Enhanced in vitro midbrain dopamine neuron differentiation, dopaminergic function, neurite outgrowth, and 1-methyl-4-phenylpyridium resistance in mouse embryonic stem cells overexpressing Bcl-XL
Enhanced in vitro midbrain dopamine neuron differentiation, dopaminergic function, neurite outgrowth, and 1-methyl-4-phenylpyridium resistance in mouse embryonic stem cells overexpressing Bcl-XL
复制标题
DOI：
10.1523/jneurosci.3977-03.2004
复制
发表时间：
2004-01-28
影响因子：
5.3
通讯作者：
Lee, SH
中科院分区：
文献类型：
--
作者：
Shim, JW;Koh, HC;Lee, SH
胚胎干细胞（ES）为再生医学提供了潜在的无限特化细胞来源。在ES细胞中诱导稳定遗传修饰的容易性允许体外操作以增强分化成特定细胞类型并优化疾病动物模型中分化后代的体内功能。我们已经产生了小鼠ES细胞，组成型表达Bcl-2家族的抗凋亡蛋白Bcl-XL。在体外分化的Bcl-XL过表达ES（Bcl-ES）细胞导致更高的表达基因中脑多巴胺（DA）神经元的发展和增加的数量的ES-衍生的神经元表达中脑DA标记物相比，野生型ES细胞的分化。此外，来自Bcl-ES细胞的DA神经元对DA神经元的神经毒素1-甲基-4-苯基吡啶不太敏感。移植到帕金森病大鼠，Bcl-ES衍生的DA神经元表现出更广泛的纤维生长，并导致更明显的逆转行为症状比野生型ES衍生的DA神经元。这些数据表明Bcl-XL在体外中脑DA神经元分化过程中的作用，并为帕金森病临床前动物模型中的细胞移植提供了改进的系统。
Embryonic stem (ES) cells provide a potentially unlimited source of specialized cells for regenerative medicine. The ease of inducing stable genetic modifications in ES cells allows for in vitro manipulations to enhance differentiation into specific cell types and to optimize in vivo function of differentiated progeny in animal models of disease. We have generated mouse ES cells that constitutively express Bcl-XL, an antiapoptotic protein of Bcl-2 family. In vitro differentiation of Bcl-XL overexpressing ES (Bcl-ES) cells resulted in higher expression of genes related to midbrain dopamine (DA) neuron development and increased the number of ES-derived neurons expressing midbrain DA markers compared with differentiation of wild-type ES cells. Moreover, DA neurons derived from Bcl-ES cells were less susceptible to 1-methyl-4-phenylpyridium, a neurotoxin for DA neurons. On transplantation into parkinsonian rats, the Bcl-ES-derived DA neurons exhibited more extensive fiber outgrowth and led to a more pronounced reversal of behavioral symptoms than wild-type ES-derived DA neurons. These data suggest a role for Bcl-XL during in vitro midbrain DA neuron differentiation and provide an improved system for cell transplantation in a preclinical animal model of Parkinson's disease.