Reference Citation Analysis: Find an Article, Find a Category, Find a Journal, Find a Scholar

For: Lund RD, Wang S, Klimanskaya I, Holmes T, Ramos-Kelsey R, Lu B, Girman S, Bischoff N, Sauvé Y, Lanza R. Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats. Cloning Stem Cells 2006;8:189-99. [PMID: 17009895 DOI: 10.1089/clo.2006.8.189] [Citation(s) in RCA: 281] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [What about the content of this article? (0)] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]

For:	Lund RD, Wang S, Klimanskaya I, Holmes T, Ramos-Kelsey R, Lu B, Girman S, Bischoff N, Sauvé Y, Lanza R. Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats. Cloning Stem Cells 2006;8:189-99. [PMID: 17009895 DOI: 10.1089/clo.2006.8.189] [Citation(s) in RCA: 281] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [What about the content of this article? (0)] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]

Number

Cited by Other Article(s)

Hushmandi K, Lam HY, Wong WM, Tan W, Daryabari SH, Reiter RJ, Farahani N, Kumar AP. Gene therapy for age-related macular degeneration: a promising frontier in vision preservation. Cell Commun Signal 2025;23:233. [PMID: 40394614 PMCID: PMC12090701 DOI: 10.1186/s12964-025-02246-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 05/11/2025] [Indexed: 05/22/2025] Open

Wu KY, Dhaliwal JK, Sasitharan A, Kalevar A. Cell Therapy for Retinal Degenerative Diseases: Progress and Prospects. Pharmaceutics 2024;16:1299. [PMID: 39458628 PMCID: PMC11510658 DOI: 10.3390/pharmaceutics16101299] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 10/28/2024] Open

Rajendran Nair DS, Camarillo JCM, Lu G, Thomas BB. Measuring spatial visual loss in rats by retinotopic mapping of the superior colliculus using a novel multi-electrode array technique. J Neurosci Methods 2024;405:110095. [PMID: 38403001 PMCID: PMC11363873 DOI: 10.1016/j.jneumeth.2024.110095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 02/06/2024] [Accepted: 02/22/2024] [Indexed: 02/27/2024]

Abstract

BACKGROUND

The retinotopic map property of the superior colliculus (SC) is a reliable indicator of visual functional changes in rodents. Electrophysiological mapping of the SC using a single electrode has been employed for measuring visual function in rat and mouse disease models. Single electrode mapping is highly laborious requiring long-term exposure to the SC surface and prolonged anesthetic conditions that can adversely affect the mapping data.

NEW METHOD

To avoid the above-mentioned issues, we fabricated a fifty-six (56) electrode multi-electrode array (MEA) for rapid and reliable visual functional mapping of the SC. Since SC is a dome-shaped structure, the array was made of electrodes with dissimilar tip lengths to enable simultaneous and uniform penetration of the SC.

RESULTS

SC mapping using the new MEA was conducted in retinal degenerate (RD) Royal College of Surgeons (RCS) rats and rats with focal retinal damage induced by green diode laser. For SC mapping, the MEA was advanced into the SC surface and the visual activities were recorded during full-filed light stimulation of the eye. Based on the morphological examination, the MEA electrodes covered most of the exposed SC area and penetrated the SC surface at a relatively uniform depth. MEA mapping in RCS rats (n=9) demonstrated progressive development of a scotoma in the SC that corresponded to the degree of photoreceptor loss. MEA mapping in the laser damaged rats demonstrated the presence of a scotoma in the SC area that corresponded to the location of retinal laser injury.

COMPARISON WITH EXISTING METHODS AND CONCLUSIONS

The use of MEA for SC mapping is advantageous over single electrode recording by enabling faster recordings and reducing anesthesia time. This study establishes the feasibility of the MEA technique for rapid and efficient SC mapping, particularly advantageous for evaluating therapeutic effects in retinal degenerate rat disease models.

Collapse

Ahluwalia K, Du Z, Martinez-Camarillo JC, Naik A, Thomas BB, Pollalis D, Lee SY, Dave P, Zhou E, Li Z, Chester C, Humayun MS, Louie SG. Unveiling Drivers of Retinal Degeneration in RCS Rats: Functional, Morphological, and Molecular Insights. Int J Mol Sci 2024;25:3749. [PMID: 38612560 PMCID: PMC11011632 DOI: 10.3390/ijms25073749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/12/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open

Affiliation(s)

