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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors
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Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors

机译：小分子抑制剂对人胚胎干细胞中原始神经前体的快速诱导和长期自我更新

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摘要

Human embryonic stem cells (hESCs) hold enormous promise for regenerative medicine. Typically, hESC-based applications would require their in vitro differentiation into a desirable homogenous cell population. A major challenge of the current hESC differentiation paradigm is the inability to effectively capture and, in the long-term, stably expand primitive lineage-specific stem/precursor cells that retain broad differentiation potential and, more importantly, developmental stage-specific differentiation propensity. Here, we report synergistic inhibition of glycogen synthase kinase 3 (GSK3), transforming growth factor β (TGF-β), and Notch signaling pathways by small molecules can efficiently convert mono-layer cultured hESCs into homogenous primitive neuroepithelium within 1 wk under chemically defined condition. These primitive neuroepithelia can stably self-renew in the presence of leukemia inhibitory factor, GSK3 inhibitor (CHIR99021), and TGF-p receptor inhibitor (SB431542); retain high neurogenic potential and responsiveness to instructive neural patterning cues toward midbrain and hindbrain neuronal subtypes; and exhibit in vivo integration. Our work uniformly captures and maintains primitive neural stem cells from hESCs.
机译：人类胚胎干细胞（hESCs）对于再生医学具有广阔的前景。通常，基于hESC的应用需要体外分化为所需的同质细胞群。当前hESC分化范例的主要挑战是无法有效捕获并长期稳定扩展原始谱系特异性干细胞/前体细胞，这些细胞保留了广泛的分化潜能，更重要的是发育阶段特异性分化倾向。在这里，我们报告糖原合酶激酶3（GSK3），转化生长因子β（TGF-β）和Notch信号通路的协同抑制作用由小分子可以有效地将单层培养的hESCs在化学定义的1 wk内转化为均质的原始神经上皮健康）状况。在白血病抑制因子，GSK3抑制剂（CHIR99021）和TGF-p受体抑制剂（SB431542）存在的情况下，这些原始神经上皮细胞可以稳定地自我更新。保留对中脑和后脑神经元亚型具有指导意义的神经形态线索的高神经源性潜力和响应能力；并表现出体内整合。我们的工作从hESC统一捕获和维护原始神经干细胞。

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    Wenlin Li; Woong Sun; Yu Zhang; Wanguo Wei; Rajesh Ambasudhan; Peng Xia; Maria Talantova; Tongxiang Lin; Janghwan Kim; Xiaolei Wang; Woon Ryoung Kim; Stuart A. Lipton; Kang Zhang; Sheng Ding;

  • 作者单位

    Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037,Department of Cell Biology, Second Military Medical University, Shanghai 200433, China;

    Institute for Genomic Medicine and Shiley Eye Center, University of California, San Diego, CA 92093,Department of Anatomy, Korea University College of Medicine, Brain Korea 21 Program, Seoul, 136-705, Korea;

    Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;

    Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research,Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research,Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;

    Institute for Genomic Medicine and Shiley Eye Center, University of California, San Diego, CA 92093;

    Department of Anatomy, Korea University College of Medicine, Brain Korea 21 Program, Seoul, 136-705, Korea;

    Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research,Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Institute for Genomic Medicine and Shiley Eye Center, University of California, San Diego, CA 92093,Molecular Medicine Research Center and Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610065, China;

    Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037,Gladstone Institute of Cardiovascular Disease, Department of Pharmaceutical Chemistry,University of California, San Francisco, CA 94158;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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