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      Transplantation of Embryonic and Induced Pluripotent Stem Cell-Derived 3D Retinal Sheets into Retinal Degenerative Mice

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          Summary

          In this article, we show that mouse embryonic stem cell- or induced pluripotent stem cell-derived 3D retinal tissue developed a structured outer nuclear layer (ONL) with complete inner and outer segments even in an advanced retinal degeneration model (rd1) that lacked ONL. We also observed host-graft synaptic connections by immunohistochemistry. This study provides a “proof of concept” for retinal sheet transplantation therapy for advanced retinal degenerative diseases.

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          Highlights

          • •

            3D retina was formed from ESCs/iPSCs using retinoic acid receptor antagonist

          • •

            ESC/iPSC retina developed a structured layer of photoreceptors in rd1 host mice

          • •

            Transplanted photoreceptors formed complete inner and outer segments

          • •

            Transplanted photoreceptors morphologically made synapses with host bipolar cells

          Abstract

          In this article, Mandai and colleagues show that mouse embryonic stem cell- or induced pluripotent stem cell-derived 3D retinal tissue developed a structured outer nuclear layer (ONL) with complete inner and outer segments even in an advanced retinal degeneration model (rd1) that lacked ONL. They also observed host-graft synaptic connections by immunohistochemistry. This study provides a “proof of concept” for retinal sheet transplantation therapy for advanced retinal degenerative diseases.

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          Most cited references26

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          Modeling early retinal development with human embryonic and induced pluripotent stem cells.

          Jason S. Meyer, Rebecca L Shearer, Elizabeth Capowski … (2009)
          Human pluripotent stem cells have the potential to provide comprehensive model systems for the earliest stages of human ontogenesis. To serve in this capacity, these cells must undergo a targeted, stepwise differentiation process that follows a normal developmental timeline. Here we demonstrate the ability of both human embryonic stem cells (hESCs) and induced pluripotent stem (iPS) cells to meet these requirements for human retinogenesis. Upon differentiation, hESCs initially yielded a highly enriched population of early eye field cells. Thereafter, a subset of cells acquired features of advancing retinal differentiation in a sequence and time course that mimicked in vivo human retinal development. Application of this culture method to a human iPS cell line also generated retina-specific cell types at comparable times in vitro. Lastly, altering endogenous signaling during differentiation affected lineage-specific gene expression in a manner consistent with established mechanisms of early neural and retinal cell fate determination. These findings should aid in the investigation of the molecular events governing retinal specification from human pluripotent stem cells.
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            Interim results from the international trial of Second Sight's visual prosthesis.

            Mark S Humayun, Jessy Dorn, Lyndon da Cruz … (2012)
            This study evaluated the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA) in blind subjects with severe outer retinal degeneration. Single-arm, prospective, multicenter clinical trial. Thirty subjects were enrolled in the United States and Europe between June 6, 2007, and August 11, 2009. All subjects were followed up for a minimum of 6 months and up to 2.7 years. The electronic stimulator and antenna of the implant were sutured onto the sclera using an encircling silicone band. Next, a pars plana vitrectomy was performed, and the electrode array and cable were introduced into the eye via a pars plana sclerotomy. The microelectrode array then was tacked to the epiretinal surface. The primary safety end points for the trial were the number, severity, and relation of adverse events. Principal performance end points were assessments of visual function as well as performance on orientation and mobility tasks. Subjects performed statistically better with the system on versus off in the following tasks: object localization (96% of subjects), motion discrimination (57%), and discrimination of oriented gratings (23%). The best recorded visual acuity to date is 20/1260. Subjects' mean performance on orientation and mobility tasks was significantly better when the system was on versus off. Seventy percent of the patients did not have any serious adverse events (SAEs). The most common SAE reported was either conjunctival erosion or dehiscence over the extraocular implant and was treated successfully in all subjects except in one, who required explantation of the device without further complications. The long-term safety results of Second Sight's retinal prosthesis system are acceptable, and most subjects with profound visual loss perform better on visual tasks with system than without it. Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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              Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice.

              Deepak Lamba, Juliane Gust, Thomas Reh (2009)
              Some of the most common causes of blindness involve the degeneration of photoreceptors in the neural retina; photoreceptor replacement therapy might restore some vision in these individuals. Embryonic stem cells (ESCs) could, in principle, provide a source of photoreceptors to repair the retina. We have previously shown that retinal progenitors can be efficiently derived from human ESCs. We now show that retinal cells derived from human ESCs will migrate into mouse retinas following intraocular injection, settle into the appropriate layers, and express markers for differentiated cells, including both rod and cone photoreceptor cells. After transplantation of the cells into the subretinal space of adult Crx(-/-) mice (a model of Leber's Congenital Amaurosis), the hESC-derived retinal cells differentiate into functional photoreceptors and restore light responses to the animals. These results demonstrate that hESCs can, in principle, be used for photoreceptor replacement therapies.
              Article 0 comments Cited 163 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Michiko Mandai
                Journal
                Journal ID (nlm-ta): Stem Cell Reports
                Journal ID (iso-abbrev): Stem Cell Reports
                Title: Stem Cell Reports
                Publisher: Elsevier
                ISSN (Electronic): 2213-6711
                Publication date PMC-release: 24 April 2014
                Publication date (Electronic): 24 April 2014
                Publication date Collection: 06 May 2014
                Volume: 2
                Issue: 5
                Pages: 662-674
                Affiliations
                [1 ]Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan
                [2 ]Organogenesis and Neurogenesis Group, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan
                [3 ]Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan
                [4 ]Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
                [5 ]Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
                Author notes
                [∗ ]Corresponding author mmandai@ 123456cdb.riken.jp
                Article
                Publisher ID: S2213-6711(14)00090-3
                DOI: 10.1016/j.stemcr.2014.03.011
                PMC ID: 4050483
                PubMed ID: 24936453
                SO-VID: 92fa088a-9417-4e80-94a1-f48d2eda0b5f
                Copyright © © 2014 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                Date received : 20 November 2013
                Date revision received : 27 March 2014
                Date accepted : 27 March 2014
                Categories
                Subject: Article

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