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1
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Ozaki A, Sakai D, Mandai M. hPSC-based treatment of retinal diseases - Current progress and challenges. Adv Drug Deliv Rev 2025; 221:115587. [PMID: 40228605 DOI: 10.1016/j.addr.2025.115587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 03/26/2025] [Accepted: 04/11/2025] [Indexed: 04/16/2025]
Abstract
Degenerative retinal diseases, such as age-related macular degeneration (AMD) and inherited retinal diseases (IRDs), cause visual impairment due to irreversible damage to the retinal pigment epithelium (RPE) and photoreceptor cells (PRCs). Currently, no definitive treatment exists. However, cell-based therapies using induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs) offer potential solutions for restoring damaged retinal cells. This review summarizes recent advances in RPE and PRC transplantation, highlighting the benefits of each approach. For RPE transplantation, we focus on the outcomes of clinical studies involving three formulations: RPE sheets, RPE suspensions, and RPE strips. In the context of PRC transplantation, we trace the progress from fetal retinal transplantation to the latest studies. Additionally, we discuss our recent clinical work with retinal sheet transplantation and genome-edited retinal organoid sheets, which aim to improve functional integration by reducing bipolar cells in grafts. Finally, with the overall safety of the regenerative cell-based therapies demonstrated in past clinical applications, we explore future prospects for these therapies.
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Affiliation(s)
- Atsuta Ozaki
- Research Center, Kobe City Eye Hospital, 2-1-8 Minatojima Minaminachi, Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan; Department of Ophthalmology, Mie University Graduate school of Medicine, 2-174 Edobashi, Tsu-shi, Mie 514-8507, Japan
| | - Daiki Sakai
- Research Center, Kobe City Eye Hospital, 2-1-8 Minatojima Minaminachi, Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan; Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe, Japan, 2-1-1 Minatojima Minaminachi, Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan; Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki, Chuo-ku, Kobe-shi, Hyogo 650-0017 Japan
| | - Michiko Mandai
- Research Center, Kobe City Eye Hospital, 2-1-8 Minatojima Minaminachi, Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan; Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe, Japan, 2-1-1 Minatojima Minaminachi, Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan.
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2
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Beaver D, Limnios IJ. A treatment within sight: challenges in the development of stem cell-derived photoreceptor therapies for retinal degenerative diseases. FRONTIERS IN TRANSPLANTATION 2023; 2:1130086. [PMID: 38993872 PMCID: PMC11235385 DOI: 10.3389/frtra.2023.1130086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 09/07/2023] [Indexed: 07/13/2024]
Abstract
Stem cell therapies can potentially treat various retinal degenerative diseases, including age-related macular degeneration (AMD) and inherited retinal diseases like retinitis pigmentosa. For these diseases, transplanted cells may include stem cell-derived retinal pigmented epithelial (RPE) cells, photoreceptors, or a combination of both. Although stem cell-derived RPE cells have progressed to human clinical trials, therapies using photoreceptors and other retinal cell types are lagging. In this review, we discuss the potential use of human pluripotent stem cell (hPSC)-derived photoreceptors for the treatment of retinal degeneration and highlight the progress and challenges for their efficient production and clinical application in regenerative medicine.
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Affiliation(s)
- Davinia Beaver
- Clem Jones Centre for Regenerative Medicine, Bond University, Gold Coast, QL, Australia
| | - Ioannis Jason Limnios
- Clem Jones Centre for Regenerative Medicine, Bond University, Gold Coast, QL, Australia
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3
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Karamali F, Behtaj S, Babaei-Abraki S, Hadady H, Atefi A, Savoj S, Soroushzadeh S, Najafian S, Nasr Esfahani MH, Klassen H. Potential therapeutic strategies for photoreceptor degeneration: the path to restore vision. J Transl Med 2022; 20:572. [PMID: 36476500 PMCID: PMC9727916 DOI: 10.1186/s12967-022-03738-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/29/2022] [Indexed: 12/12/2022] Open
Abstract
Photoreceptors (PRs), as the most abundant and light-sensing cells of the neuroretina, are responsible for converting light into electrical signals that can be interpreted by the brain. PR degeneration, including morphological and functional impairment of these cells, causes significant diminution of the retina's ability to detect light, with consequent loss of vision. Recent findings in ocular regenerative medicine have opened promising avenues to apply neuroprotective therapy, gene therapy, cell replacement therapy, and visual prostheses to the challenge of restoring vision. However, successful visual restoration in the clinical setting requires application of these therapeutic approaches at the appropriate stage of the retinal degeneration. In this review, firstly, we discuss the mechanisms of PR degeneration by focusing on the molecular mechanisms underlying cell death. Subsequently, innovations, recent developments, and promising treatments based on the stage of disorder progression are further explored. Then, the challenges to be addressed before implementation of these therapies in clinical practice are considered. Finally, potential solutions to overcome the current limitations of this growing research area are suggested. Overall, the majority of current treatment modalities are still at an early stage of development and require extensive additional studies, both pre-clinical and clinical, before full restoration of visual function in PR degeneration diseases can be realized.
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Affiliation(s)
- Fereshteh Karamali
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Sanaz Behtaj
- grid.1022.10000 0004 0437 5432Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Queensland, Australia ,grid.1022.10000 0004 0437 5432Menzies Health Institute Queensland, Griffith University, Southport, QLD 4222 Australia
| | - Shahnaz Babaei-Abraki
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Hanieh Hadady
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Atefeh Atefi
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Soraya Savoj
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Sareh Soroushzadeh
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Samaneh Najafian
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Mohammad Hossein Nasr Esfahani
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Henry Klassen
- grid.266093.80000 0001 0668 7243Gavin Herbert Eye Institute, Irvine, CA USA
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4
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Arthur P, Muok L, Nathani A, Zeng EZ, Sun L, Li Y, Singh M. Bioengineering Human Pluripotent Stem Cell-Derived Retinal Organoids and Optic Vesicle-Containing Brain Organoids for Ocular Diseases. Cells 2022; 11:3429. [PMID: 36359825 PMCID: PMC9653705 DOI: 10.3390/cells11213429] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/13/2022] [Accepted: 10/23/2022] [Indexed: 08/24/2023] Open
Abstract
Retinal organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that mimic the retina's spatial and temporal differentiation, making them useful as in vitro retinal development models. Retinal organoids can be assembled with brain organoids, the 3D self-assembled aggregates derived from hPSCs containing different cell types and cytoarchitectures that resemble the human embryonic brain. Recent studies have shown the development of optic cups in brain organoids. The cellular components of a developing optic vesicle-containing organoids include primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. The importance of retinal organoids in ocular diseases such as age-related macular degeneration, Stargardt disease, retinitis pigmentosa, and diabetic retinopathy are described in this review. This review highlights current developments in retinal organoid techniques, and their applications in ocular conditions such as disease modeling, gene therapy, drug screening and development. In addition, recent advancements in utilizing extracellular vesicles secreted by retinal organoids for ocular disease treatments are summarized.
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Affiliation(s)
- Peggy Arthur
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Laureana Muok
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32306, USA
| | - Aakash Nathani
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Eric Z. Zeng
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32306, USA
| | - Li Sun
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32306, USA
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
| | - Yan Li
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL 32306, USA
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
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5
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German OL, Vallese-Maurizi H, Soto TB, Rotstein NP, Politi LE. Retina stem cells, hopes and obstacles. World J Stem Cells 2021; 13:1446-1479. [PMID: 34786153 PMCID: PMC8567457 DOI: 10.4252/wjsc.v13.i10.1446] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/14/2021] [Accepted: 09/17/2021] [Indexed: 02/07/2023] Open
Abstract
Retinal degeneration is a major contributor to visual dysfunction worldwide. Although it comprises several eye diseases, loss of retinal pigment epithelial (RPE) and photoreceptor cells are the major contributors to their pathogenesis. Early therapies included diverse treatments, such as provision of anti-vascular endothelial growth factor and many survival and trophic factors that, in some cases, slow down the progression of the degeneration, but do not effectively prevent it. The finding of stem cells (SC) in the eye has led to the proposal of cell replacement strategies for retina degeneration. Therapies using different types of SC, such as retinal progenitor cells (RPCs), embryonic SC, pluripotent SCs (PSCs), induced PSCs (iPSCs), and mesenchymal stromal cells, capable of self-renewal and of differentiating into multiple cell types, have gained ample support. Numerous preclinical studies have assessed transplantation of SC in animal models, with encouraging results. The aim of this work is to revise the different preclinical and clinical approaches, analyzing the SC type used, their efficacy, safety, cell attachment and integration, absence of tumor formation and immunorejection, in order to establish which were the most relevant and successful. In addition, we examine the questions and concerns still open in the field. The data demonstrate the existence of two main approaches, aimed at replacing either RPE cells or photoreceptors. Emerging evidence suggests that RPCs and iPSC are the best candidates, presenting no ethical concerns and a low risk of immunorejection. Clinical trials have already supported the safety and efficacy of SC treatments. Serious concerns are pending, such as the risk of tumor formation, lack of attachment or integration of transplanted cells into host retinas, immunorejection, cell death, and also ethical. However, the amazing progress in the field in the last few years makes it possible to envisage safe and effective treatments to restore vision loss in a near future.
