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Induction of human neuronal cells by defined transcription factors

机译:通过定义的转录因子诱导人神经元细胞

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本期三篇论文介绍了“功能性诱导神经”(iN)rn细胞由人成纤维细胞的生成,这是一个对再生rn医学来说非常有希望的过程。Pang等人发现,rn三个转录因子(分别是Ascl1,亦称Mash1;rnBrn2,或称Pou3f2;和Myt1l)的组合能大大rn增强人胚胎干细胞的神经分化。当与基本的rn“螺旋一回环一螺旋转录因子”NeuroD1相结rn合时,这些因子还能将人胎儿和新生儿成纤维rn细胞转化成iN细胞。Caiazzo等人利用三个转录rn因子的一个组合来将出生前及成年的小鼠和人rn成纤维细胞转化成功能性多巴胺能神经元。这rn三个转录因子分别是Masth1、Nurr1(或Nr4a2)rn和Lm×1a。转化是直接进行的,不用回到先祖rn细胞状态,而且这种转化在来自帕金森氏症患rn者及来自健康供者的细胞中都能发生。Yoo等rn人采用了另外一种方法。他们发现,微RNA在rn神经命运决定中有一个指导性作用。miR-9/9*rn和miR-124在人成纤维细胞中的表达诱导它们rn转化成功能性神经元,而增添一些神经元转录rn因子可以帮助这一过程的进行。%Somatic cell nuclear transfer, cell fusion, or expression of lineage-specific factors have been shown to induce cell-fate changes in diverse somatic cell types~(1-12). We recently observed that forced expression of a combination of three transcription factors, Brn2 (also known as Pou3f2), Ascll and Mytll, can efficiently convert mouse fibroblasts into functional induced neuronal (iN) cells~(13). Here we show that the same three factors can generate functional neurons from human pluripotent stem cells as early as 6 days after transgene activation. When combined with the basic helix-loop-helix transcription factor NeuroD1, these factors could also convert fetal and postnatal human fibroblasts into iN cells showing typical neuronal morphologies and expressing multiple neuronal markers, even after downregulation of the exogenous transcription factors. Importantly, the vast majority of human iN cells were able to generate action potentials and many matured to receive synaptic contacts when co-cultured with primary mouse cortical neurons. Our data demonstrate that non-neural human somatic cells, as well as pluripotent stem cells, can be converted directly into neurons by lineage-determining transcription factors. These methods may facilitate robust generation of patient-specific human neurons for in vitro disease modelling or future applications in regenerative medicine.
机译:本期三篇论文介绍了“功能性诱导神经”(iN)rn细胞由人成纤维细胞的生成,这是一个对再生rn医学来说非常有希望的过程。Pang等人发现,rn三个转录因子(分别是Ascl1,亦称Mash1;rnBrn2,或称Pou3f2;和Myt1l)的组合能大大rn增强人胚胎干细胞的神经分化。当与基本的rn“螺旋一回环一螺旋转录因子”NeuroD1相结rn合时,这些因子还能将人胎儿和新生儿成纤维rn细胞转化成iN细胞。Caiazzo等人利用三个转录rn因子的一个组合来将出生前及成年的小鼠和人rn成纤维细胞转化成功能性多巴胺能神经元。这rn三个转录因子分别是Masth1、Nurr1(或Nr4a2)rn和Lm×1a。转化是直接进行的,不用回到先祖rn细胞状态,而且这种转化在来自帕金森氏症患rn者及来自健康供者的细胞中都能发生。Yoo等rn人采用了另外一种方法。他们发现,微RNA在rn神经命运决定中有一个指导性作用。miR-9/9*rn和miR-124在人成纤维细胞中的表达诱导它们rn转化成功能性神经元,而增添一些神经元转录rn因子可以帮助这一过程的进行。%Somatic cell nuclear transfer, cell fusion, or expression of lineage-specific factors have been shown to induce cell-fate changes in diverse somatic cell types~(1-12). We recently observed that forced expression of a combination of three transcription factors, Brn2 (also known as Pou3f2), Ascll and Mytll, can efficiently convert mouse fibroblasts into functional induced neuronal (iN) cells~(13). Here we show that the same three factors can generate functional neurons from human pluripotent stem cells as early as 6 days after transgene activation. When combined with the basic helix-loop-helix transcription factor NeuroD1, these factors could also convert fetal and postnatal human fibroblasts into iN cells showing typical neuronal morphologies and expressing multiple neuronal markers, even after downregulation of the exogenous transcription factors. Importantly, the vast majority of human iN cells were able to generate action potentials and many matured to receive synaptic contacts when co-cultured with primary mouse cortical neurons. Our data demonstrate that non-neural human somatic cells, as well as pluripotent stem cells, can be converted directly into neurons by lineage-determining transcription factors. These methods may facilitate robust generation of patient-specific human neurons for in vitro disease modelling or future applications in regenerative medicine.

著录项

  • 来源
    《Nature》 |2011年第7359期|p.220-223|共4页
  • 作者单位

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

    Institute for Stem Cell Biology and Regenerative Medicine,Department of Pathology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

    Institute for Stem Cell Biology and Regenerative Medicine,Department of Pathology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA,Program in Cancer Biology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

    Institute for Stem Cell Biology and Regenerative Medicine,Department of Pathology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA,Program in Cancer Biology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

    Institute for Stem Cell Biology and Regenerative Medicine,Department of Pathology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

    Institute for Stem Cell Biology and Regenerative Medicine,Department of Pathology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

    Institute for Stem Cell Biology and Regenerative Medicine,Department of Pathology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

    Institute for Stem Cell Biology and Regenerative Medicine,Department of Pathology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA,Howard Hughes Medical Institute, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

    Institute for Stem Cell Biology and Regenerative Medicine,Department of Pathology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA,Program in Cancer Biology, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA;

  • 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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  • 正文语种 eng
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  • 入库时间 2022-08-18 02:54:43

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