Prolonged Maturation Culture Favors a Reduction in the Tumorigenicity and the Dopaminergic Function of Human ESC-Derived Neural Cells in a Primate Model of Parkinson's Disease§

Authors

  • Daisuke Doi,

    1. Department of Biological Repair, Institute for Frontier Medical SciencesInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    2. Department of Cell Growth and Differentiation, Center for iPS Cell Research and ApplicationInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    3. Department of Neurosurgery, Clinical Neuroscience, Graduate School of Medicine,Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Asuka Morizane,

    1. Department of Biological Repair, Institute for Frontier Medical SciencesInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    2. Department of Cell Growth and Differentiation, Center for iPS Cell Research and ApplicationInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Tetsuhiro Kikuchi,

    1. Department of Biological Repair, Institute for Frontier Medical SciencesInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    2. Department of Neurosurgery, Clinical Neuroscience, Graduate School of Medicine,Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Hirotaka Onoe,

    1. Functional Probe Research Laboratory, RIKEN Center for Molecular Imaging Science, Kobe, Japan
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  • Takuya Hayashi,

    1. Department of Cell Growth and Differentiation, Center for iPS Cell Research and ApplicationInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    2. Functional Probe Research Laboratory, RIKEN Center for Molecular Imaging Science, Kobe, Japan
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  • Toshiyuki Kawasaki,

    1. Functional Probe Research Laboratory, RIKEN Center for Molecular Imaging Science, Kobe, Japan
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  • Makoto Motono,

    1. Department of Cell Growth and Differentiation, Center for iPS Cell Research and ApplicationInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Yoshiki Sasai,

    1. Organogenesis and Neurogenesis Group, RIKEN Center for Developmental Biology, Kobe, Japan
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  • Hidemoto Saiki,

    1. Department of Biological Repair, Institute for Frontier Medical SciencesInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Masanori Gomi,

    1. Department of Biological Repair, Institute for Frontier Medical SciencesInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    2. Department of Neurosurgery, Clinical Neuroscience, Graduate School of Medicine,Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Tatsuya Yoshikawa,

    1. Department of Biological Repair, Institute for Frontier Medical SciencesInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Hideki Hayashi,

    1. Department of Biological Repair, Institute for Frontier Medical SciencesInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    2. Department of Neurosurgery, Clinical Neuroscience, Graduate School of Medicine,Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Mizuya Shinoyama,

    1. Department of Biological Repair, Institute for Frontier Medical SciencesInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    2. Department of Neurosurgery, Clinical Neuroscience, Graduate School of Medicine,Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Mohamed M. Refaat,

    1. Department of Biological Repair, Institute for Frontier Medical SciencesInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    2. Department of Neurosurgery, Clinical Neuroscience, Graduate School of Medicine,Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Hirofumi Suemori,

    1. Laboratory of Embryonic Stem Cell Research, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Susumu Miyamoto,

    1. Department of Neurosurgery, Clinical Neuroscience, Graduate School of Medicine,Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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  • Jun Takahashi

    Corresponding author
    1. Department of Biological Repair, Institute for Frontier Medical SciencesInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    2. Department of Cell Growth and Differentiation, Center for iPS Cell Research and ApplicationInstitute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    3. Department of Neurosurgery, Clinical Neuroscience, Graduate School of Medicine,Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    • Department of Biological Repair, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
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    • Telephone: 81-75-751-4840; Fax: 81-75-751-4840


  • Author contributions: D.D. and A.M.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; T.K., H.O., T.H., and T.K.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; Y.S.: administrative support, data analysis and interpretation, and manuscript writing; M.M., H.S., M.G., T.Y., H.H., M.S., M.M.R., and H.S.: collection and/or assembly of data; S.M.: administrative support and data analysis and interpretation; J.T.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. D.D. and A.M. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS February 10, 2012; available online without subscription thorugh the open access option.

Abstract

For the safe clinical application of embryonic stem cells (ESCs) for neurological diseases, it is critical to evaluate the tumorigenicity and function of human ESC (hESC)-derived neural cells in primates. We have herein, for the first time, compared the growth and function of hESC-derived cells with different stages of neural differentiation implanted in the brains of primate models of Parkinson's disease. We herein show that residual undifferentiated cells expressing ESC markers present in the cell preparation can induce tumor formation in the monkey brain. In contrast, a cell preparation matured by 42-day culture with brain-derived neurotrophic factor/glial cell line-derived neurotrophic factor (BDNF/GDNF) treatment did not form tumors and survived as primarily dopaminergic (DA) neurons. In addition, the monkeys with such grafts showed behavioral improvement for at least 12 months. These results support the idea that hESCs, if appropriately matured, can serve as a source for DA neurons without forming any tumors in a primate brain. STEM CELLS 2012;30:935–945

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