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首页> 外文期刊>The European Journal of Neuroscience >Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft.
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Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft.

机译：源自灵长类ES细胞的移植多巴胺神经元优先支配移植物中的DARPP-32纹状体祖细胞。

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The correct identity and functional capacity of transplanted dopamine (DA) neurons derived in vitro from embryonic stem (ES) cells is a critical factor for the development of an ES cell-based replacement therapy for Parkinson's disease. We transplanted primate Cyno-1 ES cells differentiated in vitro for 4 (progenitor ES cells) or 6 (differentiated ES cells) weeks, or control fetal primate cells into the striatum of hemi-parkinsonian rats. Partial behavioral recovery in amphetamine-induced rotation was correlated with the number of ES-derived tyrosine hydroxylase-positive (TH+) neurons in the grafts (r=0.5, P<0.05). Post mortem analysis of ES-derived grafts revealed TH+neurons with mature morphology, similar to fetal DA neurons, and expression of midbrain transcription factors, such as Engrailed (En) and Nurr-1. While the total number of TH+neurons was not different between the two groups, TH/En co-expression was significantly higher (>90%) in grafts from differentiated ES cells than in grafts derived from progenitor cells (<50%), reflecting a more heterogeneous cellular composition. Within the grafts there was an overlap between ES-derived TH+axonal arbors and clusters of primate ES-derived striatal neurons expressing brain factor 1 (Bf-1, Foxg1) and DA and cAMP-regulated phosphoprotein (DARPP-32). Such overlap was never observed for other regional transcription factors that define neighboring forebrain domains in the developing brain, such as Nkx2.1 (medial ganglionic eminence), Nkx2.2 (pallidal and diencephalic progenitors) or Pax6 (dorsal telencephalic progenitors). Despite the heterogeneity of ES-derived graft cell composition, these results demonstrate normal phenotypic specification, conserved natural axonal target selectivity and functionality of DA neurons derived from primate ES cells.
机译：体外衍生自胚胎干（ES）细胞的移植多巴胺（DA）神经元的正确身份和功能能力是开发基于ES细胞的帕金森氏病替代疗法的关键因素。我们将在体外分化的灵长类Cyno-1 ES细胞移植了4周（祖细胞）或6周（分化的ES细胞），或将胎儿灵长类细胞移植到半帕金森病大鼠的纹状体中。苯丙胺诱导的旋转中的部分行为恢复与移植物中ES衍生的酪氨酸羟化酶阳性（TH +）神经元的数量相关（r = 0.5，P <0.05）。对源自ES的移植物的验尸分析显示，TH +神经元具有成熟的形态，类似于胎儿DA神经元，并表达了中脑转录因子，例如Engrailed（En）和Nurr-1。尽管两组中TH +神经元的总数没有差异，但分化的ES细胞移植物中的TH / En共表达显着高于祖细胞移植的TH / En共表达（<50％），反映了更多样化的细胞组成。在移植物中，ES衍生的TH +轴突柄与表达脑因子1（Bf-1，Foxg1）和DA和cAMP调控的磷蛋白（DARPP-32）的灵长类ES衍生的纹状体神经元簇重叠。对于在发育中的大脑中定义相邻前脑结构域的其他区域转录因子（例如Nkx2.1（中枢神经节突突），Nkx2.2（苍白球和双脑祖细胞）或Pax6（背侧脑神经祖细胞）），从未观察到这种重叠。尽管ES来源的移植细胞组成具有异质性，但这些结果证明了正常的表型规范，保守的天然轴突靶标选择性和源自灵长类ES细胞的DA神经元的功能。

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