A Genetic modification that reduces ON-bipolar cells in hESC-derived retinas enhances functional integration after transplantation
Suguru Yamasaki,
Hung-Ya Tu,
Take Matsuyama,
Matsuri Horiuchi,
Tomoyo Hashiguchi,
Junki Sho,
Atsushi Kuwahara,
Akiyoshi Kishino,
Toru Kimura,
Masayo Takahashi,
Michiko Mandai
Affiliations
Suguru Yamasaki
Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; Regenerative & Cellular Medicine Kobe Center, Sumitomo Dainippon Pharma Co., Ltd., Kobe 650-0047, Japan
Hung-Ya Tu
Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan
Take Matsuyama
Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan
Matsuri Horiuchi
Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; Regenerative & Cellular Medicine Kobe Center, Sumitomo Dainippon Pharma Co., Ltd., Kobe 650-0047, Japan
Tomoyo Hashiguchi
Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
Junki Sho
Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
Atsushi Kuwahara
Regenerative & Cellular Medicine Kobe Center, Sumitomo Dainippon Pharma Co., Ltd., Kobe 650-0047, Japan
Akiyoshi Kishino
Regenerative & Cellular Medicine Kobe Center, Sumitomo Dainippon Pharma Co., Ltd., Kobe 650-0047, Japan
Toru Kimura
Regenerative & Cellular Medicine Kobe Center, Sumitomo Dainippon Pharma Co., Ltd., Kobe 650-0047, Japan
Masayo Takahashi
Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
Michiko Mandai
Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; RIKEN Program for Drug Discovery and Medical Technology Platforms (DMP), RIKEN Cluster for Science, Technology and Innovation Hub., Saitama, 351-0198, Japan; Corresponding author
Summary: Pluripotent stem cell (PSC)-derived retinal sheet transplanted in vivo can form structured photoreceptor layers, contact with host bipolar cells, and transmit light signals to host retinas. However, a major concern is the presence of graft bipolar cells that may impede host-graft interaction. In this study, we used human ESC-retinas with the deletion of Islet-1 (ISL1) gene to achieve the reduced graft ON-bipolar cells after xenotransplantation into end-stage retinal degeneration model rats. Compared with wild-type graft, ISL1−/− hESC-retinas showed better host-graft contact, with indication of host-graft synapse formation and significant restoration of light responsiveness in host ganglion cells. We further analyzed to find out that improved functional integration of ISL1−/− hESC-retinas seemed attributed by a better host-graft contact and a better preservation of host inner retina. ISL1−/− hESC-retinas are promising for the efficient reconstruction of a degenerated retinal network in future clinical application.
