膜结合型肿瘤坏死因子相关凋亡诱导配体修饰的人骨髓基质干细胞对脑胶质瘤细胞的体外靶向抗肿瘤作用

Dual-targeted Antitumor Effects against Brainstem Glioma of Tumor Necrosis Factor-related,Apoptosis-inducing,Ligand-engineered Human Mesenchymal Stem Cells in Vitro

目的:探索经膜结合型肿瘤坏死因子相关凋亡诱导配体(TRAIL)修饰的人骨髓基质干细胞(hMSCs)对脑胶质瘤的靶向抗肿瘤作用。方法:通过体外Transwell系统研究hMSCs向胶质瘤的迁徙能力。采用经全长人TRAIL(hTRAIL)重组的腺相关病毒(rAAV)载体(rAAV hTRAIL)对骨髓基质干细胞(MSCs)进行修饰。将hTRAIL修饰的MSCs与人胶质瘤细胞(U87MG)在体外共同培养,分析其对脑胶质瘤的靶向抗肿瘤作用。结果:hMSCs向胶质瘤细胞的迁徙具有高度特异性。经TRAIL修饰的hMSCs不仅在MSCs表面表达全长TRAIL,且能在培养基中分泌可溶性TRAIL。经rAAV-hTRAIL转染后,hMSCs细胞凋亡作用无增加。将TRAIL修饰的hMSCs与U87MG细胞共培养,与采用可溶性TRAIL治疗后相比较,可明显提高U87MG细胞的凋亡率。结论:在体外实验中,hMSCs向胶质瘤细胞的迁徒具有高度特异性,且能诱导胶质瘤细胞凋亡,并提高对sTRAIL不敏感胶质瘤细胞的凋亡率。由此推测膜结合型TRAIL修饰的MSCs在肿瘤微环境中对脑胶质瘤具备靶向抗肿瘤效应。MSCs可能成为脑胶质瘤靶向治疗的有效载体。

Aim：To explore the dual-targeted antitumor effects of membrane-spanned,tumor necrosis factor-related,apoptosis-inducing ligand（TRALL）-engineered human mesenchymal stem cells（hMSCs） against brainstem gliomas in vitro.Methods：The migration capacity of hMSCs toward gliomas was studied by the Transwell system in vitro.MSCs were engineered with native full-length human tumor necrosis factorrelated, apoptosis-inducing ligand（hTRAIL） by a recombinant adeno-associated virus（rAAV） vector（rAAVhTRAIL）. The targeted antiglioma effect was analyzed by co-culture of hTRAIL-engineered MSCs with glioma in vitro.Results：Transplanted MSCs migrated to a brain-stem glioma with a high specificity. Membrane-spanned,TRAIL-engineered MSCs not only expressed full-length TRAIL in MSC surface,but secreted some soluble TRAIL in medium.After being infected with rAAV-hTRATL,hMSCs showed no increase in apoptosis.After co-culture of hTRAIL-engineered MSCs and U87MG cells,the apoptosis of U87MG cells significantly increased more than soluble TRAIL-treated U87MG cells.Conclusion：In vitro,hMSCs can migrate to gliomas with a high specificity,and also induce apoptosis in gliomas and enhance apoptosis in insensitive-to-sTRAIL gliomas.It is suggested that through a dual-targeted effect of membrane-spanned, TRAIL-engineered MSCs in the tumor microenvironment have the effect of targeted antiglioma.MSCs may be an effective vehicle for the targeted delivery of therapeutic agents to brainstem gliomas.