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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Self-renewal induced efficiently, safely, and effective therapeutically with one regulatable gene in a human somatic progenitor cell
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Self-renewal induced efficiently, safely, and effective therapeutically with one regulatable gene in a human somatic progenitor cell

机译：用一种可调节基因在人体祖细胞中有效，安全和有效地诱导自我更新

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摘要

In the field of induced potency and fate reprogramming, it remains unclear what the best starting cell might be and to what extent a cell need be transported back to a more primitive state for translational purposes. Reprogramming a committed cell back to pluripotence to then instruct it toward a particular specialized cell type is demanding and may increase risks of neoplasia and undesired cell types. Precursor/progenitor cells from the organ of therapeutic concern typically lack only one critical attribute-the capacity for sustained self-renewal. We speculated that this could be induced in a regulatable manner such that cells proliferate only in vitro and differentiate in vivo without the need for promoting pluripotence or specifying lineage identity. As proof-of-concept, we generated and tested the efficiency, safety, engraftability, and therapeutic utility of "induced conditional self-renewing progenitor (ICSP) cells" derived from the human central nervous system (CNS); we conditionally induced self-renewal efficiently within neural progenitors solely by introducing v-myc tightly regulated by a tetracy-cline (Tet)-on gene expression system. Tet in the culture medium activated myctranscription and translation, allowing efficient expansion of homogeneous, clonal, karyotypically normal human CNS precursors ex vivo; in vivo, where Tet was absent myc was not expressed, and self-renewal was entirely inactivated (as was tumorigenic potential). Cell proliferation ceased, and differentiation into electrophysiologically active neurons and other CNS cell types in vivo ensued upon transplantation into rats, both during development and after adult injury-with functional improvement and without neoplasia, overgrowth, deformation, emergence of non-neural cell types, phenotypic or genomic instability, or need for immunosup-pression. This strategy of inducing self-renewal might be applied to progenitors from other organs and may prove to be a safe, effective, efficient, and practical method for optimizing insights gained from the ability to reprogram cells.
机译：在诱导效力和命运重编程领域中，尚不清楚最佳起始细胞可能是什么，以及为了翻译目的将细胞转移到更原始状态的程度。将已定型的细胞重编程为多能性，然后指示其朝特定的特殊细胞类型发展，可能会增加瘤形成和不良细胞类型的风险。来自治疗关注器官的前体/祖细胞通常仅缺乏一个关键属性-持续自我更新的能力。我们推测这可以以可调节的方式诱导，使得细胞仅在体外增殖并在体内分化，而无需促进多能性或指定谱系同一性。作为概念验证，我们产生并测试了源自人中枢神经系统（CNS）的“诱导型条件性自我更新祖细胞（ICSP）”的效率，安全性，可移植性和治疗用途；我们仅通过引入由四环素（Tet）-on基因表达系统严格调控的v-myc，有条件地在神经祖细胞中有效地诱导自我更新。培养基中的Tet激活了myctranscription和翻译，从而允许离体的同质，克隆，核型正常人CNS前体的有效扩增；在体内，不存在Tet的myc不会表达，自我更新完全失活（致瘤潜力也是如此）。在发育过程中和成年后损伤后，细胞增殖停止，并在体内分化为电生理活性神经元和其他中枢神经系统细胞类型-功能有所改善，而没有瘤形成，过度生长，变形，非神经细胞类型的出现，表型或基因组不稳定，或需要免疫抑制。这种诱导自我更新的策略可能会应用于其他器官的祖细胞，并且可能被证明是一种安全，有效，高效且实用的方法，可以优化从重新编程细胞的能力中获得的见解。

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  • 作者

    Kwang S. Kim; Hong J. Lee; Han S. Jeong; Jianxue Li; Yang D. Teng; Richard L. Sidman; Evan Y. Snyder; Seung U. Kim;

  • 作者单位

    Medical Research Institute, Chung-Ang University College of Medicine, 440-746 Seoul, Korea,Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 2B5;

    Medical Research Institute, Chung-Ang University College of Medicine, 440-746 Seoul, Korea,Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 2B5;

    Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 2B5,Department of Physiology, Chonnam National University Medical School, 500-757 Gwangju, Korea;

    Department of Neurology, Beth Israel Beaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Department of Neurology, Beth Israel Beaconess Medical Center, Harvard Medical School, Boston, MA 02215;

    Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Medical Research Institute, Chung-Ang University College of Medicine, 440-746 Seoul, Korea,Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 2B5;

  • 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);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    stem cells; stroke; multipotence; hemorrhage;

    机译：干细胞中风多能性出血;

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