Kabir Ahluwalia Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.N.); (P.D.); (E.Z.); (Z.L.); (C.C.)
Zhaodong Du USC Ginsburg Institute of for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA; (Z.D.); (J.C.M.-C.); (B.B.T.); (D.P.); (S.Y.L.); (M.S.H.)
Juan Carlos Martinez-Camarillo USC Ginsburg Institute of for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA; (Z.D.); (J.C.M.-C.); (B.B.T.); (D.P.); (S.Y.L.); (M.S.H.) Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Aditya Naik Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.N.); (P.D.); (E.Z.); (Z.L.); (C.C.)
Biju B. Thomas USC Ginsburg Institute of for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA; (Z.D.); (J.C.M.-C.); (B.B.T.); (D.P.); (S.Y.L.); (M.S.H.) Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Dimitrios Pollalis USC Ginsburg Institute of for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA; (Z.D.); (J.C.M.-C.); (B.B.T.); (D.P.); (S.Y.L.); (M.S.H.) Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Sun Young Lee USC Ginsburg Institute of for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA; (Z.D.); (J.C.M.-C.); (B.B.T.); (D.P.); (S.Y.L.); (M.S.H.) Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA Department of Physiology & Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
Priyal Dave Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.N.); (P.D.); (E.Z.); (Z.L.); (C.C.)
Eugene Zhou Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.N.); (P.D.); (E.Z.); (Z.L.); (C.C.)
Zeyang Li Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.N.); (P.D.); (E.Z.); (Z.L.); (C.C.)
Catherine Chester Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.N.); (P.D.); (E.Z.); (Z.L.); (C.C.)
Mark S. Humayun USC Ginsburg Institute of for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA; (Z.D.); (J.C.M.-C.); (B.B.T.); (D.P.); (S.Y.L.); (M.S.H.) Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Stan G. Louie Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.N.); (P.D.); (E.Z.); (Z.L.); (C.C.) USC Ginsburg Institute of for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA; (Z.D.); (J.C.M.-C.); (B.B.T.); (D.P.); (S.Y.L.); (M.S.H.)

Collapse

Pollalis D, Calle AG, Martinez-Camarillo JC, Ahluwalia K, Hinman C, Mitra D, Lebkowski J, Lee SY, Thomas BB, Ahmed F, Chan V, Junge JA, Fraser S, Louie S, Humayun M. Scaling up polarized RPE cell supernatant production on parylene membrane. Exp Eye Res 2024;240:109789. [PMID: 38242423 DOI: 10.1016/j.exer.2024.109789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/09/2024] [Accepted: 01/10/2024] [Indexed: 01/21/2024]

Abstract

Age-related macular degeneration (AMD), a leading cause of vision loss, primarily arises from the degeneration of retinal pigment epithelium (RPE) and photoreceptors. Current therapeutic options for dry AMD are limited. Encouragingly, cultured RPE cells on parylene-based biomimetic Bruch's membrane demonstrate characteristics akin to the native RPE layer. In this study, we cultivated human embryonic stem cell-derived polarized RPE (hESC-PRPE) cells on parylene membranes at both small- and large-scale settings, collecting conditioned supernatant, denoted as PRPE-SF. We conducted a comprehensive analysis of the morphology of the cultured hESC-RPE cells and the secreted growth factors in PRPE-SF. To evaluate the in vivo efficacy of these products, the product was administered via intravitreal injections of PRPE-SF in immunodeficient Royal College of Surgeons (iRCS) rats, a model for retinal degeneration. Our study not only demonstrated the scalability of PRPE-SF production while maintaining RPE cell phenotype but also showed consistent protein concentrations between small- and large-scale batches. We consistently identified 10 key factors in PRPE-SF, including BMP-7, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6, MANF, PEDF, PDGF-AA, TGFβ1, and VEGF. Following intravitreal administration of PRPE-SF, we observed a significant increase in the thickness of the outer nuclear layer (ONL) and photoreceptor preservation in iRCS rats. Furthermore, correlation analysis revealed that IGFBP-3, IGFBP-4, MANF, PEDF, and TGFβ1 displayed positive associations with in vivo bioactivity, while GDF-15 exhibited a negative correlation. Overall, this study highlights the feasibility of scaling up PRPE-SF production on parylene membranes without compromising its essential constituents. The outcomes of PRPE-SF administration in an animal model of retinal degeneration present substantial potential for photoreceptor preservation. Moreover, the identification of candidate surrogate potency markers, showing strong positive associations with in vivo bioactivity, lays a solid foundation for the development of a promising therapeutic intervention for retinal degenerative diseases.

Collapse

Affiliation(s)

Dimitrios Pollalis USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA
Alejandra Gonzalez Calle USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA
Juan Carlos Martinez-Camarillo USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA
Kabir Ahluwalia USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA; USC Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA
Cassidy Hinman USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA
Debbie Mitra USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA
Jane Lebkowski Regenerative Patch Technologies LLC, Menlo Park, CA 94028, USA
Sun Young Lee USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA
Biju B Thomas USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA
Faizah Ahmed USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA
Victoria Chan USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA
Jason A Junge Translational Imaging Center, University of Southern California, Los Angeles, CA 90089, USA
Scott Fraser Translational Imaging Center, University of Southern California, Los Angeles, CA 90089, USA
Stan Louie USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA; USC Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA
Mark Humayun USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; USC Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA.

Collapse

Lu B, Avalos P, Svendsen S, Zhang C, Nocito L, Jones MK, Pieplow C, Saylor J, Ghiam S, Block A, Fernandez M, Ljubimov AV, Small K, Liao D, Svendsen CN, Wang S. GMP-grade human neural progenitors delivered subretinally protect vision in rat model of retinal degeneration and survive in minipigs. J Transl Med 2023;21:650. [PMID: 37743503 PMCID: PMC10519102 DOI: 10.1186/s12967-023-04501-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 09/02/2023] [Indexed: 09/26/2023] Open

Affiliation(s)

Bin Lu Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Pablo Avalos Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Soshana Svendsen Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Changqing Zhang Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Laura Nocito Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Melissa K Jones Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Cosmo Pieplow Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Joshua Saylor Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Sean Ghiam Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Amanda Block Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Michael Fernandez Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Alexander V Ljubimov Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
Kent Small Macula& Retina Institute, Glendale, CA, 91203, USA
David Liao Retina Vitreous Associates Medical Group, Beverly Hills, CA, 90211, USA
Clive N Svendsen Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Shaomei Wang Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.

