Center for Stem Cell Therapeutics and Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Stem Cells. 2018 Jun;36(6):932-942. doi: 10.1002/stem.2805. Epub 2018 Apr 1.
Stem cells are emerging as promising treatment strategies for several brain disorders and pathologies. In this study, we explored the potential of creating induced pluripotent stem cell-derived neural stem cells (ipNSC) by using either unmodified or gene-modified somatic cells and tested their fate and therapeutic efficacies in vitro and in vivo. We show that cells engineered in somatic state lose transgene-expression during the neural induction process, which is partially restored by histone deacetylase inhibitor treatment whereas cells engineered at the ipNSC state have sustained expression of transgenes. In vivo, bimodal mouse and human ipNSCs engineered to express tumor specific death-receptor ligand and suicide-inducing therapeutic proteins have profound anti-tumor efficacy when encapsulated in synthetic extracellular matrix and transplanted in mouse models of resected-glioblastoma. This study provides insights into using somatic cells for treating CNS disorders and presents a receptor-targeted cancer therapeutic approach for brain tumors. Stem Cells 2018;36:932-942.
干细胞作为有前途的治疗策略，正在被探索应用于多种脑疾病和病变。在本研究中，我们探索了使用未修饰或基因修饰的体细胞核来产生诱导多能干细胞源性神经干细胞（ipNSC）的可能性，并在体外和体内检测了它们的命运和治疗效果。我们发现，在神经诱导过程中，处于体细胞核状态的细胞会丢失转基因表达，而组蛋白去乙酰化酶抑制剂处理会部分恢复这种表达，而处于 ipNSC 状态的细胞则持续表达转基因。在体内，双模态小鼠和人源 ipNSC 被设计表达肿瘤特异性死亡受体配体和自杀诱导治疗蛋白，当封装在合成细胞外基质中并移植到切除胶质母细胞瘤的小鼠模型中时，具有显著的抗肿瘤疗效。本研究为利用体细胞治疗中枢神经系统疾病提供了新的思路，并为脑肿瘤提供了一种受体靶向的癌症治疗方法。Stem Cells 2018;36:932-942.