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Affiliation(s)
- Olga L German
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Harmonie Vallese-Maurizi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Tamara B Soto
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Nora P Rotstein
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Luis Enrique Politi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
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6
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Uyama H, Mandai M, Takahashi M. Stem-cell-based therapies for retinal degenerative diseases: Current challenges in the establishment of new treatment strategies. Dev Growth Differ 2021; 63:59-71. [PMID: 33315237 PMCID: PMC7986097 DOI: 10.1111/dgd.12704] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/13/2020] [Accepted: 12/04/2020] [Indexed: 12/17/2022]
Abstract
Various advances have been made in the treatment of retinal diseases, including new treatment strategies and innovations in surgical devices. However, the treatment of degenerative retinal diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), continues to pose a significant challenge. In this review, we focus on the use of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to treat retinal diseases by harnessing the ability of stem cells to differentiate into different body tissues. The retina is a tissue specialized for light sensing, and its degradation leads to vision loss. As part of the central nervous system, the retina has very low regenerative capability, and therefore, treatment options are limited once it degenerates. Nevertheless, innovations in methods to induce the generation of retinal cells and tissues from ESCs/iPSCs enable the development of novel approaches for these irreversible diseases. Here we review some historical background and current clinical trials involving the use of stem-cell-derived retinal pigment epithelial cells for AMD treatment and stem cell-derived retinal cells/tissues for RP therapy. Finally, we discuss our future vision of regenerative treatment for retinal diseases with a partial focus on our studies and introduce other interesting approaches for restoring vision.
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Affiliation(s)
- Hirofumi Uyama
- Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.,Department of Ophthalmology, Kobe City Eye Hospital, Kobe, Japan
| | - Michiko Mandai
- Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.,Department of Ophthalmology, Kobe City Eye Hospital, Kobe, Japan
| | - Masayo Takahashi
- Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.,Department of Ophthalmology, Kobe City Eye Hospital, Kobe, Japan
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7
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Tezel T, Ruff A. Retinal cell transplantation in retinitis pigmentosa. Taiwan J Ophthalmol 2021; 11:336-347. [PMID: 35070661 PMCID: PMC8757529 DOI: 10.4103/tjo.tjo_48_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 10/10/2021] [Indexed: 11/25/2022] Open
Abstract
Retinitis pigmentosa is the most common hereditary retinal disease. Dietary supplements, neuroprotective agents, cytokines, and lately, prosthetic devices, gene therapy, and optogenetics have been employed to slow down the retinal degeneration or improve light perception. Completing retinal circuitry by transplanting photoreceptors has always been an appealing idea in retinitis pigmentosa. Recent developments in stem cell technology, retinal imaging techniques, tissue engineering, and transplantation techniques have brought us closer to accomplish this goal. The eye is an ideal organ for cell transplantation due to a low number of cells required to restore vision, availability of safe surgical and imaging techniques to transplant and track the cells in vivo, and partial immune privilege provided by the subretinal space. Human embryonic stem cells, induced pluripotential stem cells, and especially retinal organoids provide an adequate number of cells at a desired developmental stage which may maximize integration of the graft to host retina. However, stem cells must be manufactured under strict good manufacturing practice protocols due to known tumorigenicity as well as possible genetic and epigenetic stabilities that may pose a danger to the recipient. Immune compatibility of stem cells still stands as a problem for their widespread use for retinitis pigmentosa. Transplantation of stem cells from different sources revealed that some of the transplanted cells may not integrate the host retina but slow down the retinal degeneration through paracrine mechanisms. Discovery of a similar paracrine mechanism has recently opened a new therapeutic path for reversing the cone dormancy and restoring the sight in retinitis pigmentosa.
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8
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Ghareeb AE, Lako M, Steel DH. Coculture techniques for modeling retinal development and disease, and enabling regenerative medicine. Stem Cells Transl Med 2020; 9:1531-1548. [PMID: 32767661 PMCID: PMC7695644 DOI: 10.1002/sctm.20-0201] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/22/2020] [Accepted: 07/05/2020] [Indexed: 12/14/2022] Open
Abstract
Stem cell-derived retinal organoids offer the opportunity to cure retinal degeneration of wide-ranging etiology either through the study of in vitro models or the generation of tissue for transplantation. However, despite much work in animals and several human pilot studies, satisfactory therapies have not been developed. Two major challenges for retinal regenerative medicine are (a) physical cell-cell interactions, which are critical to graft function, are not formed and (b) the host environment does not provide suitable queues for development. Several strategies offer to improve the delivery, integration, maturation, and functionality of cell transplantation. These include minimally invasive delivery, biocompatible material vehicles, retinal cell sheets, and optogenetics. Optimizing several variables in animal models is practically difficult, limited by anatomical and disease pathology which is often different to humans, and faces regulatory and ethical challenges. High-throughput methods are needed to experimentally optimize these variables. Retinal organoids will be important to the success of these models. In their current state, they do not incorporate a representative retinal pigment epithelium (RPE)-photoreceptor interface nor vascular elements, which influence the neural retina phenotype directly and are known to be dysfunctional in common retinal diseases such as age-related macular degeneration. Advanced coculture techniques, which emulate the RPE-photoreceptor and RPE-Bruch's-choriocapillaris interactions, can incorporate disease-specific, human retinal organoids and overcome these drawbacks. Herein, we review retinal coculture models of the neural retina, RPE, and choriocapillaris. We delineate the scientific need for such systems in the study of retinal organogenesis, disease modeling, and the optimization of regenerative cell therapies for retinal degeneration.
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Affiliation(s)
- Ali E. Ghareeb
- Sunderland Eye Infirmary, South Tyneside and Sunderland NHS Foundation TrustSunderlandUK
- Biosciences Institute, Newcastle UniversityNewcastle‐upon‐TyneUK
| | - Majlinda Lako
- Biosciences Institute, Newcastle UniversityNewcastle‐upon‐TyneUK
| | - David H. Steel
- Sunderland Eye Infirmary, South Tyneside and Sunderland NHS Foundation TrustSunderlandUK
- Biosciences Institute, Newcastle UniversityNewcastle‐upon‐TyneUK
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9
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Zhang CJ, Ma Y, Jin ZB. The road to restore vision with photoreceptor regeneration. Exp Eye Res 2020; 202:108283. [PMID: 33010290 DOI: 10.1016/j.exer.2020.108283] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 09/13/2020] [Accepted: 09/24/2020] [Indexed: 12/12/2022]
Abstract
Neuroretinal diseases are the predominant cause of irreversible blindness worldwide, mainly due to photoreceptor loss. Currently, there are no radical treatments to fully reverse the degeneration or even stop the disease progression. Thus, it is urgent to develop new biological therapeutics for these diseases on the clinical side. Stem cell-based treatments have become a promising therapeutic for neuroretinal diseases through the replacement of damaged cells with photoreceptors and some allied cells. To date, considerable efforts have been made to regenerate the diseased retina based on stem cell technology. In this review, we overview the current status of stem cell-based treatments for photoreceptor regeneration, including the major cell sources derived from different stem cells in pre-clinical or clinical trial stages. Additionally, we discuss herein the major challenges ahead for and potential new strategy toward photoreceptor regeneration.
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Affiliation(s)
- Chang-Jun Zhang
- Laboratory for Stem Cell & Retinal Regeneration, The Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Ya Ma
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Science Key Laboratory, Beijing, 100730, China
| | - Zi-Bing Jin
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Science Key Laboratory, Beijing, 100730, China.
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10
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Wang Y, Tang Z, Gu P. Stem/progenitor cell-based transplantation for retinal degeneration: a review of clinical trials. Cell Death Dis 2020; 11:793. [PMID: 32968042 PMCID: PMC7511341 DOI: 10.1038/s41419-020-02955-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/21/2020] [Accepted: 08/27/2020] [Indexed: 12/14/2022]
Abstract
Retinal degeneration (RD) is one of the dominant causes of irreversible vision impairment and blindness worldwide. However, the current effective therapeutics for RD in the ophthalmologic clinic are unclear and controversial. In recent years, extensively investigated stem/progenitor cells-including retinal progenitor cells (RPCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and mesenchymal stromal cells (MSCs)-with proliferation and multidirectional differentiation potential have presented opportunities to revolutionise the ultimate clinical management of RD. Herein, we provide a comprehensive overview on the progression of clinical trials for RD treatment using four types of stem/progenitor cell-based transplantation to replace degenerative retinal cells and/or to supplement trophic factors from the aspects of safety, effectiveness and their respective advantages and disadvantages. In addition, we also discuss the emerging role of stem cells in the secretion of multifunctional nanoscale exosomes by which stem cells could be further exploited as a potential RD therapy. This review will facilitate the understanding of scientists and clinicians of the enormous promise of stem/progenitor cell-based transplantation for RD treatment, and provide incentive for superior employment of such strategies that may be suitable for treatment of other diseases, such as stroke and ischaemia-reperfusion injury.
