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Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):E81-90. doi: 10.1073/pnas.1512590113. Epub 2015 Dec 22.

Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration.

Author information

1
Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8550, Aichi, Japan;
2
Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan; mmandai@cdb.riken.jp.
3
Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan; Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd., Chuo, Kobe 650-0047, Japan;
4
Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd., Chuo, Kobe 650-0047, Japan; Neurogenesis and Organogenesis Group, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Konohana, Osaka 554-8558, Japan;
5
Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan;
6
Neurogenesis and Organogenesis Group, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Konohana, Osaka 554-8558, Japan;
7
Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan;
8
Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd., Chuo, Kobe 650-0047, Japan;
9
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Konohana, Osaka 554-8558, Japan;
10
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8550, Aichi, Japan;
11
Laboratory for in Vitro Histogenesis, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan.
12
Neurogenesis and Organogenesis Group, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan;

Abstract

Retinal transplantation therapy for retinitis pigmentosa is increasingly of interest due to accumulating evidence of transplantation efficacy from animal studies and development of techniques for the differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells into retinal tissues or cells. In this study, we aimed to assess the potential clinical utility of hESC-derived retinal tissues (hESC-retina) using newly developed primate models of retinal degeneration to obtain preparatory information regarding the potential clinical utility of these hESC-retinas in transplantation therapy. hESC-retinas were first transplanted subretinally into nude rats with or without retinal degeneration to confirm their competency as a graft to mature to form highly specified outer segment structure and to integrate after transplantation. Two focal selective photoreceptor degeneration models were then developed in monkeys by subretinal injection of cobalt chloride or 577-nm optically pumped semiconductor laser photocoagulation. The utility of the developed models and a practicality of visual acuity test developed for monkeys were evaluated. Finally, feasibility of hESC-retina transplantation was assessed in the developed monkey models under practical surgical procedure and postoperational examinations. Grafted hESC-retina was observed differentiating into a range of retinal cell types, including rod and cone photoreceptors that developed structured outer nuclear layers after transplantation. Further, immunohistochemical analyses suggested the formation of host-graft synaptic connections. The findings of this study demonstrate the clinical feasibility of hESC-retina transplantation and provide the practical tools for the optimization of transplantation strategies for future clinical applications.

KEYWORDS:

human embryonic stem cells; photoreceptors; primate model; retinal degeneration; transplantation

PMID:
26699487
PMCID:
PMC4711854
DOI:
10.1073/pnas.1512590113
[Indexed for MEDLINE]
Free PMC Article

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