Generation of Rx <sup>+</sup> /Pax6 <sup>+</sup> neural retinal precursors from embryonic stem cells

  • Hanako Ikeda
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Fumitaka Osakada
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Kiichi Watanabe
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Kenji Mizuseki
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Tomoko Haraguchi
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Hiroyuki Miyoshi
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Daisuke Kamiya
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Yoshihito Honda
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Noriaki Sasai
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Nagahisa Yoshimura
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Masayo Takahashi
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan
  • Yoshiki Sasai
    Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan; Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, and Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8507, Japan; and BioResource Center, RIKEN, Tsukuba 305-0074, Japan

抄録

<jats:p> We report directed differentiaion of retinal precursors <jats:italic>in vitro</jats:italic> from mouse ES cells. Six3 <jats:sup>+</jats:sup> rostral brain progenitors are generated by culturing ES cells under serum-free suspension conditions (SFEB culture) in the presence of Wnt and Nodal antagonists (Dkk1 and LeftyA), and subsequently steered to differentiate into Rx <jats:sup>+</jats:sup> cells (16%) by treatment with activin and serum. Consistent with the characteristics of early neural retinal precursors, the induced Rx <jats:sup>+</jats:sup> cells coexpress Pax6 and the mitotic marker Ki67, but not Nestin. The ES cell-derived precursors efficiently generate cells with the photoreceptor phenotype (rhodopsin <jats:sup>+</jats:sup> , recoverin <jats:sup>+</jats:sup> ) when cocultured with embryonic retinal cells. Furthermore, organotypic culture studies demonstrate the selective integration and survival of ES cell-derived cells with the photoreceptor phenotype (marker expression and morphology) in the outer nuclear layer of the retina. Taken together, ES cells treated with SFEB/Dkk1/LeftyA/serum/activin generate neural retinal precursors, which have the competence of photoreceptor differentiation. </jats:p>

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