Collapse

Voisin A, Pénaguin A, Gaillard A, Leveziel N. Stem cell therapy in retinal diseases. Neural Regen Res 2023;18:1478-1485. [PMID: 36571345 PMCID: PMC10075102 DOI: 10.4103/1673-5374.361537] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open

Zhen F, Zou T, Wang T, Zhou Y, Dong S, Zhang H. Rhodopsin-associated retinal dystrophy: Disease mechanisms and therapeutic strategies. Front Neurosci 2023;17:1132179. [PMID: 37077319 PMCID: PMC10106759 DOI: 10.3389/fnins.2023.1132179] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 03/13/2023] [Indexed: 04/05/2023] Open

TRANSPLANTATION OF SUBRETINAL STEM CELL-DERIVED RETINAL PIGMENT EPITHELIUM FOR STARGARDT DISEASE: A Phase I Clinical Trial. Retina 2023;43:263-274. [PMID: 36223778 DOI: 10.1097/iae.0000000000003655] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]

Daniele E, Ferrari B, Rassu N, Ben-Nun J, Bosio L, Barbaro V, Ferrari S, Ponzin D. Comparison of human amniotic membrane decellularisation approaches for hESC-derived RPE cells culture. BMJ Open Ophthalmol 2022;7:bmjophth-2022-000981. [PMID: 36161850 PMCID: PMC9454075 DOI: 10.1136/bmjophth-2022-000981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 08/24/2022] [Indexed: 11/12/2022] Open

The Age-Related Macular Degeneration (AMD)-Preventing Mechanism of Natural Products. Processes (Basel) 2022. [DOI: 10.3390/pr10040678] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open

Embryonic stem cells-derived exosomes enhance retrodifferentiation of retinal Müller cells by delivering BDNF protein to activate Wnt pathway. Immunobiology 2022;227:152211. [DOI: 10.1016/j.imbio.2022.152211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 03/11/2022] [Accepted: 03/24/2022] [Indexed: 11/22/2022]

Sanie-Jahromi F, Nowroozzadeh MH. RPE based gene and cell therapy for inherited retinal diseases: A review. Exp Eye Res 2022;217:108961. [DOI: 10.1016/j.exer.2022.108961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 11/29/2022]

Christelle M, Lise M, Ben M'Barek K. Challenges of cell therapies for retinal diseases. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022;166:49-77. [DOI: 10.1016/bs.irn.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]

Rajendran Nair DS, Zhu D, Sharma R, Martinez Camarillo JC, Bharti K, Hinton DR, Humayun MS, Thomas BB. Long-Term Transplant Effects of iPSC-RPE Monolayer in Immunodeficient RCS Rats. Cells 2021;10:cells10112951. [PMID: 34831174 PMCID: PMC8616297 DOI: 10.3390/cells10112951] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 10/24/2021] [Accepted: 10/25/2021] [Indexed: 12/29/2022] Open

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.

Collapse

Hinkle JW, Mahmoudzadeh R, Kuriyan AE. Cell-based therapies for retinal diseases: a review of clinical trials and direct to consumer "cell therapy" clinics. Stem Cell Res Ther 2021;12:538. [PMID: 34635174 PMCID: PMC8504041 DOI: 10.1186/s13287-021-02546-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 08/04/2021] [Indexed: 02/02/2023] Open

Abstract

Background

The retinal pigment epithelium (RPE) is implicated in the pathophysiology of many retinal degenerative diseases. This cell layer is also an ideal target for cell-based therapies. Several early phase clinical trials evaluating cell therapy approaches for diseases involving the RPE, such as age-related macular degeneration and Stargardt's macular dystrophy have been published. However, there have also been numerous reports of complications from unproven “cell therapy” treatments marketed by “cell therapy” clinics. This review aims to outline the particular approaches in the different published clinical trials for cell-based therapies for retinal diseases. Additionally, the controversies surrounding experimental treatments offered outside of legitimate studies are presented.

Main body

Cell-based therapies can be applied to disorders that involve the RPE via a variety of techniques. A defining characteristic of any cell therapy treatment is the cell source used: human embryonic stem cells, induced pluripotent stem cells, and human umbilical tissue-derived cells have all been studied in published trials. In addition to the cell source, various trials have evaluated particular immunosuppression regiments, surgical approaches, and outcome measures. Data from early phase studies investigating cell-based therapies in non-neovascular age-related macular degeneration (70 patients, five trials), neovascular age-related macular degeneration (12 patients, four trials), and Stargardt’s macular dystrophy (23 patients, three trials) have demonstrated safety related to the cell therapies, though evidence of significant efficacy has not been reported. This is in contrast to the multiple reports of serious complications and permanent vision loss in patients treated at “cell therapy” clinics. These interventions are marketed directly to patients, funded by the patient, lack Food and Drug Administration approval, and lack significant oversight.

Conclusion

Currently, there are no proven effective cell-based treatments for retinal diseases, although several trials have investigated potential therapies. These studies reported favorable safety profiles with multiple surgical approaches, with cells derived from multiple sources, and with utilized different immunosuppressive regiments. However, data demonstrating the efficacy and long-term safety are still pending. Nevertheless, “cell therapy” clinics continue to conduct direct-to consumer marketing for non-FDA-approved treatments with potentially blinding complications.