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Affiliation(s)
- Yiqi Wang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China
| | - Zhimin Tang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China
| | - Ping Gu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China.
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11
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Shen Y. Stem cell therapies for retinal diseases: from bench to bedside. J Mol Med (Berl) 2020; 98:1347-1368. [PMID: 32794020 DOI: 10.1007/s00109-020-01960-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 07/02/2020] [Accepted: 08/06/2020] [Indexed: 12/22/2022]
Abstract
As the human retina has no regenerative ability, stem cell interventions represent potential therapies for various blinding retinal diseases. This type of therapy has been extensively studied in the human eyes through decades of preclinical studies. The safety profiles shown in clinical trials thus far have indicated that these strategies should be further explored. There are still challenges with regard to cell source, cell delivery, immuno-related adverse events and long-term maintenance of the therapeutic effects. Retinal stem cell therapy is likely to be most successful with a combination of multiple technologies, such as gene therapy. The purpose of this review is to present a synthetical and systematic coverage of stem cell therapies that target retinal diseases from bench to bedside, intending to appeal to both junior specialists and the broader community of clinical investigators alike. This review will only focus on therapies that have already been studied in clinical trials. This review summarizes key concepts, highlights the main studies in human patients and discusses the current challenges and potential methods to reduce safety concerns while enhancing the therapeutic effects.
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Affiliation(s)
- Yuening Shen
- Institute of Ophthalmology, University College London , 11-43 Bath St, London, EC1V 9EL, UK. .,Department of Medical Retina, Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London, EC1V 2PD, UK.
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12
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West EL, Ribeiro J, Ali RR. Development of Stem Cell Therapies for Retinal Degeneration. Cold Spring Harb Perspect Biol 2020; 12:cshperspect.a035683. [PMID: 31818854 DOI: 10.1101/cshperspect.a035683] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Degenerative retinal disease is the major cause of sight loss in the developed world and currently there is a lack of effective treatments. As the loss of vision is directly the result of the loss of retinal cells, effective cell replacement through stem-cell-based therapies may have the potential to treat a great number of retinal diseases whatever their underlying etiology. The eye is an ideal organ to develop cell therapies as it is immune privileged, and modern surgical techniques enable precise delivery of cells to the retina. Furthermore, a range of noninvasive diagnostic tests and high-resolution imaging techniques facilitate the evaluation of any therapeutic intervention. In this review, we evaluate the progress to date of current cell therapy strategies for retinal repair, focusing on transplantation of pluripotent stem-cell-derived retinal pigment epithelium (RPE) and photoreceptor cells.
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Affiliation(s)
- Emma L West
- Division of Molecular Therapy, UCL Institute of Ophthalmology, London EC1V 9EL, United Kingdom
| | - Joana Ribeiro
- Division of Molecular Therapy, UCL Institute of Ophthalmology, London EC1V 9EL, United Kingdom
| | - Robin R Ali
- Division of Molecular Therapy, UCL Institute of Ophthalmology, London EC1V 9EL, United Kingdom.,Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan 48105, USA
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13
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Li XX, Yuan XJ, Zhai Y, Yu S, Jia RX, Yang LP, Ma ZZ, Zhao YM, Wang YX, Ge LH. Treatment with Stem Cells from Human Exfoliated Deciduous Teeth and Their Derived Conditioned Medium Improves Retinal Visual Function and Delays the Degeneration of Photoreceptors. Stem Cells Dev 2019; 28:1514-1526. [PMID: 31544584 DOI: 10.1089/scd.2019.0158] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Retinitis pigmentosa (RP) is a hereditary disease characterized by degeneration and the loss of photoreceptors. Stem cell-based therapy has emerged as a promising strategy for treating RP. Stem cells from exfoliated deciduous teeth (SHEDs), a type of mesenchymal stem cell from human exfoliated deciduous teeth, have the potential to differentiate into photoreceptor-like cells under specific induction in vitro. It has been confirmed that through paracrine secreta, SHEDs exert neurotrophic, angiogenic, immunoregulatory, and antiapoptotic functions in injured tissues. This study was designed to determine whether retinal-differentiated SHEDs and the conditioned medium derived from SHEDs (SHEDs-CM) have therapeutic effects in a mouse model of RP. The results showed that both SHEDs and SHEDs-CM improved electroretinogram responses, ameliorated photoreceptor degeneration, and maintained the structure of the outer segments of photoreceptors. The therapeutic effects were related to antiapoptotic activity of SHEDs and SHEDs-CM. Thus, SHEDs may be a promising stem cell source for treating retinal degeneration.
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Affiliation(s)
- Xiao-Xia Li
- Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Xiao-Jing Yuan
- Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Yue Zhai
- Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Shi Yu
- Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Rui-Xuan Jia
- Institute of Systems Biomedicine and Department of Ophthalmology, School of Basic Medical Sciences, Peking University Third Hospital, Beijing, China
| | - Li-Ping Yang
- Institute of Systems Biomedicine and Department of Ophthalmology, School of Basic Medical Sciences, Peking University Third Hospital, Beijing, China
| | - Zhi-Zhong Ma
- Institute of Systems Biomedicine and Department of Ophthalmology, School of Basic Medical Sciences, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, Beijing, China
| | - Yu-Ming Zhao
- Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Yi-Xiang Wang
- Central Laboratory, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Li-Hong Ge
- Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing, China
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14
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Lorach H, Kang S, Bhuckory MB, Trouillet A, Dalal R, Marmor M, Palanker D. Transplantation of Mature Photoreceptors in Rodents With Retinal Degeneration. Transl Vis Sci Technol 2019; 8:30. [PMID: 31171997 PMCID: PMC6543858 DOI: 10.1167/tvst.8.3.30] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 04/01/2019] [Indexed: 11/24/2022] Open
Abstract
Purpose To demonstrate survival and integration of mature photoreceptors transplanted with the retinal pigment epithelium (RPE). Methods Full-thickness retina with attached RPE was harvested from healthy adult rats. Grafts were implanted into two rat models of retinal degeneration, Royal College of Surgeons (RCS) and S334ter-3. Survival of the host and transplanted retina was monitored using optical coherence tomography (OCT) for up to 6 months. The retinal structure and synaptogenesis between the host and transplant was assessed by histology and immunohistochemistry. Results OCT and histology demonstrated a well-preserved photoreceptor layer with inner and outer segments, while the inner retinal layers of the transplant largely disappeared. Grafts, including RPE, survived better than without and the transplanted RPE appeared as a monolayer integrated with the native one. Synaptogenesis was observed through sprouting of new dendrites from the host bipolar cells and synaptic connections forming with cells of the transplant. However, in many samples, a glial fibrillary acidic protein–positive membrane separated the host retina and the graft. Conclusions Presence of RPE in the graft improved the survival of transplanted photoreceptors. Functional integration between the transplant and the host retina is likely to be further enhanced if formation of a glial seal could be prevented. Transplantation of the mature photoreceptors with RPE may be a practical approach to restoration of sight in retinal degeneration. Translational Relevance This approach to restoration of sight in patients with photoreceptor degeneration can be rapidly advanced to clinical testing. In patients with central scotoma, autologous transplantation of the peripheral retina can be an option.
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Affiliation(s)
- Henri Lorach
- Hansen Experimental Physics Laboratory, Stanford University, CA, USA
| | - Seungbum Kang
- Hansen Experimental Physics Laboratory, Stanford University, CA, USA.,Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Mohajeet B Bhuckory
- Hansen Experimental Physics Laboratory, Stanford University, CA, USA.,Department of Ophthalmology, Stanford University, CA, USA
| | - Alix Trouillet
- Department of Otolaryngology, Stanford University, CA, USA
| | - Roopa Dalal
- Department of Ophthalmology, Stanford University, CA, USA
| | - Michael Marmor
- Department of Ophthalmology, Stanford University, CA, USA
| | - Daniel Palanker
- Hansen Experimental Physics Laboratory, Stanford University, CA, USA.,Department of Ophthalmology, Stanford University, CA, USA
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15
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Kramer J, Chirco KR, Lamba DA. Immunological Considerations for Retinal Stem Cell Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1186:99-119. [PMID: 31654387 DOI: 10.1007/978-3-030-28471-8_4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
There is an increasing effort toward generating replacement cells for neuronal application due to the nonregenerative nature of these tissues. While much progress has been made toward developing methodologies to generate these cells, there have been limited improvements in functional restoration. Some of these are linked to the degenerative and often nonreceptive microenvironment that the new cells need to integrate into. In this chapter, we will focus on the status and role of the immune microenvironment of the retina during homeostasis and disease states. We will review changes in both innate and adaptive immunity as well as the role of immune rejection in stem cell replacement therapies. The chapter will end with a discussion of immune-modulatory strategies that have helped to ameliorate these effects and could potentially improve functional outcome for cell replacement therapies for the eye.
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Affiliation(s)
- Joshua Kramer
- Buck Institute for Research on Aging, Novato, CA, USA
| | | | - Deepak A Lamba
- Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA. .,Buck Institute for Research on Aging, Novato, CA, USA.
