Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease.
Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease.
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DOI：
10.1038/nature10648
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发表时间：
2011-11-06
期刊：
影响因子：
64.8
通讯作者：
Studer, Lorenz
中科院分区：
文献类型：
--
作者：
Kriks, Sonja;Shim, Jae-Won;Piao, Jinghua;Ganat, Yosif M.;Wakeman, Dustin R.;Xie, Zhong;Carrillo-Reid, Luis;Auyeung, Gordon;Antonacci, Chris;Buch, Amanda;Yang, Lichuan;Beal, M. Flint;Surmeier, D. James;Kordower, Jeffrey H.;Tabar, Viviane;Studer, Lorenz
人类多能干细胞（hPSCs）是再生医学应用中有前景的细胞来源。hPSCs定向分化为诸如脊髓运动神经元或中脑多巴胺（DA）神经元等特定细胞已取得成功。然而，hPSCs在细胞治疗中的有效应用却进展滞后。虽然小鼠多能干细胞衍生的DA神经元在帕金森病（PD）模型中已显示出疗效，但人类多能干细胞衍生的DA神经元通常在体内表现不佳。hPSCs还存在与畸胎瘤形成或神经过度生长的可能性相关的重大安全问题。
在此，我们提出一种基于底板的新策略来诱导人类DA神经元，这些神经元能在体内有效移植，这表明过去的失败是由于细胞分化不完全，而非细胞的特定脆弱性。中脑底板前体细胞在暴露于音猬因子（SHH）和经典WNT信号通路的小分子激活剂11天后从hPSCs中诱导产生。可移植的中脑DA神经元在第25天获得，并可在体外维持数月。大量的分子图谱分析、生化和电生理数据确定了发育进程，并确认了hPSC衍生的中脑DA神经元的特性。在使用三种宿主物种的PD模型中证明了其在体内的存活和功能。在6 - 羟基多巴胺损伤的小鼠和大鼠中的长期移植表明中脑DA神经元具有良好的存活率，能完全恢复安非他明诱导的旋转行为，并改善前肢使用和运动不能的测试结果。最后，通过移植到帕金森病猴体内证明了其可扩展性。在三种动物模型中DA神经元良好的存活率、功能以及无神经过度生长的情况表明，其在开发基于细胞的帕金森病治疗方法方面具有前景。
Human pluripotent stem cells (hPSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of hPSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of hPSCs for cell therapy has lagged behind. While mouse PSC-derived DA neurons have shown efficacy in models of Parkinson’s disease (PD), DA neurons from human PSCs generally display poor in vivo performance. There are also considerable safety concerns for hPSCs related to their potential for teratoma formation or neural overgrowth Here we present a novel floor plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor plate precursors are derived from hPSCs in 11 days following exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signaling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of hPSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in PD models using three host species. Long-term engraftment in 6-OHDA-lesioned mice and rats demonstrates robust survival of midbrain DA neurons, complete restoration of amphetamine-induced rotation behavior and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into Parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell based therapies in PD.
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DOI：
10.1073/pnas.0808488105
发表时间：
2008-10-28
影响因子：
11.1
作者：
Aubry, Laetitia;Bugi, Aurore;Perrier, Anselme L.
通讯作者：
Perrier, Anselme L.
影响因子：
23.9
作者：
Fasano CA;Chambers SM;Lee G;Tomishima MJ;Studer L
通讯作者：
Studer L
DOI：
10.1073/pnas.0404700101
发表时间：
2004-08-24
影响因子：
11.1
作者：
Perrier, AL;Tabar, V;Studer, L
通讯作者：
Studer, L
DOI：
10.1523/jneurosci.2519-09.2009
发表时间：
2009-09-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Guzman JN;Sánchez-Padilla J;Chan CS;Surmeier DJ
通讯作者：
Surmeier DJ
影响因子：
64.8
作者：
Quintana, Elsa;Shackleton, Mark;Sabel, Michael S.;Fullen, Douglas R.;Johnson, Timothy M.;Morrison, Sean J.
通讯作者：
Morrison, Sean J.