Collapse

Huang D, Heath Jeffery RC, Aung-Htut MT, McLenachan S, Fletcher S, Wilton SD, Chen FK. Stargardt disease and progress in therapeutic strategies. Ophthalmic Genet 2021;43:1-26. [PMID: 34455905 DOI: 10.1080/13816810.2021.1966053] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]

Affiliation(s)

Di Huang Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Western Australia, Australia.,Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), the University of Western Australia, Nedlands, Western Australia, Australia.,Perron Institute for Neurological and Translational Science & the University of Western Australia, Nedlands, Western Australia, Australia
Rachael C Heath Jeffery Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), the University of Western Australia, Nedlands, Western Australia, Australia
May Thandar Aung-Htut Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Western Australia, Australia.,Perron Institute for Neurological and Translational Science & the University of Western Australia, Nedlands, Western Australia, Australia
Samuel McLenachan Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), the University of Western Australia, Nedlands, Western Australia, Australia
Sue Fletcher Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Western Australia, Australia.,Perron Institute for Neurological and Translational Science & the University of Western Australia, Nedlands, Western Australia, Australia
Steve D Wilton Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Western Australia, Australia.,Perron Institute for Neurological and Translational Science & the University of Western Australia, Nedlands, Western Australia, Australia
Fred K Chen Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), the University of Western Australia, Nedlands, Western Australia, Australia.,Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.,Department of Ophthalmology, Royal Perth Hospital, Perth, Western Australia, Australia.,Department of Ophthalmology, Perth Children's Hospital, Nedlands, Western Australia, Australia

Collapse

Petrash CC, Palestine AG, Canto-Soler MV. Immunologic Rejection of Transplanted Retinal Pigmented Epithelium: Mechanisms and Strategies for Prevention. Front Immunol 2021;12:621007. [PMID: 34054796 PMCID: PMC8153373 DOI: 10.3389/fimmu.2021.621007] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/28/2021] [Indexed: 12/15/2022] Open

Limnios IJ, Chau YQ, Skabo SJ, Surrao DC, O'Neill HC. Efficient differentiation of human embryonic stem cells to retinal pigment epithelium under defined conditions. Stem Cell Res Ther 2021;12:248. [PMID: 33883023 PMCID: PMC8058973 DOI: 10.1186/s13287-021-02316-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 03/30/2021] [Indexed: 11/11/2022] Open

Pennington BO, Bailey JK, Faynus MA, Hinman C, Hee MN, Ritts R, Nadar V, Zhu D, Mitra D, Martinez-Camarillo JC, Lin TC, Thomas BB, Hinton DR, Humayun MS, Lebkowski J, Johnson LV, Clegg DO. Xeno-free cryopreservation of adherent retinal pigmented epithelium yields viable and functional cells in vitro and in vivo. Sci Rep 2021;11:6286. [PMID: 33737600 PMCID: PMC7973769 DOI: 10.1038/s41598-021-85631-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 03/03/2021] [Indexed: 01/31/2023] Open

Affiliation(s)

Britney O. Pennington grid.133342.40000 0004 1936 9676Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, University of California, 6131 Biology 2 Bldg 571, NRI, UC Santa Barbara, Santa Barbara, CA 93106 USA ,2Regenerative Patch Technologies LLC, Portola Valley, CA USA
Jeffrey K. Bailey grid.133342.40000 0004 1936 9676Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, University of California, 6131 Biology 2 Bldg 571, NRI, UC Santa Barbara, Santa Barbara, CA 93106 USA ,2Regenerative Patch Technologies LLC, Portola Valley, CA USA
Mohamed A. Faynus grid.133342.40000 0004 1936 9676Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, University of California, 6131 Biology 2 Bldg 571, NRI, UC Santa Barbara, Santa Barbara, CA 93106 USA ,2Regenerative Patch Technologies LLC, Portola Valley, CA USA
Cassidy Hinman grid.133342.40000 0004 1936 9676Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, University of California, 6131 Biology 2 Bldg 571, NRI, UC Santa Barbara, Santa Barbara, CA 93106 USA ,2Regenerative Patch Technologies LLC, Portola Valley, CA USA
Mitchell N. Hee grid.133342.40000 0004 1936 9676College of Creative Studies, Biology, University of California, Santa Barbara, CA USA
Rory Ritts grid.133342.40000 0004 1936 9676Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, CA USA
Vignesh Nadar Regenerative Patch Technologies LLC, Portola Valley, CA USA
Danhong Zhu grid.42505.360000 0001 2156 6853Department of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA USA
Debbie Mitra grid.42505.360000 0001 2156 6853Department of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA USA
Juan Carlos Martinez-Camarillo grid.42505.360000 0001 2156 6853Department of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA USA ,7grid.42505.360000 0001 2156 6853USC Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA USA
Tai-Chi Lin grid.42505.360000 0001 2156 6853Department of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA USA
Biju B. Thomas grid.42505.360000 0001 2156 6853Department of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA USA ,7grid.42505.360000 0001 2156 6853USC Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA USA
David R. Hinton grid.42505.360000 0001 2156 6853Department of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA USA ,7grid.42505.360000 0001 2156 6853USC Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA USA
Mark S. Humayun grid.42505.360000 0001 2156 6853Department of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA USA ,6grid.42505.360000 0001 2156 6853Department of Biomedical Engineering, Denney Research Center (DRB) of the University of Southern California, Los Angeles, CA USA ,7grid.42505.360000 0001 2156 6853USC Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA USA
Jane Lebkowski Regenerative Patch Technologies LLC, Portola Valley, CA USA
Lincoln V. Johnson Regenerative Patch Technologies LLC, Portola Valley, CA USA
Dennis O. Clegg grid.133342.40000 0004 1936 9676Center for Stem Cell Biology and Engineering, Neuroscience Research Institute, University of California, 6131 Biology 2 Bldg 571, NRI, UC Santa Barbara, Santa Barbara, CA 93106 USA ,2Regenerative Patch Technologies LLC, Portola Valley, CA USA ,4grid.133342.40000 0004 1936 9676Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, CA USA

