title: Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration.
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.
authors.affiliation: 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;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shirai
authors.affiliation: Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan; mmandai@cdb.riken.jp.
authors.forename: Michiko
authors.initials: M
authors.lastname: Mandai
authors.affiliation: 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;
authors.forename: Keizo
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: 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;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuwahara
authors.affiliation: Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan;
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Yonemura
authors.affiliation: 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;
authors.forename: Tokushige
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan;
authors.forename: Juthaporn
authors.initials: J
authors.lastname: Assawachananont
authors.affiliation: Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd., Chuo, Kobe 650-0047, Japan;
authors.forename: Toru
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Konohana, Osaka 554-8558, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8550, Aichi, Japan;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Terasaki
authors.affiliation: Laboratory for in Vitro Histogenesis, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Eiraku
authors.affiliation: Neurogenesis and Organogenesis Group, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan;
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sasai
authors.affiliation: Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Chuo, Kobe 650-0047, Japan;
authors.forename: Masayo
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003035:Cobalt / Q000633:toxicity; D004195:Disease Models, Animal; D000882:Haplorhini; D000066449:Human Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D010786:Photoreceptor Cells / Q000473:pathology; D011323:Primates; D051381:Rats; D012160:Retina / Q000166:cytology* / Q000637:transplantation*; D012162:Retinal Degeneration / Q000139:chemically induced / Q000473:pathology / Q000601:surgery*
chemical_list: D003035:Cobalt; C018021:cobaltous chloride
keywords: human embryonic stem cells; photoreceptors; primate model; retinal degeneration; transplantation