Objective: 

Glioblastoma is one of the most lethal tumors in adult central nervous system with a median survival of a year and half and effective therapeutic strategy is urgently needed. For that reason, stem cell-based suicide gene therapies have attracted much interest because of potent tumor tropism of stem cells and bystander effect. In this current clinical situation, stem cells are promising delivery tool of suicide genes for glioma therapy. Since habitual cigarette smoking still prevails worldwide, we investigated the effect of nicotine on stem cell tropism toward glioma and gap junctional intercellular communication (GJIC) function between glioma and stem cells, both of which are important for suicide gene therapies. Methods: Mouse induced pluripotent stem cell-derived neural stem cells (iPS-NSCs) and human dental pulp mesenchymal stem cells (DPSCs) were used. The effect of nicotine on tumor tropism to glioma-conditioned medium (CM) at a non-cytotoxic concentration was assessed with Matrigel invasion assay. Nicotine effect on GJIC was assessed with the scrape loading/dye transfer (SL/DT) assay for co-culture of glioma and stem cells and the parachute assay among glioma cells using high-content analysis. Results: Tumor tropism of iPS-NSCs toward GL261-CM and DPSCs toward U251-CM was not affected by nicotine (0.1 and 1 µM). Nicotine at the concentrations equivalent to habitual smoking (1 µM) did not affect GJIC of iPS-NSC/GL261 and DPSC/U251 and GJIC among each glioma cells. Conclusions: The study demonstrated that non-cytotoxic concentrations of nicotine did not significantly change the stem cell properties requisite for stem cell-based suicide gene therapy.

中文翻译：

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尼古丁不会影响神经胶质瘤自杀基因治疗所需的干细胞特性

目的： 

胶质母细胞瘤是成人中枢神经系统中最致命的肿瘤之一，中位生存期为一年半，因此迫切需要有效的治疗策略。出于这个原因，基于干细胞的自杀基因疗法由于干细胞的强大肿瘤嗜性和旁观者效应而引起了人们的极大兴趣。在目前的临床情况下，干细胞有望成为神经胶质瘤治疗中自杀基因的传递工具。由于习惯性吸烟仍在世界范围内盛行，因此我们研究了尼古丁对神经胶质瘤干细胞向神经胶质瘤的趋向性以及神经胶质瘤与干细胞之间的间隙连接细胞间通讯（GJIC）功能的影响，这两者对于自杀基因治疗都很重要。方法： 使用小鼠诱导的多能干细胞来源的神经干细胞（iPS-NSC）和人牙髓间充质干细胞（DPSC）。通过基质胶侵袭试验评估了尼古丁在非细胞毒性浓度下对肿瘤向神经胶质瘤条件培养基（CM）嗜性的影响。尼古丁对GJIC的影响通过胶质瘤和干细胞共培养的刮擦加载/染料转移（SL / DT）测定法和胶质瘤细胞间降落伞测定法进行了高含量分析。结果：  iPS-NSCs对GL261-CM和DPSCs对U251-CM的肿瘤趋向性不受烟碱（0.1和1 µM）的影响。尼古丁的浓度相当于习惯吸烟（1 µM），不影响每个神经胶质瘤细胞中iPS-NSC / GL261和DPSC / U251的GJIC和GJIC。结论： 该研究表明，尼古丁的无细胞毒性浓度并未显着改变基于干细胞的自杀基因治疗所需的干细胞特性。