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16
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Gasparini SJ, Llonch S, Borsch O, Ader M. Transplantation of photoreceptors into the degenerative retina: Current state and future perspectives. Prog Retin Eye Res 2018; 69:1-37. [PMID: 30445193 DOI: 10.1016/j.preteyeres.2018.11.001] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/29/2018] [Accepted: 11/06/2018] [Indexed: 12/12/2022]
Abstract
The mammalian retina displays no intrinsic regenerative capacities, therefore retinal degenerative diseases such as age-related macular degeneration (AMD) or retinitis pigmentosa (RP) result in a permanent loss of the light-sensing photoreceptor cells. The degeneration of photoreceptors leads to vision impairment and, in later stages, complete blindness. Several therapeutic strategies have been developed to slow down or prevent further retinal degeneration, however a definitive cure i.e. replacement of the lost photoreceptors, has not yet been established. Cell-based treatment approaches, by means of photoreceptor transplantation, have been studied in pre-clinical animal models over the last three decades. The introduction of pluripotent stem cell-derived retinal organoids represents, in principle, an unlimited source for the generation of transplantable human photoreceptors. However, safety, immunological and reproducibility-related issues regarding the use of such cells still need to be solved. Moreover, the recent finding of cytoplasmic material transfer between donor and host photoreceptors demands reinterpretation of several former transplantation studies. At the same time, material transfer between healthy donor and dysfunctional patient photoreceptors also offers a potential alternative strategy for therapeutic intervention. In this review we discuss the history and current state of photoreceptor transplantation, the techniques used to assess rescue of visual function, the prerequisites for effective transplantation as well as the main roadblocks, including safety and immune response to the graft, that need to be overcome for successful clinical translation of photoreceptor transplantation approaches.
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Affiliation(s)
- Sylvia J Gasparini
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany
| | - Sílvia Llonch
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany
| | - Oliver Borsch
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany
| | - Marius Ader
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307, Dresden, Germany.
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18
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Graca AB, Hippert C, Pearson RA. Müller Glia Reactivity and Development of Gliosis in Response to Pathological Conditions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1074:303-308. [PMID: 29721957 DOI: 10.1007/978-3-319-75402-4_37] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Within the mammalian retina, both Müller glia and astrocytes display reactivity in response to many forms of retinal injury and disease in a process termed gliosis. Reactive gliosis is a complex process that is considered to represent a cellular response to protect the retina from further damage and to promote its repair following pathological insult. It includes morphological, biochemical and physiological changes, which may vary depending on the type and degree of the initial injury. Not only does gliosis have numerous triggers, but also there is a great degree of heterogeneity in the glial response, creating multiple levels of complexity. For these reasons, understanding the process of glial scar formation and how this process differs in different pathological conditions and finding strategies to circumvent these barriers represent major challenges to the advancement of many ocular therapies.
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Affiliation(s)
- Anna B Graca
- Department of Genetics, University College London Institute of Ophthalmology, London, UK.
| | - Claire Hippert
- Roche, Stem Cell Platform, Chemical Biology Roche Pharma Research and Early Development, Basel, Switzerland
| | - Rachael A Pearson
- Department of Genetics, University College London Institute of Ophthalmology, London, UK.
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19
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Llonch S, Carido M, Ader M. Organoid technology for retinal repair. Dev Biol 2017; 433:132-143. [PMID: 29291970 DOI: 10.1016/j.ydbio.2017.09.028] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 09/05/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023]
Abstract
A major cause for vision impairment and blindness in industrialized countries is the loss of the light-sensing retinal tissue in the eye. Photoreceptor damage is one of the main characteristics found in retinal degeneration diseases, such as Retinitis Pigmentosa or age-related macular degeneration. The lack of effective therapies to stop photoreceptor loss together with the absence of significant intrinsic regeneration in the human retina converts such degenerative diseases into permanent conditions that are currently irreversible. Cell replacement by means of photoreceptor transplantation has been proposed as a potential approach to tackle cell loss in the retina. Since the first attempt of photoreceptor transplantation in humans, about twenty years ago, several research groups have focused in the development and improvement of technologies necessary to bring cell transplantation for retinal degeneration diseases to reality. Progress in recent years in the generation of human tissue derived from pluripotent stem cells (PSCs) has significantly improved our tools to study human development and disease in the dish. Particularly the availability of 3D culture systems for the generation of PSC-derived organoids, including the human retina, has dramatically increased access to human material for basic and medical research. In this review, we focus on important milestones towards the generation of transplantable photoreceptor precursors from PSC-derived retinal organoids and discuss recent pre-clinical transplantation studies using organoid-derived photoreceptors in context to related in vivo work using primary photoreceptors as donor material. Additionally, we summarize remaining challenges for developing photoreceptor transplantation towards clinical application.
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Affiliation(s)
- Sílvia Llonch
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany
| | - Madalena Carido
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany; German Center for Neurodegenerative Diseases Dresden (DZNE), Arnoldstraße 18, 01307 Dresden, Germany
| | - Marius Ader
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
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20
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Abstract
The recent advances in cell-based therapies for the repair of the pigmented epithelium is providing additional impetus for the translation of photoreceptor transplantation to eventual clinical trials. The prospects for transplantation of photoreceptors as a potential therapy for the treatment of photoreceptor degeneration will depend on successfully addressing many critical issues in preclinical studies. Although most of the studies that have carried out transplants of photoreceptors have primarily used normal mice, there have been recent reports that have also shown some success following transplantation to mouse models of retinitis pigmentosa. However, while these results are promising, there are several key issues that require further investigation in order to better understand the optimum timing for transplantation, given the extensive remodeling of the retina that occurs in late stage disease.
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21
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Tang Z, Zhang Y, Wang Y, Zhang D, Shen B, Luo M, Gu P. Progress of stem/progenitor cell-based therapy for retinal degeneration. J Transl Med 2017; 15:99. [PMID: 28486987 PMCID: PMC5424366 DOI: 10.1186/s12967-017-1183-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 04/14/2017] [Indexed: 01/14/2023] Open
Abstract
Retinal degeneration (RD), such as age-related macular degeneration (AMD) and retinitis pigmentosa, is one of the leading causes of blindness. Presently, no satisfactory therapeutic options are available for these diseases principally because the retina and retinal pigmented epithelium (RPE) do not regenerate, although wet AMD can be prevented from further progression by anti-vascular endothelial growth factor therapy. Nevertheless, stem/progenitor cell approaches exhibit enormous potential for RD treatment using strategies mainly aimed at the rescue and replacement of photoreceptors and RPE. The sources of stem/progenitor cells are classified into two broad categories in this review, which are (1) ocular-derived progenitor cells, such as retinal progenitor cells, and (2) non-ocular-derived stem cells, including embryonic stem cells, induced pluripotent stem cells, and mesenchymal stromal cells. Here, we discuss in detail the progress in the study of four predominant stem/progenitor cell types used in animal models of RD. A short overview of clinical trials involving the stem/progenitor cells is also presented. Currently, stem/progenitor cell therapies for RD still have some drawbacks such as inhibited proliferation and/or differentiation in vitro (with the exception of the RPE) and limited long-term survival and function of grafts in vivo. Despite these challenges, stem/progenitor cells represent the most promising strategy for RD treatment in the near future.
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Affiliation(s)
- Zhimin Tang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China
| | - Yi Zhang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China
| | - Yuyao Wang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China
| | - Dandan Zhang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China
| | - Bingqiao Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China
| | - Min Luo
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China.
| | - Ping Gu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China.
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Aghaizu ND, Kruczek K, Gonzalez-Cordero A, Ali RR, Pearson RA. Pluripotent stem cells and their utility in treating photoreceptor degenerations. PROGRESS IN BRAIN RESEARCH 2017; 231:191-223. [PMID: 28554397 DOI: 10.1016/bs.pbr.2017.01.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Age-related macular degeneration and inherited retinal degenerations represent the leading causes of blindness in industrialized countries. Despite different initiating causes, they share a common final pathophysiology, the loss of the light sensitive photoreceptors. Replacement by transplantation may offer a potential treatment strategy for both patient populations. The last decade has seen remarkable progress in our ability to generate retinal cell types, including photoreceptors, from a variety of murine and human pluripotent stem cell sources. Driven in large part by the requirement for renewable cell sources, stem cells have emerged not only as a promising source of replacement photoreceptors but also to provide in vitro systems with which to study retinal development and disease processes and to test therapeutic agents.