Collapse

Gao F, Li Z, Kang Z, Liu D, Li P, Ou Q, Xu JY, Li W, Tian H, Jin C, Wang J, Zhang J, Zhang J, Lu L, Xu GT. Inhibition of PARP activity improves therapeutic effect of ARPE-19 transplantation in RCS rats through decreasing photoreceptor death. Exp Eye Res 2021;204:108448. [PMID: 33484702 DOI: 10.1016/j.exer.2021.108448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 01/06/2021] [Accepted: 01/11/2021] [Indexed: 01/19/2023]

Affiliation(s)

Furong Gao Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China
Zongyi Li Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China
Ziwei Kang Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China
Dandan Liu Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China
Peng Li Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China
Qingjian Ou Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China
Jing-Ying Xu Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China
Weiye Li Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China; Department of Ophthalmology, Drexel University College of Medicine, Philadelphia, USA
Haibin Tian Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China
Caixia Jin Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China
Juan Wang Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China
Jieping Zhang Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China
Jingfa Zhang Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, China.
Lixia Lu Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China; Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; The Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, China.
Guo-Tong Xu Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China; Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; The Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, China.

Collapse

Zhang H, Su B, Jiao L, Xu ZH, Zhang CJ, Nie J, Gao ML, Zhang YV, Jin ZB. Transplantation of GMP-grade human iPSC-derived retinal pigment epithelial cells in rodent model: the first pre-clinical study for safety and efficacy in China. ANNALS OF TRANSLATIONAL MEDICINE 2021;9:245. [PMID: 33708872 PMCID: PMC7940887 DOI: 10.21037/atm-20-4707] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]

Abstract

Background

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly due in large part to age-dependent atrophy of retinal pigment epithelium (RPE) cells. RPE cells form a monolayer located between the choroid and the outer segments of photoreceptors, playing multifarious roles in maintenance of visual function. Allogeneically induced pluripotent stem cell-derived RPE (iPSC-RPE or iRPE) has become a potential approach for providing an abundant source of donors for clinical cell products. Transplantation of iRPE has been proven effective in rescuing impaired retinas in Royal College of Surgeons (RCS) rats after approximately 5 to 6 weeks. Here, we explore the long-term (19 weeks) safety and efficacy of human iRPE cell transplantation in pre-clinical animal models.

Methods

The expression of human RPE-specific markers in iRPE cells was determined using immunofluorescence staining. For the proliferative test, Ki-67 expression was also verified by immunofluorescence and flow cytometric analysis. Then, iRPE cells were transplanted into the subretinal space of immune-deficient NOD/SCID/IL-2Rgc^null (NSG) mice to assess their safety. To evaluate whether the transplanted cells could survive and rescue visual function, we performed color fundus photography, focal electroretinogram and immunostaining after delivering iRPE cells into the subretinal space of RCS rats.

Results

Human iRPE cells expressed native RPE-specific markers, such as microphthalmia-associated transcription factor (MiTF), retinal pigment epithelium-specific 65-kDa protein (RPE65) and tight-junction associated structural protein (ZO-1), and their proliferative capacity (Ki-67 expression) was poor after 25 days of induction. A tumorigenicity test revealed no tumor formation or abnormal proliferation in the immunodeficient mice after subretinal injection of 5×10⁵ iRPE cells. The transplanted iRPE cells survived for at least 19 weeks and maintained visual function for 15 weeks.

Conclusions

In the present study, we provided further evidence for the use of human iRPE transplantation to treat retinal degenerative disease in pre-clinical animal models. Therefore, we consider human iRPE cells a promising source of cell replacement therapy for AMD.

Collapse

The Future of Regenerative Medicine: Cell Therapy Using Pluripotent Stem Cells and Acellular Therapies Based on Extracellular Vesicles. Cells 2021;10:cells10020240. [PMID: 33513719 PMCID: PMC7912181 DOI: 10.3390/cells10020240] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/13/2021] [Accepted: 01/23/2021] [Indexed: 12/11/2022] Open

Sugita S, Mandai M, Kamao H, Takahashi M. Immunological aspects of RPE cell transplantation. Prog Retin Eye Res 2021;84:100950. [PMID: 33482342 DOI: 10.1016/j.preteyeres.2021.100950] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/04/2021] [Accepted: 01/11/2021] [Indexed: 01/12/2023]

Surendran H, Nandakumar S, Reddy K VB, Stoddard J, Mohan K V, Upadhyay PK, McGill TJ, Pal R. Transplantation of retinal pigment epithelium and photoreceptors generated concomitantly via small molecule-mediated differentiation rescues visual function in rodent models of retinal degeneration. Stem Cell Res Ther 2021;12:70. [PMID: 33468244 PMCID: PMC7814459 DOI: 10.1186/s13287-021-02134-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 01/01/2021] [Indexed: 01/01/2023] Open

Abstract

Background

Age-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors. A promising therapeutic approach for both is the replacement of lost/damaged cells with human induced pluripotent stem cell (hiPSC)-derived retinal cells.

