Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth
Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth
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DOI：
10.1038/s41417-022-00527-5
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发表时间：
2022-09-08
影响因子：
6.4
通讯作者：
Kurozumi，Kazuhiko
中科院分区：
文献类型：
--
作者：
Horikawa，Makoto;Koizumi，Shinichiro;Kurozumi，Kazuhiko
单纯疱疹病毒胸苷激酶(HSVtk)/更昔洛韦(GCV)自杀基因治疗恶性胶质瘤已有很长的历史。近年来，从乳牙中采集的具有良好的可采收性、伦理学意义和自我更新能力的脱落牙干细胞主要在基因治疗领域引起了人们的关注。在目前的研究中，我们评估了SHEAD作为一种新的细胞载体用于恶性胶质瘤的自杀基因治疗，正如我们之前在各种细胞类型中所展示的那样。将HSVtk基因(SHEDTK)导入SHEAD。体外实验显示SHEDTK与胶质瘤细胞株共培养时存在明显的旁观者效应。此外，在SHEDTK和胶质瘤细胞中同时观察到由caspase3/7激活引起的细胞凋亡的变化。植入U87和SHEDTK混合物并经腹腔注射GCV治疗的小鼠存活超过100天。此外，治疗模型小鼠的肿瘤在治疗期间显著缩小。移植于对侧大脑半球的SHEDTK向穿过胼胝体的肿瘤迁移。这些结果表明基于SHEDTK的自杀基因治疗具有强大的肿瘤亲和性和旁观者杀伤效应，可能为恶性胶质瘤的治疗提供一种新的有前途的治疗方式。
Herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) suicide gene therapy has a long history of treating malignant gliomas. Recently, stem cells from human exfoliated deciduous teeth (SHED), which are collected from deciduous teeth and have excellent harvestability, ethical aspects, and self-renewal, have been attracting attention mainly in the field of gene therapy. In the present study, we assessed SHED as a novel cellular vehicle for suicide gene therapy in malignant gliomas, as we have previously demonstrated with various cell types. SHED was transduced with the HSVTK gene (SHEDTK). In vitro experiments showed a significant bystander effect between SHEDTK and glioma cell lines in coculture. Furthermore, apoptotic changes caused by caspase 3/7 activation were simultaneously observed in SHEDTK and glioma cells. Mice implanted with a mixture of U87 and SHEDTK and treated with intraperitoneal GCV survived for longer than 100 days. Additionally, tumors in treatment model mice were significantly reduced in size during the treatment period. SHEDTK implanted at the contralateral hemisphere migrated toward the tumor crossing the corpus callosum. These results suggested that SHEDTK-based suicide gene therapy has potent tumor tropism and a bystander-killing effect, potentially offering a new promising therapeutic modality for malignant gliomas.