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Affiliation(s)
| | - Kamil Kruczek
- UCL Institute of Ophthalmology, London, United Kingdom
| | | | - Robin R Ali
- UCL Institute of Ophthalmology, London, United Kingdom
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23
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Zarbin M. Cell-Based Therapy for Degenerative Retinal Disease. Trends Mol Med 2016; 22:115-134. [PMID: 26791247 DOI: 10.1016/j.molmed.2015.12.007] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Revised: 12/16/2015] [Accepted: 12/17/2015] [Indexed: 12/21/2022]
Abstract
Stem cell-derived retinal pigment epithelium (RPE) and photoreceptors (PRs) have restored vision in preclinical models of human retinal degenerative disease. This review discusses characteristics of stem cell therapy in the eye and the challenges to clinical implementation that are being confronted today. Based on encouraging results from Phase I/II trials, the first Phase II clinical trials of stem cell-derived RPE transplantation are underway. PR transplant experiments have demonstrated restoration of visual function in preclinical models of retinitis pigmentosa and macular degeneration, but also indicate that no single approach is likely to succeed in overcoming PR loss in all cases. A greater understanding of the mechanisms controlling synapse formation as well as the immunoreactivity of transplanted retinal cells is urgently needed.
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Affiliation(s)
- Marco Zarbin
- Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
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24
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Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration. Proc Natl Acad Sci U S A 2015; 113:E81-90. [PMID: 26699487 DOI: 10.1073/pnas.1512590113] [Citation(s) in RCA: 233] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
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.
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Abstract
INTRODUCTION After decades of basic science research involving the testing of regenerative strategies in animal models of retinal degenerative diseases, a number of clinical trials are now underway, with additional trials set to begin shortly. These efforts will evaluate the safety and preliminary efficacy of cell-based products in the eyes of patients with a number of retinal conditions, notably including age-related macular degeneration, retinitis pigmentosa and Stargardt's disease. AREAS COVERED This review considers the scientific work and early trials with fetal cells and tissues that set the stage for the current clinical investigatory work, as well the trials themselves, specifically those either now completed, underway or close to initiation. The cells of interest include retinal pigment epithelial cells derived from embryonic stem or induced pluripotent stem cells, undifferentiated neural or retinal progenitors or cells from the vascular/bone marrow compartment or umbilical cord tissue. EXPERT OPINION Degenerative diseases of the retina represent a popular target for emerging cell-based therapeutics and initial data from early stage clinical trials suggest that short-term safety objectives can be met in at least some cases. The question of efficacy will require additional time and testing to be adequately resolved.
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Affiliation(s)
- Henry Klassen
- a University of California, Gavin Herbert Eye Institute & Stem Cell Research Center , Sue & Bill Gross Hall, Room 2006, 845 Health Sciences Road, Irvine, CA 92697-1705, USA +1 94 98 24 77 50 ; +1 94 98 24 96 26 ;
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Singh RK, Mallela RK, Cornuet PK, Reifler AN, Chervenak AP, West MD, Wong KY, Nasonkin IO. Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures. Stem Cells Dev 2015; 24:2778-95. [PMID: 26283078 DOI: 10.1089/scd.2015.0144] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Stem cell-based therapy of retinal degenerative conditions is a promising modality to treat blindness, but requires new strategies to improve the number of functionally integrating cells. Grafting semidifferentiated retinal tissue rather than progenitors allows preservation of tissue structure and connectivity in retinal grafts, mandatory for vision restoration. Using human embryonic stem cells (hESCs), we derived retinal tissue growing in adherent conditions consisting of conjoined neural retina and retinal pigment epithelial (RPE) cells and evaluated cell fate determination and maturation in this tissue. We found that deriving such tissue in adherent conditions robustly induces all eye field genes (RX, PAX6, LHX2, SIX3, SIX6) and produces four layers of pure populations of retinal cells: RPE (expressing NHERF1, EZRIN, RPE65, DCT, TYR, TYRP, MITF, PMEL), early photoreceptors (PRs) (coexpressing CRX and RCVRN), inner nuclear layer neurons (expressing CALB2), and retinal ganglion cells [RGCs, expressing BRN3B and Neurofilament (NF) 200]. Furthermore, we found that retinal progenitors divide at the apical side of the hESC-derived retinal tissue (next to the RPE layer) and then migrate toward the basal side, similar to that found during embryonic retinogenesis. We detected synaptogenesis in hESC-derived retinal tissue, and found neurons containing many synaptophysin-positive boutons within the RGC and PR layers. We also observed long NF200-positive axons projected by RGCs toward the apical side. Whole-cell recordings demonstrated that putative amacrine and/or ganglion cells exhibited electrophysiological responses reminiscent of those in normal retinal neurons. These responses included voltage-gated Na(+) and K(+) currents, depolarization-induced spiking, and responses to neurotransmitter receptor agonists. Differentiation in adherent conditions allows generation of long and flexible pieces of 3D retinal tissue suitable for isolating transplantable slices of tissue for retinal replacement therapies.
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Affiliation(s)
- Ratnesh K Singh
- 1 Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania
| | - Ramya K Mallela
- 1 Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania
| | - Pamela K Cornuet
- 1 Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania
| | - Aaron N Reifler
- 2 Department of Ophthalmology and Visual Sciences, University of Michigan , Ann Arbor, Michigan
| | - Andrew P Chervenak
- 2 Department of Ophthalmology and Visual Sciences, University of Michigan , Ann Arbor, Michigan
| | | | - Kwoon Y Wong
- 2 Department of Ophthalmology and Visual Sciences, University of Michigan , Ann Arbor, Michigan
| | - Igor O Nasonkin
- 1 Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania
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Popelka Š, Studenovská H, Abelová L, Ardan T, Studený P, Straňák Z, Klíma J, Dvořánková B, Kotek J, Hodan J, Rypáček F. A frame-supported ultrathin electrospun polymer membrane for transplantation of retinal pigment epithelial cells. Biomed Mater 2015; 10:045022. [DOI: 10.1088/1748-6041/10/4/045022] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Chapter 4 - Restoring Vision to the Blind: Stem Cells and Transplantation. Transl Vis Sci Technol 2015; 3:6. [PMID: 25653890 DOI: 10.1167/tvst.3.7.6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 10/27/2014] [Indexed: 11/24/2022] Open
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Pearson RA. Advances in repairing the degenerate retina by rod photoreceptor transplantation. Biotechnol Adv 2014; 32:485-91. [PMID: 24412415 PMCID: PMC4070022 DOI: 10.1016/j.biotechadv.2014.01.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 09/26/2013] [Accepted: 01/01/2014] [Indexed: 02/01/2023]
Abstract
Despite very different aetiologies, age-related macular degeneration (AMD) and most inherited retinal disorders culminate in the same final common pathway, loss of the light-sensitive photoreceptors. There are few clinical treatments and none can reverse the loss of vision. Photoreceptor replacement by transplantation is proposed as a broad treatment strategy applicable to all degenerations. The past decade has seen a number of landmark achievements in this field, which together provide strong justification for continuing investigation into photoreceptor replacement strategies. These include proof of principle for restoring vision by rod-photoreceptor transplantation in mice with congenital stationary night blindness and advances in stem cell biology, which have led to the generation of complete optic structures in vitro from embryonic stem cells. The latter represents enormous potential for generating suitable and renewable donor cells with which to achieve the former. However, there are still challenges presented by the degenerating recipient retinal environment that must be addressed as we move to translating these technologies towards clinical application.
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Affiliation(s)
- Rachael A Pearson
- Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
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Gullapalli VK, Khodair MA, Wang H, Sugino IK, Madreperla S, Zarbin MA. Transplantation Frontiers. Retina 2013. [DOI: 10.1016/b978-1-4557-0737-9.00125-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Transplantation of photoreceptor and total neural retina preserves cone function in P23H rhodopsin transgenic rat. PLoS One 2010; 5:e13469. [PMID: 20976047 PMCID: PMC2957406 DOI: 10.1371/journal.pone.0013469] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Accepted: 07/27/2010] [Indexed: 01/13/2023] Open
Abstract
Background Transplantation as a therapeutic strategy for inherited retinal degeneration has been historically viewed to restore vision as a method by replacing the lost retinal cells and attempting to reconstruct the neural circuitry with stem cells, progenitor cells and mature neural retinal cells. Methods and Findings We present evidence for an alternative strategy aimed at preventing the secondary loss of cones, the most crucial photoreceptors for vision, by transplanting normal photoreceptors cells into the eye of the P23H rat, a model of dominant retinitis pigmentosa. We carried out transplantation of photoreceptors or total neural retina in 3-month-old P23H rats and evaluated the function and cell counts 6 months after surgery. In both groups, cone loss was significantly reduced (10%) in the transplanted eyes where the cone outer segments were found to be considerably longer. This morphological effect correlated with maintenance of the visual function of cones as scored by photopic ERG recording, but more precisely with an increase in the photopic b-wave amplitudes by 100% and 78% for photoreceptor transplantation and whole retinal transplantation respectively. Conclusions We demonstrate here that the transplanted tissue prevents the loss of cone function, which is further translated into cone survival.