Methods

The aim of this study was to investigate the in vivo functionality of RPE and photoreceptor progenitor (PRP) cells derived from a clinical-grade hiPSC line through a unified protocol. De novo-generated RPE and PRP were characterized extensively to validate their identity, purity, and potency.

Results

RPE expressed tight junction proteins, showed pigmentation and ciliation, and secreted polarization-related factors vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). PRP expressed neural retina proteins and cone and rod markers, and responded to KCl-induced polarization. Transcriptomic analysis demonstrated an increase in the expression of mature retinal tissue-specific genes coupled with concomitant downregulation of genes from undesired lineages. RPE transplantation rescued visual function in RCS rats shown via optokinetic tracking and photoreceptor rescue. PRP transplantation improved light perception in NOD.SCID-rd1 mice, and positive electroretinography signals indicated functional photoreceptor activity in the host’s outer nuclear layer. Graft survival and integration were confirmed using immunohistochemistry, and no animals showed teratoma formation or any kind of ectopic growth in the eye.

Conclusions

To our knowledge, this is the first demonstration of a unified, scalable, and GMP-adaptable protocol indicating strong animal efficacy and safety data with hiPSC-derived RPE and PRP cells. These findings provide robust proof-of-principle results for IND-enabling studies to test these potential regenerative cell therapies in patients.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-021-02134-x.

Collapse

Bagewadi S, Parameswaran S, Krishnakumar S, Sethuraman S, Subramanian A. Tissue engineering approaches towards the regeneration of biomimetic scaffolds for age-related macular degeneration. J Mater Chem B 2021;9:5935-5953. [PMID: 34254105 DOI: 10.1039/d1tb00976a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]

The Effects of Prolonged Storage on ARPE-19 Cells Stored at Three Different Storage Temperatures. Molecules 2020;25:molecules25245809. [PMID: 33317020 PMCID: PMC7763992 DOI: 10.3390/molecules25245809] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/29/2020] [Accepted: 12/04/2020] [Indexed: 12/02/2022] Open

Subramaniam MD, Iyer M, Nair AP, Venkatesan D, Mathavan S, Eruppakotte N, Kizhakkillach S, Chandran MK, Roy A, Gopalakrishnan AV, Vellingiri B. Oxidative stress and mitochondrial transfer: A new dimension towards ocular diseases. Genes Dis 2020;9:610-637. [PMID: 35782976 PMCID: PMC9243399 DOI: 10.1016/j.gendis.2020.11.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/18/2020] [Accepted: 11/27/2020] [Indexed: 12/12/2022] Open

Affiliation(s)

Mohana Devi Subramaniam SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India Corresponding author.
Mahalaxmi Iyer SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore 641 043, Tamil Nadu, India
Aswathy P. Nair SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India
Dhivya Venkatesan Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
Sinnakaruppan Mathavan SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India
Nimmisha Eruppakotte Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
Soumya Kizhakkillach Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
Manoj kumar Chandran Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
Ayan Roy Department of Biotechnology, Lovely Professional University, Punjab 144411, India
Abilash Valsala Gopalakrishnan Department of Biomedical Sciences, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore 600127, India
Balachandar Vellingiri Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India Corresponding author. Human Molecular Cytogenetics and Stem Cell, Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India.Fax: +91 422 2422387.

Collapse

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]

Al-Ani A, Sunba S, Hafeez B, Toms D, Ungrin M. In Vitro Maturation of Retinal Pigment Epithelium Is Essential for Maintaining High Expression of Key Functional Genes. Int J Mol Sci 2020;21:ijms21176066. [PMID: 32842471 PMCID: PMC7503905 DOI: 10.3390/ijms21176066] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/08/2020] [Accepted: 08/19/2020] [Indexed: 12/03/2022] Open

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]

Kobold S, Guhr A, Mah N, Bultjer N, Seltmann S, Seiler Wulczyn AEM, Stacey G, Jie H, Liu W, Löser P, Kurtz A. A Manually Curated Database on Clinical Studies Involving Cell Products Derived from Human Pluripotent Stem Cells. Stem Cell Reports 2020;15:546-555. [PMID: 32679065 PMCID: PMC7419703 DOI: 10.1016/j.stemcr.2020.06.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/17/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open

Morizur L, Herardot E, Monville C, Ben M'Barek K. Human pluripotent stem cells: A toolbox to understand and treat retinal degeneration. Mol Cell Neurosci 2020;107:103523. [PMID: 32634576 DOI: 10.1016/j.mcn.2020.103523] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/24/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022] Open

Recent developments in regenerative ophthalmology. SCIENCE CHINA-LIFE SCIENCES 2020;63:1450-1490. [PMID: 32621058 DOI: 10.1007/s11427-019-1684-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 03/21/2020] [Indexed: 12/13/2022]

Hua ZQ, Liu H, Wang N, Jin ZB. Towards stem cell-based neuronal regeneration for glaucoma. PROGRESS IN BRAIN RESEARCH 2020;257:99-118. [PMID: 32988476 DOI: 10.1016/bs.pbr.2020.05.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]

