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

Satoshi Iraha; Hung-Ya Tu; Suguru Yamasaki; Takahiro Kagawa; Motohito Goto; Riichi Takahashi; Takehito Watanabe; Sunao Sugita; Shigenobu Yonemura; Genshiro A Sunagawa; Take Matsuyama; Momo Fujii; Atsushi Kuwahara; Akiyoshi Kishino; Naoshi Koide; Mototsugu Eiraku; Hidenobu Tanihara; Masayo Takahashi; Michiko Mandai

doi:10.1016/j.stemcr.2018.01.032

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

Stem Cell Reports. 2018 Mar 13;10(3):1059-1074. doi: 10.1016/j.stemcr.2018.01.032. Epub 2018 Mar 1.

Authors

Satoshi Iraha¹, Hung-Ya Tu², Suguru Yamasaki³, Takahiro Kagawa⁴, Motohito Goto⁴, Riichi Takahashi⁴, Takehito Watanabe², Sunao Sugita², Shigenobu Yonemura⁵, Genshiro A Sunagawa², Take Matsuyama², Momo Fujii², Atsushi Kuwahara⁶, Akiyoshi Kishino⁶, Naoshi Koide², Mototsugu Eiraku⁷, Hidenobu Tanihara⁸, Masayo Takahashi⁹, Michiko Mandai¹⁰

Affiliations

¹ Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, Kobe, Hyogo 650-0047, Japan; Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Application Biology and Regenerative Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
² Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, Kobe, Hyogo 650-0047, Japan.
³ Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, Kobe, Hyogo 650-0047, Japan; Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd., Kobe, Hyogo 650-0047, Japan.
⁴ Central Institute for Experimental Animals, Animal Resources and Technical Research Center, Kawasaki, Kanagawa 210-0821, Japan.
⁵ Ultrastructural Research Team, RIKEN Center for Life Science Technologies., Kobe, Hyogo 650-0047, Japan; Department of Cell Biology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan.
⁶ Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd., Kobe, Hyogo 650-0047, Japan.
⁷ Laboratory for in vitro Histogenesis, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan.
⁸ Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
⁹ Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, Kobe, Hyogo 650-0047, Japan; Application Biology and Regenerative Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
¹⁰ Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, Kobe, Hyogo 650-0047, Japan; RIKEN Program for Drug Discovery and Medical Technology Platforms (DMP), Kobe, Hyogo 650-0047, Japan. Electronic address: mmandai@cdb.riken.jp.

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.

Keywords: human ESC; multiple electrode array; photoreceptor transplantation; retinal degeneration; retinal regeneration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Embryonic Stem Cells / pathology*
Female
Humans
Induced Pluripotent Stem Cells / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Transgenic
Photoreceptor Cells / pathology
Retina / pathology*
Retinal Degeneration / pathology*
Stem Cell Transplantation / methods