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Direct generation of functional dopaminergic neurons from mouse and human fibroblasts

机译:从小鼠和人类成纤维细胞直接产生功能性多巴胺能神经元

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摘要

Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson's disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons~(1,2. In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency~(3,4). However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled~5. Here we identified a minimal set of three transcription factors-MasAi (also known as Ascll), Nurrl (also known as Nr4a2) and Lmxla-that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson's disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies.
机译:多巴胺能神经元的移植可以潜在地改善帕金森氏病的临床结果,帕金森氏病是中脑多巴胺能神经元变性导致的神经系统疾病〜(1,2。特别是,胚胎干细胞源性多巴胺能神经元的移植已被证明是有效的在多巴胺缺乏的情况下恢复运动症状〜(3,4)。但是,如果控制不当,使用多能细胞可能会导致肿瘤的发展〜5。在这里,我们确定了一组最少的三种转录因子- MasAi(也称为Ascll),Nurrl(也称为Nr4a2)和Lmxla-能够从小鼠和人类成纤维细胞直接产生功能性的多巴胺能神经元,而不会恢复到祖细胞阶段,诱导的多巴胺能(iDA)细胞释放多巴胺并显示自发性电活动以规律的峰值组织,与脑多巴胺能神经元的起搏器活动一致。能够在健康捐献者和帕金森氏病患者的产前和成年成纤维细胞中引起多巴胺能神经元转化。从体细胞直接生成iDA细胞可能对理解神经元发育,体外疾病建模和细胞替代疗法的关键过程具有重要意义。

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  • 来源
    《Nature》 |2011年第7359期|p.224-227|共4页
  • 作者单位

    Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy;

    Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy;

    Department of Neuroscienceand Brain Technologies, Istituto Italiano di Tecnologia, via Morego,30,16163 Genoa, Italy;

    CBM Sri. Area Science park, Basovizza,SS14, km 165,34149 Trieste, Italy,Sector of Neurobiology, International School for Advanced Studies (SISSA), via Bonomea, 265 34136 Trieste, Italy;

    Department of Neuroscienceand Brain Technologies, Istituto Italiano di Tecnologia, via Morego,30,16163 Genoa, Italy;

    Department of Neuroscienceand Brain Technologies, Istituto Italiano di Tecnologia, via Morego,30,16163 Genoa, Italy;

    Department of Neuroscienceand Brain Technologies, Istituto Italiano di Tecnologia, via Morego,30,16163 Genoa, Italy;

    Advanced Light and Electron Microscopy Bio-Imaging Centre, Experimental Imaging Centre, San Raffaele Scientific Institute, 20132 Milan, Italy;

    Sector of Neurobiology, International School for Advanced Studies (SISSA), via Bonomea, 265 34136 Trieste, Italy;

    Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy;

    Department of Neuroscienceand Brain Technologies, Istituto Italiano di Tecnologia, via Morego,30,16163 Genoa, Italy;

    Parkinson Institute, IstitutiClinicidi Perfezionamento, 20126 Milan, Italy;

    Department of Neuroscienceand Brain Technologies, Istituto Italiano di Tecnologia, via Morego,30,16163 Genoa, Italy;

    Sector of Neurobiology, International School for Advanced Studies (SISSA), via Bonomea, 265 34136 Trieste, Italy;

    The Giovanni Armenise-Harvard Foundation Laboratory, 34136 Trieste, Italy;

    Department of Neuroscienceand Brain Technologies, Istituto Italiano di Tecnologia, via Morego,30,16163 Genoa, Italy;

    Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 入库时间 2022-08-18 02:54:43

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