Background: Mesenchymal stem cells (MSCs) have been applied as a promising vehicle for tumour-targeted delivery of suicide genes in the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) suicide gene therapy against malignant gliomas. The efficiency of this strategy is largely dependent on the bystander effect, which relies on high suicide gene expression levels and efficient transportation of activated GCV towards glioma cells. However, up to now, the methods to enhance the bystander effect of this strategy in an efficient and safe way are still lacking and new approaches to improve this therapeutic strategy are required./nMethods: In this study, MSCs were gene transfected using magnetosome-like ferrimagnetic iron oxide nanochains (MFIONs) to highly express HSV-tk. Both the suicide and bystander effects of HSV-tk expressed MSCs (MSCs-tk) were quantitatively evaluated. Connexin 43 (Cx43) expression by MSCs and glioma cells was measured under different treatments. Intercellular communication between MSCs and C6 glioma cells was examined using a dye transfer assay. Glioma tropism and the bio-distribution of MSCs-tk were observed. Anti-tumour activity was investigated in the orthotopic glioma of rats after intravenous administration of MSCs-tk followed by intraperitoneal injection of GCV./nResults: Gene transfection using MFIONs achieved sufficient expression of HSV-tk and triggered Cx43 overexpression in MSCs. These Cx43 overexpressing MSCs promoted gap junction intercellular communication (GJIC) between MSCs and glioma cells, resulting in significantly inhibited growth of glioma through an improved bystander effect. Outstanding tumour targeting and significantly prolonged survival with decreased tumour size were observed after the treatment using MFION-transfected MSCs in glioma model rats./nConclusion: Our results show that iron oxide nanoparticles have the potential to improve the suicide gene expression levels of transfected MSCs, while promoting the GJIC formation between MSCs and tumour cells, which enhances the sensitivity of glioma cells to HSV-tk/GCV suicide gene therapy.

中文翻译：

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氧化铁纳米颗粒促进间充质干细胞的 Cx43 过度表达，用于在胶质瘤治疗期间进行有效的自杀基因治疗

背景：间充质干细胞 (MSCs) 已被用作在针对恶性胶质瘤的单纯疱疹病毒胸苷激酶 (HSV-tk)/更昔洛韦 (GCV) 自杀基因治疗中肿瘤靶向递送自杀基因的有前景的载体。这种策略的效率很大程度上取决于旁观者效应，旁观者效应依赖于高自杀基因表达水平和激活的 GCV 向神经胶质瘤细胞的有效运输。然而，到目前为止，仍然缺乏以有效和安全的方式增强这种策略的旁观者效应的方法，需要新的方法来改进这种治疗策略。/n方法：在本研究中，使用磁小体样亚铁磁性氧化铁纳米链 (MFIONs) 对 MSCs 进行基因转染，以高度表达 HSV-tk。定量评估 HSV-tk 表达的 MSCs (MSCs-tk) 的自杀和旁观者效应。在不同的处理下测量了 MSCs 和神经胶质瘤细胞的连接蛋白 43 (Cx43) 表达。使用染料转移测定法检查了 MSCs 和 C6 神经胶质瘤细胞之间的细胞间通讯。观察了胶质瘤嗜性和MSCs-tk的生物分布。在大鼠原位神经胶质瘤静脉内给予 MSCs-tk 后腹腔注射 GCV 后，研究其抗肿瘤活性。/n结果：使用 MFIONs 的基因转染实现了 HSV-tk 的充分表达并触发了 MSCs 中的 Cx43 过表达。这些过表达 Cx43 的 MSCs 促进了 MSCs 和神经胶质瘤细胞之间的间隙连接细胞间通讯 (GJIC)，通过改善旁观者效应显着抑制了神经胶质瘤的生长。在胶质瘤模型大鼠中使用 MFION 转染的 MSCs 治疗后，观察到显着的肿瘤靶向性和显着延长的生存期。 ，同时促进间充质干细胞与肿瘤细胞之间形成GJIC，从而增强胶质瘤细胞对HSV-tk/GCV自杀基因治疗的敏感性。