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      Characterization of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cell Sheets Aiming for Clinical Application

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          Summary

          Age-related macular degeneration (AMD) causes severe visual impairment due in part to age-dependent impairment of retinal pigment epithelium (RPE). It has been suggested that autologous human induced pluripotent stem cells (hiPSCs) may represent a useful cell source for the generation of graft RPE. We generated hiPSC-derived RPE (hiPSC-RPE) cell sheets optimized to meet clinical use requirements, including quality, quantity, consistency, and safety. These cell sheets are generated as a monolayer of cells without any artificial scaffolds, express typical RPE markers, form tight junctions that exhibit polarized secretion of growth factors, and show phagocytotic ability and gene-expression patterns similar to those of native RPE. Additionally, upon transplantation, autologous nonhuman primate iPSC-RPE cell sheets showed no immune rejection or tumor formation. These results suggest that autologous hiPSC-RPE cell sheets may serve as a useful form of graft for use in tissue replacement therapy for AMD.

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          Highlights

          • •

            hiPSC-RPE cell sheets show characteristics similar to those of native RPE

          • •

            A hiPSC-RPE sheet is sufficient to transplant a patient

          • •

            All hiPSC-RPEs show gene-expression patterns similar to native RPE

          • •

            Autologous nonhuman primate iPSC-RPE cell sheets show no rejection or tumor

          Abstract

          Age-related macular degeneration is a leading cause of blindness in the elderly worldwide. As a potential treatment for this disease, Takahashi and colleagues generated hiPSC-RPE cell sheets optimized to meet clinical use requirements, including quality, quantity, consistency, and safety. hiPSC-RPE cell sheets may serve as a useful form of graft for use in tissue replacement therapy for age-related macular degeneration.

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          Most cited references29

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          Embryonic stem cell trials for macular degeneration: a preliminary report.

          Steven D Schwartz, Jean-Pierre Hubschman, Gad Heilwell … (2012)
          It has been 13 years since the discovery of human embryonic stem cells (hESCs). Our report provides the first description of hESC-derived cells transplanted into human patients. We started two prospective clinical studies to establish the safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium (RPE) in patients with Stargardt's macular dystrophy and dry age-related macular degeneration--the leading cause of blindness in the developed world. Preoperative and postoperative ophthalmic examinations included visual acuity, fluorescein angiography, optical coherence tomography, and visual field testing. These studies are registered with ClinicalTrials.gov, numbers NCT01345006 and NCT01344993. Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt's macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28). The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. The future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue. Advanced Cell Technology. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia

            D. Goodenough, R Stevenson, J Siliciano (1986)
            A tight junction-enriched membrane fraction has been used as immunogen to generate a monoclonal antiserum specific for this intercellular junction. Hybridomas were screened for their ability to both react on an immunoblot and localize to the junctional complex region on frozen sections of unfixed mouse liver. A stable hybridoma line has been isolated that secretes an antibody (R26.4C) that localizes in thin section images of isolated mouse liver plasma membranes to the points of membrane contact at the tight junction. This antibody recognizes a polypeptide of approximately 225,000 D, detectable in whole liver homogenates as well as in the tight junction-enriched membrane fraction. R26.4C localizes to the junctional complex region of a number of other epithelia, including colon, kidney, and testis, and to arterial endothelium, as assayed by immunofluorescent staining of cryostat sections of whole tissue. This antibody also stains the junctional complex region in confluent monolayers of the Madin-Darby canine kidney epithelial cell line. Immunoblot analysis of Madin-Darby canine kidney cells demonstrates the presence of a polypeptide similar in molecular weight to that detected in liver, suggesting that this protein is potentially a ubiquitous component of all mammalian tight junctions. The 225-kD tight junction-associated polypeptide is termed "ZO-1."
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              Directed differentiation of telencephalic precursors from embryonic stem cells.

              Kiichi Watanabe, Daisuke Kamiya, Ayaka Nishiyama … (2005)
              We demonstrate directed differentiation of telencephalic precursors from mouse embryonic stem (ES) cells using optimized serum-free suspension culture (SFEB culture). Treatment with Wnt and Nodal antagonists (Dkk1 and LeftyA) during the first 5 d of SFEB culture causes nearly selective neural differentiation in ES cells ( approximately 90%). In the presence of Dkk1, with or without LeftyA, SFEB induces efficient generation ( approximately 35%) of cells expressing telencephalic marker Bf1. Wnt3a treatment during the late culture period increases the pallial telencephalic population (Pax6(+) cells yield up to 75% of Bf1(+) cells), whereas Shh promotes basal telencephalic differentiation (into Nkx2.1(+) and/or Islet1/2(+) cells) at the cost of pallial telencephalic differentiation. Thus, in the absence of caudalizing signals, floating aggregates of ES cells generate naive telencephalic precursors that acquire subregional identities by responding to extracellular patterning signals.
              Article 0 comments Cited 220 times – based on 0 reviews     Review now
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                Author and article information

                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: 23 January 2014
                Publication date (Electronic): 23 January 2014
                Publication date Collection: 11 February 2014
                Volume: 2
                Issue: 2
                Pages: 205-218
                Affiliations
                [1 ]Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan
                [2 ]Department of Ophthalmology, Kawasaki Medical School, Kurashiki, Okayama 701-0114, Japan
                Author notes
                [∗ ]Corresponding author mretina@ 123456cdb.riken.jp
                Article
                Publisher ID: S2213-6711(13)00175-6
                DOI: 10.1016/j.stemcr.2013.12.007
                PMC ID: 3923225
                PubMed ID: 24527394
                SO-VID: 891ed72b-deee-4e14-964b-27c16aae830e
                Copyright © © 2014 The Authors
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 6 September 2013
                Date revision received : 11 December 2013
                Date accepted : 11 December 2013
                Categories
                Subject: Article

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