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

IR
  • 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)

Abstract

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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