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

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

Author information

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

PMID:
29503091
PMCID:
PMC5918611
DOI:
10.1016/j.stemcr.2018.01.032
[Indexed for MEDLINE]
Free PMC Article

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