Neuronal Reprogramming for Tissue Repair and Neuroregeneration. Int J Mol Sci 2020;21:ijms21124273. [PMID: 32560072 PMCID: PMC7352898 DOI: 10.3390/ijms21124273] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/08/2020] [Accepted: 06/08/2020] [Indexed: 02/07/2023] Open

Talib M, Boon CJF. Retinal Dystrophies and the Road to Treatment: Clinical Requirements and Considerations. Asia Pac J Ophthalmol (Phila) 2020;9:159-179. [PMID: 32511120 PMCID: PMC7299224 DOI: 10.1097/apo.0000000000000290] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 04/01/2020] [Indexed: 12/15/2022] Open

Koster C, Wever KE, Wagstaff EL, van den Hurk KT, Hooijmans CR, Bergen AA. A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models. Int J Mol Sci 2020;21:E2719. [PMID: 32295315 PMCID: PMC7216090 DOI: 10.3390/ijms21082719] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/02/2020] [Accepted: 04/10/2020] [Indexed: 01/18/2023] Open

Abstract

The retinal pigment epithelium (RPE) and the adjacent light-sensitive photoreceptors form a single functional unit lining the back of the eye. Both cell layers are essential for normal vision. RPE degeneration is usually followed by photoreceptor degeneration and vice versa. There are currently almost no effective therapies available for RPE disorders such as Stargardt disease, specific types of retinitis pigmentosa, and age-related macular degeneration. RPE replacement for these disorders, especially in later stages of the disease, may be one of the most promising future therapies. There is, however, no consensus regarding the optimal RPE source, delivery strategy, or the optimal experimental host in which to test RPE replacement therapy. Multiple RPE sources, delivery methods, and recipient animal models have been investigated, with variable results. So far, a systematic evaluation of the (variables influencing) efficacy of experimental RPE replacement parameters is lacking. Here we investigate the effect of RPE transplantation on vision and vision-based behavior in animal models of retinal degenerated diseases. In addition, we aim to explore the effect of RPE source used for transplantation, the method of intervention, and the animal model which is used.

METHODS

In this study, we systematically identified all publications concerning transplantation of RPE in experimental animal models targeting the improvement of vision (e.g., outcome measurements related to the morphology or function of the eye). A variety of characteristics, such as species, gender, and age of the animals but also cell type, number of cells, and other intervention characteristics were extracted from all studies. A risk of bias analysis was performed as well. Subsequently, all references describing one of the following outcomes were analyzed in depth in this systematic review: a-, b-, and c-wave amplitudes, vision-based, thickness analyses based on optical coherence tomography (OCT) data, and transplant survival based on scanning laser ophthalmoscopy (SLO) data. Meta-analyses were performed on the a- and b-wave amplitudes from electroretinography (ERG) data as well as data from vision-based behavioral assays.

RESULTS

original research articles met the inclusion criteria after two screening rounds. Overall, most studies were categorized as unclear regarding the risk of bias, because many experimental details were poorly reported. Twenty-three studies reporting one or more of the outcome measures of interest were eligible for either descriptive (thickness analyses based on OCT data; n = 2) or meta-analyses. RPE transplantation significantly increased ERG a-wave (Hedges' g 1.181 (0.471-1.892), n = 6) and b-wave (Hedges' g 1.734 (1.295-2.172), n = 42) amplitudes and improved vision-based behavior (Hedges' g 1.018 (0.826-1.209), n = 96). Subgroup analyses revealed a significantly increased effect of the use of young and adolescent animals compared to adult animals. Moreover, transplanting more cells (in the range of 105 versus in the range of 104) resulted in a significantly increased effect on vision-based behavior as well. The origin of cells mattered as well. A significantly increased effect was found on vision-based behavior when using ARPE-19 and OpRegen® RPE.

CONCLUSIONS

This systematic review shows that RPE transplantation in animal models for retinal degeneration significantly increases a- and b- wave amplitudes and improves vision-related behavior. These effects appear to be more pronounced in young animals, when the number of transplanted cells is larger and when ARPE-19 and OpRegen® RPE cells are used. We further emphasize that there is an urgent need for improving the reporting and methodological quality of animal experiments, to make such studies more comparable.

Collapse

Petrus-Reurer S, Winblad N, Kumar P, Gorchs L, Chrobok M, Wagner AK, Bartuma H, Lardner E, Aronsson M, Plaza Reyes Á, André H, Alici E, Kaipe H, Kvanta A, Lanner F. Generation of Retinal Pigment Epithelial Cells Derived from Human Embryonic Stem Cells Lacking Human Leukocyte Antigen Class I and II. Stem Cell Reports 2020;14:648-662. [PMID: 32197113 PMCID: PMC7160308 DOI: 10.1016/j.stemcr.2020.02.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 02/18/2020] [Accepted: 02/19/2020] [Indexed: 01/17/2023] Open

Affiliation(s)