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Dutt K, Cao Y. Engineering retina from human retinal progenitors (cell lines). Tissue Eng Part A 2009; 15:1401-13. [PMID: 19113950 DOI: 10.1089/ten.tea.2007.0358] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Retinal degeneration resulting in the loss of photoreceptors is the leading cause of blindness. Several therapeutic protocols are under consideration for treatment of this disease. Tissue replacement is one such strategy currently being explored. However, availability of tissues for transplant poses a major obstacle. Another strategy with great potential is the use of adult stem cells, which could be expanded in culture and then utilized to engineer retinal tissue. In this study, we have explored a spontaneously immortalized human retinal progenitor cell line for its potential in retinal engineering using rotary cultures to generate three-dimensional (3D) structures. Retinal progenitors cultured alone or cocultured with retinal pigment epithelial cells form aggregates. The aggregate size increases between days 1 and 10. The cells grown as a 3D culture rotary system, which promotes cell-cell interaction, retain a spectrum of differentiation capability. Photoreceptor differentiation in these cultures is confirmed by significant upregulation of rhodopsin and AaNat, an enzyme implicated in melatonin synthesis (immunohistochemistry and Western blot analysis). Photoreceptor induction and differentiation is further attested to by the upregulation of rod transcription factor Nrl, Nr(2)e(3), expression of interstitial retinal binding protein, and rhodopsin kinase by reverse transcription-polymerase chain reaction. Differentiation toward other cell lineages is confirmed by the expression of tyrosine hydroxylase in amacrine cells, thy 1.1 expression in ganglion cells and calbindin, and GNB3 expression in cone cells. The capability of retinal progenitors to give rise to several retinal cell types when grown as aggregated cells in rotary culture offers hope that progenitor stem cells under appropriate culture conditions will be valuable to engineer retinal constructs, which could be further tested for their transplant potential. The fidelity with which this multipotential cell line retains its capacity to differentiate into multiple cell types holds great promise for the use of tissue-specific adult stem cells for therapy.
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Affiliation(s)
- Kamla Dutt
- Department of Pathology, Morehouse School of Medicine, Atlanta, Georgia 30310-1495, USA.
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Abstract
While a number of retinal transplantation studies using various types of donor cells have been performed thus far, our study focused on iris tissue as a donor cell source. This is because donor cells from iris pigment epithelium have the following characteristics: (1) they are embryonically related to the neural retina; (2) autologous iris tissue can be obtained via a surgical approach; and (3) they can be cultured to increase the number of donor cells and establish photoreceptor-like cells from iris-derived cells by means of the appropriate gene transfer. Although the potential of iris-derived cells has been indicated, there remain many issues to be investigated.
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Affiliation(s)
- Tadamichi Akagi
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Kyoto, Japan.
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Seiler MJ, Aramant RB. Transplantation of Neuroblastic Progenitor Cells as a Sheet Preserves and Restores Retinal Function. Semin Ophthalmol 2009; 20:31-42. [PMID: 15804842 DOI: 10.1080/08820530590921873] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Diseases affecting the outer retina are incurable once photoreceptors are lost, and these diseases usually cause retinal pigment epithelium (RPE) dysfunction. However, the inner retina can remain functional for some time, even though retinal remodeling occurs as compensation for photoreceptor loss. If the damaged part can be replaced with neuroblastic progenitor and RPE cells as sheets with a beneficial effect on function, vision loss may be prevented and vision may be restored. This review presents an overview of the research of transplanting sheets of neural retina, with or without its RPE, to the subretinal space. In different animal models of retinal degeneration, retinal transplants can morphologically reconstruct a damaged retina, and restore visual sensitivity. Good morphological integration of transplants with the host retina can occur, whereas other transplants exhibit a glial barrier. Synaptic connections between transplant and host have been indicated by transsynaptic tracing. Retinal transplants can restore and preserve visual responses in a small area of the superior colliculus corresponding to the placement of the transplant in the retina. The beneficial effect of retinal transplantation likely involves two mechanisms: trophic effects, e.g., rescue of host cones; and synaptic connectivity between transplant and host retina.
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Affiliation(s)
- Magdalene J Seiler
- Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, 90033, USA.
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West E, Pearson R, MacLaren R, Sowden J, Ali R. Cell transplantation strategies for retinal repair. PROGRESS IN BRAIN RESEARCH 2009; 175:3-21. [PMID: 19660645 PMCID: PMC3272389 DOI: 10.1016/s0079-6123(09)17501-5] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cell transplantation is a novel therapeutic strategy to restore visual responses to the degenerate adult neural retina and represents an exciting area of regenerative neurotherapy. So far, it has been shown that transplanted postmitotic photoreceptor precursors are able to functionally integrate into the adult mouse neural retina. In this review, we discuss the differentiation of photoreceptor cells from both adult and embryonic-derived stem cells and their potential for retinal cell transplantation. We also discuss the strategies used to overcome barriers present in the degenerate neural retina and improve retinal cell integration. Finally, we consider the future translation of retinal cell therapy as a therapeutic strategy to treat retinal degeneration.
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Affiliation(s)
- E.L. West
- Department of Genetics, UCL Institute of Ophthalmology, London, UK
| | - R.A. Pearson
- Department of Genetics, UCL Institute of Ophthalmology, London, UK
| | - R.E. MacLaren
- Department of Genetics, UCL Institute of Ophthalmology, London, UK
- Vitreoretinal Service, Moorfields Eye Hospital, London, UK
| | - J.C. Sowden
- Developmental Biology Unit, UCL Institute of Child Health, London, UK
| | - R.R. Ali
- Department of Genetics, UCL Institute of Ophthalmology, London, UK
- Molecular Immunology Unit, UCL Institute of Child Health, London, UK
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Tezcaner A, Hicks D. In vitro characterization of micropatterned PLGA-PHBV8 blend films as temporary scaffolds for photoreceptor cells. J Biomed Mater Res A 2008; 86:170-81. [PMID: 17957722 DOI: 10.1002/jbm.a.31600] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In developed countries the aging population faces increasing risks of blinding retinal diseases, for which there are few effective treatments available. Photoreceptor transplantation represents one approach, but generally results have been disappointing. We hypothesize that micropatterned biodegradable poly(L-lactic acid-co-glycolic acid)/poly(hydroxybutyrate-co-hydroxyvaleric acid) (PLGA-PHBV8) blend films could deliver photoreceptor cells in a more organized manner than bolus injections. Blending of PLGA and PHBV8 was used to optimize the degradation rate of the temporary template. At the end of 8 weeks, for both thin and thick films of PLGA-PHBV8 a 50% decrease of their initial weight with increasing water uptake was observed. When photoreceptor cells were seeded onto micropatterned PLGA-PHBV8 films with parallel grooves (21- and 42-microm-wide grooves and 20 microm ridge width and depth), the cells preferred laminin-deposited grooves to ridges and expressed rod- and cone-specific markers such as rhodopsin and arrestin. A loss in photoreceptor viability of 50% was observed after 7 days in culture. The effects of either retinal pigment epithelium (RPE)-derived or Muller glial cell-derived conditioned media or bFGF on the survival of photoreceptor cells seeded on PLGA-PHBV8 films were investigated. Addition of either RPE- and Muller-conditioned media increased statistically (p < 0.01) the viability of photoreceptor cells after 7 days of incubation. Our results suggest that such biodegradable micropatterned PLGA-PHBV8 blend films have a potential to deliver photoreceptor cells to the subretinal space and ensure laminar organization and maintenance of differentiation, and that incorporation of intrinsic factors within the scaffold would enhance the survival rate of transplanted cells.
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Affiliation(s)
- A Tezcaner
- Department of Engineering Sciences, Middle East Technical University, Ankara 06531, Turkey
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38
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Sheedlo HJ, Bartosh TJ, Wang Z, Srinivasan B, Brun-Zinkernagel AM, Roque RS. RPE-derived factors modulate photoreceptor differentiation: a possible role in the retinal stem cell niche. In Vitro Cell Dev Biol Anim 2007; 43:361-70. [PMID: 17924175 DOI: 10.1007/s11626-007-9051-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2007] [Accepted: 07/11/2007] [Indexed: 12/28/2022]
Abstract
A photoreceptor cell line, designated 661W, was tested for its response to growth factors secreted by retinal pigment epithelial cells including basic fibroblast growth factor, epidermal growth factor, and nerve growth factor. Early passaged 661W cells expressed high levels of retinal progenitor markers such as nestin and Pax6, but not opsin or glial fibrillary acidic protein. 661W cells grown in FGF-2 or EGF exhibited a multiple-process morphology with small phase-bright nuclei similar to neurons, whereas cells cultured in nerve growth factor (NGF) or retinal pigment epithelium (RPE)-conditioned medium (RPE-CM) displayed rounded profiles lacking processes. 661W cells grown in FGF-2 were slightly elevated, but not significantly above, control cultures; but cells treated with RPE-CM or NGF were fewer, approximately 63% and 49% of control, respectively. NGF immunodepletion of RPE-CM strongly suppressed the inhibitory activity of RPE-CM on cell proliferation. Cells treated with FGF-2, but not NGF, upregulated their expression of opsin. All treatment conditions resulted in almost 100% viability based on calcium AM staining. Cells grown on extracellular matrix proteins laminin, fibronectin, and/or collagen resembled those grown on untreated dishes. This study showed that early passaged 661W cells displayed characteristics of retinal progenitor cells. The 661W cells proliferated and appeared to mature morphologically expressing rod photoreceptor phenotype in response to FGF-2. In contrast, NGF and RPE-CM inhibited proliferation and morphological differentiation of 661W cells, possibly inducing cell cycle arrest. These findings are consistent with reports that the RPE modulates photoreceptor differentiation and retinal progenitor cells via secreted factors and may play a role in the regulation of the retinal stem cell niche.
