Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft
Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft
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DOI：
10.1111/j.1460-9568.2006.05093.x
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发表时间：
2006-10-01
影响因子：
3.4
通讯作者：
Isacson, Ole
中科院分区：
文献类型：
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作者：
Ferrari, Daniela;Sanchez-Pernaute, Rosario;Isacson, Ole
胚胎干细胞(ES细胞)体外移植的多巴胺(DA)神经元的正确身份和功能能力是开发基于ES细胞的帕金森病替代疗法的关键因素。我们将体外分化的灵长类胚胎干细胞移植到帕金森病大鼠的纹状体内，时间为4周(祖细胞)或6周(分化的ES细胞)。在安非他明诱导的旋转中，部分行为恢复与移植物中ES衍生酪氨酸羟化酶阳性(TH+)神经元的数量相关(r=0.5，P<；0.05)。对ES来源移植物的尸检分析显示，TH+神经元具有成熟的形态，类似于胎儿DA神经元，并表达中脑转录因子，如Engraded(EN)和Nurr-1。虽然TH+神经元的总数在两组之间没有差异，但分化的ES细胞移植物中TH/EN的共同表达(>；90%)显著高于来自祖细胞的移植物(<；50%)，反映了更多的细胞组成的异质性。在移植物内，ES来源的TH+轴突与表达脑因子1(Bf-1，FOXG1)、DA和cAMP调节的磷酸蛋白(DARPP-32)的灵长类动物ES来源的纹状体神经元簇之间存在重叠。在定义发育中大脑相邻前脑区的其他区域转录因子中，从未观察到这种重叠，例如Nkx2.1(内侧神经节隆起)、Nkx2.2(苍白球和间脑前体细胞)或Pax6(背侧端脑前体细胞)。尽管ES来源的移植物细胞成分存在异质性，但这些结果显示了灵长类ES细胞来源的DA神经元的正常表型特征、保守的天然轴突靶点选择和功能。
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.