Establishment of Immunodeficient Retinal Degeneration Model Mice and Functional Maturation of Human ESC-Derived Retinal Sheets after Transplantation

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  • Iraha, Satoshi
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN・Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University・Application Biology and Regenerative Medicine, Graduate School of Medicine, Kyoto University
  • Tu, Hung-Ya
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN
  • Yamasaki, Suguru
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN・Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd.
  • Kagawa, Takahiro
    Central Institute for Experimental Animals, Animal Resources and Technical Research Center
  • Goto, Motohito
    Central Institute for Experimental Animals, Animal Resources and Technical Research Center
  • Takahashi, Riichi
    Central Institute for Experimental Animals, Animal Resources and Technical Research Center
  • Watanabe, Takehito
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN
  • Sugita, Sunao
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN
  • Yonemura, Shigenobu
    Ultrastructural Research Team, RIKEN Center for Life Science Technologies.・Department of Cell Biology, Tokushima University Graduate School of Medical Science
  • Sunagawa, Genshiro A.
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN
  • Matsuyama, Take
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN
  • Fujii, Momo
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN
  • Kuwahara, Atsushi
    Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd.
  • Kishino, Akiyoshi
    Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd.
  • Koide, Naoshi
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN
  • Eiraku, Mototsugu
    Laboratory for in vitro Histogenesis, RIKEN Center for Developmental Biology
  • Tanihara, Hidenobu
    Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University
  • Takahashi, Masayo
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN・Application Biology and Regenerative Medicine, Graduate School of Medicine, Kyoto University
  • Mandai, Michiko
    Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN・RIKEN Program for Drug Discovery and Medical Technology Platforms (DMP)

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Increasing demand for clinical retinal degeneration therapies featuring human ESC/iPSC-derived retinal tissue and cells warrants proof-of-concept studies. Here, we established two mouse models of end-stage retinal degeneration with immunodeficiency, NOG-rd1-2J and NOG-rd10, and characterized disease progress and immunodeficient status. We also transplanted human ESC-derived retinal sheets into NOG-rd1-2J and confirmed their long-term survival and maturation of the structured graft photoreceptor layer, without rejection or tumorigenesis. We recorded light responses from the host ganglion cells using a multi-electrode array system; this result was consistent with whole-mount immunostaining suggestive of host-graft synapse formation at the responding sites. This study demonstrates an application of our mouse models and provides a proof of concept for the clinical use of human ESC-derived retinal sheets.

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