeal carcinoma, and changes in the localization of the BMSCs were successfully tracked with bioluminescent imaging and micro-single-photon emission computed tomography imaging. These data indicate the potential utility of BMSCs as a promising targeted-delivery vehicle for hypopharyngeal carcinoma gene therapy. Importantly, BMSCs may represent a promising targeting vector for general tumor radionuclide therapy.

更新日期：2019-11-01

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