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Affiliation(s)
- Harold J Sheedlo
- Department of Cell Biology and Genetics, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
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Lai TYY, Chan WM, Lai RYK, Ngai JWS, Li H, Lam DSC. The clinical applications of multifocal electroretinography: a systematic review. Surv Ophthalmol 2007; 52:61-96. [PMID: 17212991 DOI: 10.1016/j.survophthal.2006.10.005] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Multifocal electroretinography (mfERG) is an investigation that can simultaneously measure multiple electroretinographic responses at different retinal locations by cross-correlation techniques. mfERG therefore allows topographic mapping of retinal function in the central 40-50 degrees of the retina. The strength of mfERG lies in its ability to provide objective assessment of the central retinal function at different retinal areas within a short duration of time. Since the introduction of mfERG in 1992, mfERG has been applied in a large variety of clinical settings. This article reviews the clinical applications of mfERG based on the currently available evidence. mfERG has been found to be useful in the assessment of localized retinal dysfunction caused by various acquired or hereditary retinal disorders. The use of mfERG also enabled clinicians to objectively monitor the treatment outcomes as the changes in visual functions might not be reflected by subjective methods of assessment. By changing the stimulus, recording, and analysis parameters, investigation of specific retinal electrophysiological components can be performed topographically. Further developments and consolidations of these parameters will likely broaden the use of mfERG in the clinical setting.
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Affiliation(s)
- Timothy Y Y Lai
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
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40
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Kumar R, Dutt K. Enhanced Neurotrophin Synthesis and Molecular Differentiation in Non-Transformed Human Retinal Progenitor Cells Cultured in a Rotating Bioreactor. ACTA ACUST UNITED AC 2006; 12:141-58. [PMID: 16499451 DOI: 10.1089/ten.2006.12.141] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
One approach to the treatment of retinal diseases, such as retinitis pigmentosa, is to replace diseased or degenerating cells with healthy cells. Even if all of the problems associated with tissue transplant were to be resolved, the availability of tissue would remain an ongoing problem. We have previously shown that transformed human retinal cells can be grown in a NASA-developed horizontally rotating culture vessel (bioreactor) to form three-dimensional-like structures with the expression of several retinal specific proteins. In this study, we have investigated growth of non-transformed human retinal progenitors (retinal stem cells) in a rotating bioreactor. This rotating culture vessel promotes cell-cell interaction between similar and dissimilar cells. We cultured retinal progenitors (Ret 1-4) alone or as a co-culture with human retinal pigment epithelial cells (RPE, D407) in this system to determine if 3D structures can be generated from non-transformed progenitors. Our second goal was to determine if the formation of 3D structures correlates with the upregulation of neurotrophins, basic fibroblast growth factor (bFGF), transforming growth factor alpha (TGFalpha), ciliary neurotrophic factor (CNTF), and brain-delivered neurotrophic factor (BDNF). These factors have been implicated in progenitor cell proliferation, commitment, differentiation, and survival. We also investigated the expression of the following retinal specific proteins in this system: neuron specific enolase (NSE); tyrosine hydroxylase (TH); D(2)D(3), D(4) receptors; protein kinase-C alpha (PKCalpha), and calbindin. The 3D structures generated were characterized by phase and scanning transmission electron microscopy. Retinal progenitors, cultured alone or as a co-culture in the rotating bioreactor, formed 3D structures with some degree of differentiation, accompanied by the upregulation of bFGF, CNTF, and TGFalpha. Brain-derived neurotrophic factor, which is expressed in vivo in RPE (D407), was not expressed in monolayer cultures of RPE but expressed in the rotating bioreactor-cultured RPE and retinal progenitors (Ret 1-4). Upregulation of neurotrophins was noted in all rotating bioreactor-cultured cells. Also, upregulation of D(4) receptor, calbindin, and PKCalpha was noted in the rotating bioreactor-cultured cells. We conclude that non-transformed retinal progenitors can be grown in the rotating bioreactor to form 3D structures with some degree of differentiation. We relied on molecular and biochemical analysis to characterize differentiation in cells grown in the rotating bioreactor.
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Affiliation(s)
- Ravindra Kumar
- Department of Pathology, Morehouse School of Medicine, Atlanta, Georgia, USA
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41
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Retinal Pigment Epithelium and Photoreceptor Transplantation Frontiers. Retina 2006. [DOI: 10.1016/b978-0-323-02598-0.50159-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Feigl B, Lovie-Kitchin J, Brown B. Objective functional assessment of age‐related maculopathy: a special application for the multifocal electroretinogram. Clin Exp Optom 2005; 88:304-12. [PMID: 16255689 DOI: 10.1111/j.1444-0938.2005.tb06714.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2005] [Revised: 07/25/2005] [Accepted: 07/28/2005] [Indexed: 11/30/2022] Open
Abstract
This paper gives a brief review of methods that assess objectively function in age-related maculopathy (ARM) with emphasis on a newer method, the multifocal electroretinogram (mfERG). In contrast to other electrophysiological tests, such as the full-field and focal electroretinogram (ERG) or the electro-oculogram (EOG), which measure summed responses from various cells from larger areas of the retina, the multifocal electroretinogram maps function locally with a resolution as small as four degrees within the central 30 degrees. By using different paradigms it can measure local cone- and rod-mediated functional impairment at early and late stages of ARM. This improved mapping and higher resolution of the posterior pole compared to other objective methods might lead to earlier detection of ARM. Its usefulness has been demonstrated in documenting the effects of treatment after established laser treatments, such as photodynamic therapy (PDT) and in documenting function after retinal pigment epithelial transplantation, a possible future treatment in late neovascular ARM.
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Affiliation(s)
- Beatrix Feigl
- Queensland University of Technology, Victoria Park Road, Kelvin Grove, QLD, 4059, Australia.
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Arai S, Thomas BB, Seiler MJ, Aramant RB, Qiu G, Mui C, de Juan E, Sadda SR. Restoration of visual responses following transplantation of intact retinal sheets in rd mice. Exp Eye Res 2004; 79:331-41. [PMID: 15336495 DOI: 10.1016/j.exer.2004.05.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2003] [Accepted: 05/13/2004] [Indexed: 11/17/2022]
Abstract
PURPOSE To correlate the functional outcomes with histologic findings following transplantation of fetal retinal sheets in rd mice, and to investigate the mechanisms of visual function restoration. METHODS Twenty-one postnatal day 31-38 rd/rd (C3H/HeJ) mice were transplanted in one eye with retinal sheets (1.0 x 0.4 mm) obtained from embryonic day (E) 17 enhanced-green-fluorescent protein (eGFP) mice. Five mice underwent sham surgery without insertion of tissue. Four to five weeks after transplantation, visual responses to a light flash were recorded across the superior colliculus (SC) in seven eyes of seven transplanted mice that had clear corneas and lenses, and in all five sham surgery mice. Following the SC recording, the eyes were enucleated and processed for immunohistochemistry and examined using confocal microscopy. RESULTS In three out of the seven eyes (43%), positive responses were recorded in the SC in an area topographically corresponding to the placement of the transplant in the host retina. No responses were recorded in the untreated eyes of 5-week-old and 9-week-old rd/rd mice, and in the 9-week-old sham surgery mice. In contrast, visual responses were recorded over the entire SC in normal eyes. The response onset latencies of the 3 transplanted mice with responses were similar to those of normal control mice. The organization of the graft did not appear to correlate as expected with the electrophysiology results, as eyes with well-organized, laminated grafts showed no response whereas the three light-responsive eyes had rosetted or disorganized grafts. All three light-responsive eyes demonstrated much higher levels of recoverin immunoreactivity in the host retina overlying the graft compared with untreated age-matched rd/rd mice. CONCLUSION Restoration of the SC visual response does not appear to depend on a well-organized transplant in the rd mouse. Increased recoverin-staining in the host retina in light-responsive animals suggested that host cone rescue was the likely mechanism of vision restoration in this transplant model.
