分泌肿瘤坏死因子相关凋亡诱导配体的经血来源间充质干细胞靶向治疗胶质瘤的研究

Gliomas are the most common primary malignant brain tumors in humans. In recent years, the incidence and mortality of glioma are increasing in China. The prognosis of patients with malignant glioma is extremely poor because glioma is refractory to conventional therapies such as surgical resection, radiation and chemotherapy. Stem cell-based gene therapies provide a promising strategy for the treatment of malignant glioma because of their selective migratory ability to tumor cells. In this study, we will firstly determine the glioma tropic ability of menstrual blood-derived mesenchymal stem cells (MenSCs) by in vitro and in vivo migration assays. Then, we decide to use MenSCs as a cellular vehicle for targeted delivery and local production of the biologic agent soluble tumor necrosis factor-released apoptosis inducing ligand (sTRAIL) at the tumor site. Co-culture and Transwell experiments will be used to assess the anti-tumor efficacy of sTRAIL-secreting MenSCs in vitro. Furthermore, the in vivo therapeutic efficacies of these manipulated MenSCs transplanted through a variety of approach such as intratumoral injection, contralateral hemisphere injection, intraperitoneal injection and intravenous injection will be also determined by an established intracranial glioma tumor in a mouse xenograft model. This study will provide MenSCs as a vehicle for stem cell-based glioma-targeted gene therapy, and find an optimal transplant strategy for manipulated MenSCs.

胶质瘤是最常见的脑部肿瘤，其发病率和死亡率在我国均呈现上升趋势。由于其浸润生长和恶性病变的特点，即使予以手术、放疗和化疗等综合治疗效果仍不理想。近年来以干细胞为载体的基因治疗因具有向损伤部位迁移等特点而引起学术界的浓厚兴趣。本课题拟在先前对人经血来源间充质干细胞研究的基础上，通过体外和体内研究首先明确其对胶质瘤的趋向性及作为肿瘤治疗载体的可行性，阐释各细胞因子在此过程中发挥的作用；再以肿瘤坏死因子相关凋亡诱导配体基因对人经血来源间充质干细胞进行修饰，观察其对实验性胶质瘤的治疗效果及其作用机理。本研究不仅探讨基因修饰的人经血来源间充质干细胞对胶质瘤的趋向性和抗肿瘤效应，还对肿瘤内注射、对侧半球注射、腹腔注射和尾静脉注射等多种细胞移植方式进行比较。本课题的实施能为以人经血来源间充质干细胞为载体的胶质瘤靶向基因治疗提供实验依据，并为选择最佳的细胞移植方式提供借鉴。

胶质瘤是最常见的脑部肿瘤，其发病率和死亡率在我国均呈现上升趋势。由于其浸润生长和恶性病变的特点，即使予以手术、放疗和化疗等综合治疗效果仍不理想。近年来以干细胞为载体的基因治疗因具有向损伤部位迁移等特点而引起学术界的浓厚兴趣。在前期对人经血来源间充质干细胞研究的基础上，本课题组进一步通过体外和体内研究首先明确了其对胶质瘤的具有较强趋向性，可作为肿瘤治疗载体，且实验结果表明EGF、PDGF等细胞因子参与了人经血来源间充质干细胞的迁移过程，并在此过程中发挥的作用。之后利用腺病毒Ad5/F35携带肿瘤坏死因子相关凋亡诱导配体基因对人经血来源间充质干细胞进行修饰，首先验证了携带sTRAIL的病毒质粒感染对干细胞的生物学特性并没有产生影响；随后通过体外细胞实验及在体胶质瘤裸鼠模型评估其对实验性胶质瘤的治疗效果及其作用机理，结果表明MenSC-sTRAIL具有较好的靶向肿瘤及肿瘤杀伤作用。本课题的实施能为以人经血来源间充质干细胞为载体的胶质瘤靶向基因治疗提供实验依据，并为选择最佳的细胞移植方式提供借鉴。通过本项目的研究，培养了1名博士后及4名研究生，发表SCI论文9篇。