Bagó Juli R, Alfonso-Pecchio Adolfo, Okolie Onyi, Dumitru Raluca, Rinkenbaugh Amanda, Baldwin Albert S, Miller C Ryan, Magness Scott T, Hingtgen Shawn D
Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Department of Genetics, UNC Human Pluripotent Stem Cell Core, UNC School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Nat Commun. 2016 Feb 2;7:10593. doi: 10.1038/ncomms10593.
Transdifferentiation (TD) is a recent advancement in somatic cell reprogramming. The direct conversion of TD eliminates the pluripotent intermediate state to create cells that are ideal for personalized cell therapy. Here we provide evidence that TD-derived induced neural stem cells (iNSCs) are an efficacious therapeutic strategy for brain cancer. We find that iNSCs genetically engineered with optical reporters and tumouricidal gene products retain the capacity to differentiate and induced apoptosis in co-cultured human glioblastoma cells. Time-lapse imaging shows that iNSCs are tumouritropic, homing rapidly to co-cultured glioblastoma cells and migrating extensively to distant tumour foci in the murine brain. Multimodality imaging reveals that iNSC delivery of the anticancer molecule TRAIL decreases the growth of established solid and diffuse patient-derived orthotopic glioblastoma xenografts 230- and 20-fold, respectively, while significantly prolonging the median mouse survival. These findings establish a strategy for creating autologous cell-based therapies to treat patients with aggressive forms of brain cancer.
转分化（TD）是体细胞重编程领域的一项最新进展。TD的直接转化消除了多能中间状态，从而产生了适用于个性化细胞治疗的理想细胞。在此，我们提供证据表明，TD衍生的诱导神经干细胞（iNSCs）是一种治疗脑癌的有效策略。我们发现，用光学报告基因和杀肿瘤基因产物进行基因工程改造的iNSCs，在共培养的人胶质母细胞瘤细胞中仍保留分化能力并诱导其凋亡。延时成像显示，iNSCs具有肿瘤趋向性，能迅速归巢至共培养的胶质母细胞瘤细胞，并广泛迁移至小鼠脑内远处的肿瘤病灶。多模态成像显示，iNSC递送抗癌分子TRAIL分别使已建立的实体性和弥漫性患者来源的原位胶质母细胞瘤异种移植物的生长减少230倍和20倍，同时显著延长小鼠的中位生存期。这些发现确立了一种创建自体细胞疗法来治疗侵袭性脑癌患者的策略。
