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首页> 外文期刊>STEM CELLS >Inhibition of Notch Signaling in Human Embryonic Stem Cell-Derived Neural Stem Cells Delays G1/S Phase Transition and Accelerates Neuronal Differentiation In Vitro and In Vivo§
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Inhibition of Notch Signaling in Human Embryonic Stem Cell-Derived Neural Stem Cells Delays G1/S Phase Transition and Accelerates Neuronal Differentiation In Vitro and In Vivo§

机译：人胚胎干细胞来源的神经干细胞中Notch信号的抑制延迟G1 / S相变并加速体内和体外神经元分化 §

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摘要

The controlled in vitro differentiation of human embryonic stem cells (hESCs) and other pluripotent stem cells provides interesting prospects for generating large numbers of human neurons for a variety of biomedical applications. A major bottleneck associated with this approach is the long time required for hESC-derived neural cells to give rise to mature neuronal progeny. In the developing vertebrate nervous system, Notch signaling represents a key regulator of neural stem cell (NSC) maintenance. Here, we set out to explore whether this signaling pathway can be exploited to modulate the differentiation of hESC-derived NSCs (hESNSCs). We assessed the expression of Notch pathway components in hESNSCs and demonstrate that Notch signaling is active under self-renewing culture conditions. Inhibition of Notch activity by the -secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) in hESNSCs affects the expression of human homologues of known targets of Notch and of several cell cycle regulators. Furthermore, DAPT-mediated Notch inhibition delays G1/S-phase transition and commits hESNSCs to neurogenesis. Combined with growth factor withdrawal, inhibition of Notch signaling results in a marked acceleration of differentiation, thereby shortening the time required for the generation of electrophysiologically active hESNSC-derived neurons. This effect can be exploited for neural cell transplantation, where transient Notch inhibition before grafting suffices to promote the onset of neuronal differentiation of hESNSCs in the host tissue. Thus, interference with Notch signaling provides a tool for controlling human NSC differentiation both in vitro and in vivo. STEM CELLS 2010;28:955-964
机译：人胚胎干细胞（hESCs）和其他多能干细胞的受控体外分化为生成用于多种生物医学应用的大量人神经元提供了有趣的前景。与这种方法相关的主要瓶颈是hESC衍生的神经细胞产生成熟的神经元后代所需的时间很长。在发育中的脊椎动物神经系统中，Notch信号代表神经干细胞（NSC）维持的关键调节器。在这里，我们着手探讨是否可以利用此信号通路来调节hESC衍生的NSC（hESNSC）的分化。我们评估了hESNSCs中Notch通路成分的表达，并证明了Notch信号在自我更新的培养条件下是活跃的。 -分泌酶抑制剂N- [N-（3,5-二氟苯乙酰基）-L-丙氨酰] -S-苯基甘氨酸叔丁酯（DAPT）在hESNSC中抑制Notch活性影响Notch已知靶标的人类同源物的表达和几个细胞周期调节剂。此外，DAPT介导的Notch抑制作用会延迟G1 / S相转变，并使hESNSC参与神经发生。与生长因子戒断相结合，Notch信号的抑制导致明显的分化加速，从而缩短了产生电生理活性hESNSC衍生神经元所需的时间。此作用可用于神经细胞移植，在移植前短暂的Notch抑制足以促进宿主组织中hESNSCs神经元分化的开始。因此，对Notch信号传导的干扰提供了用于在体外和体内控制人类NSC分化的工具。干细胞2010; 28：955-964

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  • 来源
    《STEM CELLS》 |2010年第5期|955-964|共10页
  • 作者

    Lodovica Borghese; Dasa Dolezalova; Thoralf Opitz; Simone Haupt; Anke Leinhaas; Barbara Steinfarz; Philipp Koch; Frank Edenhofer; Ales Hampl; Oliver Brüstle;

  • 作者单位

    Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany;

    Biology Department, Faculty of Medicine, Masaryk University, Brno, Czech Republic|Department of Molecular Embryology, Institute of Experimental Medicine, ASCR, v.v.i., Prague, Czech Republic;

    Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany;

    Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany;

    Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany;

    Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany;

    Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany;

    Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany;

    Biology Department, Faculty of Medicine, Masaryk University, Brno, Czech Republic|Department of Molecular Embryology, Institute of Experimental Medicine, ASCR, v.v.i., Prague, Czech Republic;

    Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany;

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