Department of Neurosurgery, Mount Sinai School of Medicine, New York, New York 10029, USA.
Stem Cells Dev. 2012 Feb 10;21(3):404-10. doi: 10.1089/scd.2010.0560. Epub 2011 Jul 26.
Human high-grade gliomas (hHGG) remain a therapeutic challenge in neuro-oncology despite current multimodality treatments. We recently demonstrated that murine embryonic stem cell (mESC)-derived astrocytes conditionally expressing proapoptotic genes can successfully be used to induce apoptosis and tumor shrinkage of hHGG tumor in vitro and in an in vivo mouse model. The first step in the translation of these results to the clinical settings, however, requires availability of human embryonic stem cells (hESC)- and/or induced pluripotent cell (hiPSC)-derived astrocytes engineered to express proapoptotic genes. The potential for directed differentiation of hESCs and hiPSCs to functional postmitotic astrocytes is not fully characterized. In this study, we show that once specified to neuro-epithelial lineage, hiPSC could be differentiated to astrocytes with a similar efficiency as hESC. However, our analyses of 2 hESC and 2 hiPSC cell lines showed some variability in differentiation potential into astrocytic lineages. Both the hESC- and hiPSC-derived astrocytes appeared to follow the functional properties of mESC-derived astrocytes, namely, migration and tropism for hHGG. This work provides evidence that hESC- and hiPSC-derived cells are able to generate functionally active astrocytes. These results demonstrate the feasibility of using iPSC-derived astrocytes, a new potential source for therapeutic use for brain tumors and other neurological diseases.
尽管目前采用了多种治疗方法，但人类高级别神经胶质瘤（hHGG）仍然是神经肿瘤学中的一个治疗挑战。我们最近证明，条件性表达促凋亡基因的鼠胚胎干细胞（mESC）衍生的星形胶质细胞可成功用于诱导体外和体内小鼠模型中的 hHGG 肿瘤凋亡和肿瘤缩小。然而，将这些结果转化为临床环境的第一步是需要获得表达促凋亡基因的人胚胎干细胞（hESC）和/或诱导多能干细胞（hiPSC）衍生的星形胶质细胞。hESC 和 hiPSC 定向分化为有功能的有丝分裂后星形胶质细胞的潜力尚未完全确定。在这项研究中，我们表明，一旦被指定为神经上皮谱系，hiPSC 就可以以与 hESC 相似的效率分化为星形胶质细胞。然而，我们对 2 个 hESC 和 2 个 hiPSC 细胞系的分析显示，其向星形胶质细胞谱系分化的潜力存在一些差异。hESC 和 hiPSC 衍生的星形胶质细胞似乎都遵循 mESC 衍生的星形胶质细胞的功能特性，即迁移和对 hHGG 的趋向性。这项工作提供了证据表明 hESC 和 hiPSC 衍生的细胞能够产生功能活跃的星形胶质细胞。这些结果表明使用 iPSC 衍生的星形胶质细胞是治疗脑肿瘤和其他神经疾病的一种新的潜在方法是可行的。
