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Gene Therapy Using Neural Stem/Progenitor Cells Derived from Human Induced Pluripotent Stem Cells: Visualization of Migration and Bystander Killing Effect.
Human Gene Therapy ( IF 3.9 ) Pub Date : 2020-03-01 , DOI: 10.1089/hum.2019.326
Ryota Tamura 1 , Hiroyuki Miyoshi 2 , Yukina Morimoto 1 , Yumiko Oishi 1 , Oltea Sampetrean 3 , Chizuru Iwasawa 4 , Yutaka Mine 2 , Hideyuki Saya 3 , Kazunari Yoshida 1 , Hideyuki Okano 2 , Masahiro Toda 1
Affiliation  

Glioblastoma is the most aggressive brain tumor characterized by diffuse infiltration into the normal brain parenchyma. Neural stem cells are known to possess the tumor-tropic migratory capacity and thus can be used as cellular vehicles for targeted delivery of therapeutic agents. In the present study, we evaluated the efficacy of herpes simplex virus thymidine kinase (HSV-TK) suicide gene therapy for glioblastoma using neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs). Although transduction of hiPSCs is preferable for a safe and stable supply in the clinical setting, high-level and/or constitutive HSV-TK expression was highly cytotoxic to hiPSCs. To overcome this problem, we used the tetracycline-inducible system to control the expression of HSV-TK. hiPSC-derived NS/PCs expressing HSV-TK were transplanted in an orthotopic xenograft mouse model of human glioblastoma. Glioblastoma cell growth in mice was dramatically inhibited following ganciclovir (GCV) administration. Survival of the mice was significantly prolonged with administration of GCV compared with control groups. Time-lapse imaging of organotypic brain slice cultures first demonstrated the directional migration of NS/PCs toward glioblastoma cells and the bystander killing effect upon GCV treatment. hiPSC-derived NS/PCs with HSV-TK/GCV suicide gene system may have considerable therapeutic potential for the treatment of glioblastoma. Color images are available online.

中文翻译:

使用源自人类诱导多能干细胞的神经干细胞/祖细胞进行基因治疗:迁移和旁观者杀伤效应的可视化。

胶质母细胞瘤是最具侵袭性的脑肿瘤,其特征是弥漫性浸润到正常脑实质。已知神经干细胞具有向肿瘤迁移的能力,因此可用作靶向递送治疗剂的细胞载体。在本研究中,我们使用源自人类诱导多能干细胞 (hiPSC) 的神经干/祖细胞 (NS/PC) 评估了单纯疱疹病毒胸苷激酶 (HSV-TK) 自杀基因治疗胶质母细胞瘤的疗效。尽管 hiPSC 的转导对于临床环境中的安全和稳定供应是优选的,但高水平和/或组成型 HSV-TK 表达对 hiPSC 具有高度细胞毒性。为了克服这个问题,我们使用四环素诱导系统来控制 HSV-TK 的表达。将表达 HSV-TK 的 hiPSC 衍生的 NS/PC 移植到人胶质母细胞瘤的原位异种移植小鼠模型中。更昔洛韦 (GCV) 给药后,小鼠的胶质母细胞瘤细胞生长受到显着抑制。与对照组相比,GCV 给药后小鼠的存活率显着延长。器官型脑切片培养物的延时成像首先证明了 NS/PC 向胶质母细胞瘤细胞的定向迁移以及对 GCV 治疗的旁观者杀伤作用。具有 HSV-TK/GCV 自杀基因系统的 hiPSC 衍生的 NS/PCs 可能具有相当大的治疗胶质母细胞瘤的治疗潜力。彩色图像可在线获取。与对照组相比,GCV 给药后小鼠的存活率显着延长。器官型脑切片培养物的延时成像首先证明了 NS/PC 向胶质母细胞瘤细胞的定向迁移以及对 GCV 治疗的旁观者杀伤作用。具有 HSV-TK/GCV 自杀基因系统的 hiPSC 衍生的 NS/PCs 可能具有相当大的治疗胶质母细胞瘤的治疗潜力。彩色图像可在线获取。与对照组相比,GCV 给药后小鼠的存活率显着延长。器官型脑切片培养物的延时成像首先证明了 NS/PC 向胶质母细胞瘤细胞的定向迁移以及对 GCV 治疗的旁观者杀伤作用。具有 HSV-TK/GCV 自杀基因系统的 hiPSC 衍生的 NS/PCs 可能具有相当大的治疗胶质母细胞瘤的治疗潜力。彩色图像可在线获取。具有 HSV-TK/GCV 自杀基因系统的 hiPSC 衍生的 NS/PCs 可能具有相当大的治疗胶质母细胞瘤的治疗潜力。彩色图像可在线获取。具有 HSV-TK/GCV 自杀基因系统的 hiPSC 衍生的 NS/PCs 可能具有相当大的治疗胶质母细胞瘤的治疗潜力。彩色图像可在线获取。
更新日期:2020-02-19
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