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Affiliation(s)
- S Arai
- Doheny Retina Institute, Keck School of Medicine, University of Southern California, DEI 3610, 1450 San Pablo Street, Los Angeles 90033-3699, USA
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Wojciechowski AB, Englund U, Lundberg C, Warfvinge K. Survival and Long Distance Migration of Brain‐Derived Precursor Cells Transplanted to Adult Rat Retina. Stem Cells 2004; 22:27-38. [PMID: 14688389 DOI: 10.1634/stemcells.22-1-27] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Neural precursor cells transplanted to adult retina can integrate into the host. This is especially true when the neural precursor rat cell line RN33B is used. This cell line carries the reporter genes LacZ and green fluorescent protein (GFP). In grafted rat eyes, RN33B cells are localized from one eccentricity to the other of the host retina. In the present study, whole-mounted retinas were analyzed to obtain a more appropriate evaluation of the amount of transgene-expressing cells and the migratory capacity of these cells 3 and 8 weeks post-transplantation. Quantification was made of the number of beta-galactosidase- and GFP-expressing cells with a semiautomatized stereological cell counting system. With the same system, delineation of the distribution area of the grafted cells was also performed. At 3 weeks, 68% of the grafted eyes contained marker-expressing cells, whereas at 8 weeks only 35% of the eyes contained such cells. Counting of marker-expressing cells demonstrated a lower number of transgene-expressing cells at 3 weeks compared with 8 weeks post-transplantation. The distribution pattern of marker gene-expressing cells revealed cells occupying up to 21% at 3 weeks and up to 68% at 8 weeks of the entire host retina post-grafting. The precursor cells survived well in the adult retina although the most striking feature of the RN33B cell line was its extraordinary migratory capacity. This capability could be useful if precursor cells are used to deliver necessary genes or gene products that need to be distributed over a large diseased area.
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Affiliation(s)
- Anita Blixt Wojciechowski
- Wallenberg Retina Center, Department of Ophthalmology, Lund University Hospital, Lund University, Lund, Sweden.
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Berger AS, Tezel TH, Del Priore LV, Kaplan HJ. Photoreceptor transplantation in retinitis pigmentosa: short-term follow-up. Ophthalmology 2003; 110:383-91. [PMID: 12578785 DOI: 10.1016/s0161-6420(02)01738-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
PURPOSE To explore the use of adult human photoreceptor transplantation as a treatment for advanced retinitis pigmentosa (RP). DESIGN Prospective noncomparative case series. PARTICIPANTS Eight patients with advanced RP. INTERVENTION Transplantation of adult human cadaver photoreceptor sheets harvested with the excimer laser. No immunosuppression was used postoperatively. Patients were followed for 12 months postoperatively. MAIN OUTCOME MEASURE Visual acuity and retinal function measured by psychophysical, electrophysiologic, and clinical testing. RESULTS Best-corrected visual acuity (Bailey-Lovie chart), median reading speed, contrast sensitivity, and visual fields for the operated eye were not statistically significantly improved postoperatively. The amplitude and latency of the maculoscope electroretinogram, as well as the log threshold for dark adaptation, did not change between the operated and control (unoperated) eye. There was no detectable homograft reaction on slit-lamp biomicroscopy or fluorescein angiography. The only adverse effect observed was one patient who complained of monocular diplopia after retinal transplantation and subsequent cataract surgery. CONCLUSIONS Allogeneic adult human photoreceptor transplantation is feasible in RP but was not associated with rescue of central vision or a delay in visual loss. However, any possible slowing in the rate of retinal degeneration will take many years to determine.
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Affiliation(s)
- Adam S Berger
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA
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Akita J, Takahashi M, Hojo M, Nishida A, Haruta M, Honda Y. Neuronal differentiation of adult rat hippocampus-derived neural stem cells transplanted into embryonic rat explanted retinas with retinoic acid pretreatment. Brain Res 2002; 954:286-93. [PMID: 12414111 DOI: 10.1016/s0006-8993(02)03356-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The purpose of this study was to evaluate the effects of the retinal environment and retinoic acid (RA) pretreatment on the differentiation of transplanted adult rat hippocampus-derived neural stem cells (AHSCs). AHSCs were transplanted into embryonic (E18) or neonatal (P6) rat retinal explants and the mixture was cultured for 2 weeks. Other AHSCs were stimulated by 0.5 microM all-trans RA for 6 days before transplantation. Immunofluorescent double staining showed that a larger number of AHSCs became beta-tubulin III-positive neurons in the E18 than in P6 retinas. In addition, many AHSCs became MAP2ab-positive and MAP5-positive neurons following RA pretreatment and transplantation. Only a few AHSCs became HPC-1-, calbindin-, PKC- or rhodopsin-positive cells under these conditions. We conclude that the microenvironment supplied by embryonic retinas is conductive to neuronal differentiation in general. RA stimulation before transplantation was also effective in stimulating differentiation.
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Affiliation(s)
- Joe Akita
- Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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Lu B, Kwan T, Kurimoto Y, Shatos M, Lund RD, Young MJ. Transplantation of EGF-responsive neurospheres from GFP transgenic mice into the eyes of rd mice. Brain Res 2002; 943:292-300. [PMID: 12101053 DOI: 10.1016/s0006-8993(02)02906-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The isolation of stem cells from various regions of the central nervous system has raised the possibility of using them as a donor cell source for cell transplantation, where they offer great promise for repair of the diseased brain, spinal cord, and retina. Here, we have studied the migration, integration, and differentiation of EGF-responsive neurospheres isolated from the brains of green fluorescent protein transgenic mice and transplanted into the eyes of mature rd mice, a model of retinitis pigmentosa. While grafts of freshly isolated postnatal day 8 retina expressed many markers characteristic of mature retina (e.g. rhodopsin, protein kinase C), very few of the grafted cells migrated into host retina. EGF-responsive neurospheres, conversely, readily migrated into and integrated with the remaining host retina, but showed a very limited ability to differentiate into mature retinal neurons. While the progenitor cells used here show remarkable ability to integrate with host retina and develop some attributes of retinal cells, the failure to fully differentiate into retinal cells suggests that they already express some level of terminal commitment that precludes using them to replace lost photoreceptors.
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Affiliation(s)
- B Lu
- Moran Eye Center, 75 N. Medical Drive, University of Utah Health Science Center, Salt Lake City, UT 84132, USA
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48
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Radtke ND, Seiler MJ, Aramant RB, Petry HM, Pidwell DJ. Transplantation of intact sheets of fetal neural retina with its retinal pigment epithelium in retinitis pigmentosa patients. Am J Ophthalmol 2002; 133:544-50. [PMID: 11931789 DOI: 10.1016/s0002-9394(02)01322-3] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
PURPOSE To show the safety of transplanting sheets of fetal neural retina together with its retinal pigment epithelium (RPE) to patients with retinitis pigmentosa. DESIGN Interventional case series. METHODS Sheets of fetal neural retina and RPE were transplanted together into the subretinal space near the fovea unilaterally in the eyes of five patients with retinitis pigmentosa who had only light perception in both eyes. The patients were followed for 6 months. The main outcome measures were tissue typing of both donors and recipients, fluorescein angiography, multifocal electroretinogram (mfERG) testing, and clinical examination. No immunosuppressive medications were given. RESULTS No evidence of rejection was observed. Up to 6 months there was no evidence of tissue disintegration, retinal edema, or scarring. There was no change in vision both by Snellen acuity and with mfERGs. Growth of the transplant was noted in two of five patients at 6 months vs. 2 weeks. All patients typed were HLA mismatched with donor tissue. CONCLUSIONS This study indicates that fetal retina can be transplanted together with its RPE and survive for at least 6 months without evidence of rejection. However, no improvements in vision were observed, possibly due to the severe retinal degeneration of the patients.
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Affiliation(s)
- Norman D Radtke
- Retina Vitreous Resource Center, Norton Audubon Hospital, Louisville, Kentucky 40217, USA.
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Abstract
Retinal transplantation aims to prevent blindness and to restore eyesight, i.e., to rescue photoreceptors or to replace damaged photoreceptors with the hope of reestablishing neural circuitry. Retinal donor tissue has been transplanted as dissociated cells or intact sheets. A promising experimental paradigm is the subretinal transplantation of sheets of fetal retina with or without its attached retinal pigment epithelium (RPE) into recipient rats with retinal degeneration. As long as healthy RPE either from the host or from the graft is present, such transplants can develop lamination resembling a normal retina. Different methods have been used to demonstrate transplant/host connectivity. In two different rat retinal degeneration models, visually evoked responses can be demonstrated in an area of the superior colliculus corresponding to the placement of the transplant in the retina. In summary, sheets of fetal retina can morphologically repair an area of a degenerated retina, and there is evidence to suggest that transplants form synaptic connections with the host and restore visual responses in blind rats.
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Affiliation(s)
- Robert B Aramant
- Department of Ophthalmology and Visual Sciences, University of Louisville, School of Medicine, 301 E. Muhammad Ali Blvd., KY 40202, USA.
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Lund RD, Kwan AS, Keegan DJ, Sauvé Y, Coffey PJ, Lawrence JM. Cell transplantation as a treatment for retinal disease. Prog Retin Eye Res 2001; 20:415-49. [PMID: 11390255 DOI: 10.1016/s1350-9462(01)00003-9] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
It has been shown that photoreceptor degeneration can be limited in experimental animals by transplantation of fresh RPE to the subretinal space. There is also evidence that retinal cell transplants can be used to reconstruct retinal circuitry in dystrophic animals. Here we describe and review recent developments that highlight the necessary steps that should be taken prior to embarking on clinical trials in humans.
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Affiliation(s)
- R D Lund
- Institute of Ophthalmology, Bath Street, EC1V 9EL, London, UK
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