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

doi:10.1016/j.isci.2021.103657

A Genetic modification that reduces ON-bipolar cells in hESC-derived retinas enhances functional integration after transplantation

iScience. 2021 Dec 20;25(1):103657. doi: 10.1016/j.isci.2021.103657. eCollection 2022 Jan 21.

Authors

Suguru Yamasaki^{1

2}, Hung-Ya Tu^{1

3}, Take Matsuyama^{1

4}, Matsuri Horiuchi^{1

2}, Tomoyo Hashiguchi¹, Junki Sho¹, Atsushi Kuwahara², Akiyoshi Kishino², Toru Kimura², Masayo Takahashi¹, Michiko Mandai^{1

4

5}

Affiliations

¹ Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan.
² Regenerative & Cellular Medicine Kobe Center, Sumitomo Dainippon Pharma Co., Ltd., Kobe 650-0047, Japan.
³ Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
⁴ Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan.
⁵ RIKEN Program for Drug Discovery and Medical Technology Platforms (DMP), RIKEN Cluster for Science, Technology and Innovation Hub., Saitama, 351-0198, Japan.

Abstract

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.

Keywords: Health sciences; Human; Medicine; Stem cells research.