Sandra Petrus-Reurer Clinical Neuroscience, Section for Ophtalmology and Vision, Karolinska Institutet, St. Erik Eye Hospital, 11282 Stockholm, Sweden; Department of Clinical Sciences, Intervention and Technology, Karolinska Insitutet, 17177 Stockholm, Sweden; Gynecology and Reproductive Medicine, Karolinska Universitetssjukhuset, 14186 Stockholm, Sweden
Nerges Winblad Department of Clinical Sciences, Intervention and Technology, Karolinska Insitutet, 17177 Stockholm, Sweden; Gynecology and Reproductive Medicine, Karolinska Universitetssjukhuset, 14186 Stockholm, Sweden
Pankaj Kumar Department of Clinical Sciences, Intervention and Technology, Karolinska Insitutet, 17177 Stockholm, Sweden; Gynecology and Reproductive Medicine, Karolinska Universitetssjukhuset, 14186 Stockholm, Sweden
Laia Gorchs Department of Laboratory Medicine, Karolinska Institutet, 14152 Stockholm, Sweden
Michael Chrobok Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
Arnika Kathleen Wagner Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
Hammurabi Bartuma Clinical Neuroscience, Section for Ophtalmology and Vision, Karolinska Institutet, St. Erik Eye Hospital, 11282 Stockholm, Sweden
Emma Lardner Clinical Neuroscience, Section for Ophtalmology and Vision, Karolinska Institutet, St. Erik Eye Hospital, 11282 Stockholm, Sweden
Monica Aronsson Clinical Neuroscience, Section for Ophtalmology and Vision, Karolinska Institutet, St. Erik Eye Hospital, 11282 Stockholm, Sweden
Álvaro Plaza Reyes Department of Clinical Sciences, Intervention and Technology, Karolinska Insitutet, 17177 Stockholm, Sweden; Gynecology and Reproductive Medicine, Karolinska Universitetssjukhuset, 14186 Stockholm, Sweden
Helder André Clinical Neuroscience, Section for Ophtalmology and Vision, Karolinska Institutet, St. Erik Eye Hospital, 11282 Stockholm, Sweden
Evren Alici Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
Helen Kaipe Department of Laboratory Medicine, Karolinska Institutet, 14152 Stockholm, Sweden; Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Huddinge, 14186 Stockholm, Sweden
Anders Kvanta Clinical Neuroscience, Section for Ophtalmology and Vision, Karolinska Institutet, St. Erik Eye Hospital, 11282 Stockholm, Sweden
Fredrik Lanner Department of Clinical Sciences, Intervention and Technology, Karolinska Insitutet, 17177 Stockholm, Sweden; Gynecology and Reproductive Medicine, Karolinska Universitetssjukhuset, 14186 Stockholm, Sweden; Ming Wai Lau Center for Reparative Medicine, Stockholm Node, Karolinska Institutet, 17177 Stockholm, Sweden.

Collapse

Liu G, David BT, Trawczynski M, Fessler RG. Advances in Pluripotent Stem Cells: History, Mechanisms, Technologies, and Applications. Stem Cell Rev Rep 2020;16:3-32. [PMID: 31760627 PMCID: PMC6987053 DOI: 10.1007/s12015-019-09935-x] [Citation(s) in RCA: 303] [Impact Index Per Article: 60.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]

Abstract

Over the past 20 years, and particularly in the last decade, significant developmental milestones have driven basic, translational, and clinical advances in the field of stem cell and regenerative medicine. In this article, we provide a systemic overview of the major recent discoveries in this exciting and rapidly developing field. We begin by discussing experimental advances in the generation and differentiation of pluripotent stem cells (PSCs), next moving to the maintenance of stem cells in different culture types, and finishing with a discussion of three-dimensional (3D) cell technology and future stem cell applications. Specifically, we highlight the following crucial domains: 1) sources of pluripotent cells; 2) next-generation in vivo direct reprogramming technology; 3) cell types derived from PSCs and the influence of genetic memory; 4) induction of pluripotency with genomic modifications; 5) construction of vectors with reprogramming factor combinations; 6) enhancing pluripotency with small molecules and genetic signaling pathways; 7) induction of cell reprogramming by RNA signaling; 8) induction and enhancement of pluripotency with chemicals; 9) maintenance of pluripotency and genomic stability in induced pluripotent stem cells (iPSCs); 10) feeder-free and xenon-free culture environments; 11) biomaterial applications in stem cell biology; 12) three-dimensional (3D) cell technology; 13) 3D bioprinting; 14) downstream stem cell applications; and 15) current ethical issues in stem cell and regenerative medicine. This review, encompassing the fundamental concepts of regenerative medicine, is intended to provide a comprehensive portrait of important progress in stem cell research and development. Innovative technologies and real-world applications are emphasized for readers interested in the exciting, promising, and challenging field of stem cells and those seeking guidance in planning future research direction.

Collapse

Stem Cell Transplantation Therapy for Retinal Degenerative Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020;1266:127-139. [PMID: 33105499 DOI: 10.1007/978-981-15-4370-8_9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]

Vitillo L, Tovell VE, Coffey P. Treatment of Age-Related Macular Degeneration with Pluripotent Stem Cell-Derived Retinal Pigment Epithelium. Curr Eye Res 2019;45:361-371. [DOI: 10.1080/02713683.2019.1691237] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]

Ben M'Barek K, Bertin S, Brazhnikova E, Jaillard C, Habeler W, Plancheron A, Fovet CM, Demilly J, Jarraya M, Bejanariu A, Sahel JA, Peschanski M, Goureau O, Monville C. Clinical-grade production and safe delivery of human ESC derived RPE sheets in primates and rodents. Biomaterials 2019;230:119603. [PMID: 31732225 DOI: 10.1016/j.biomaterials.2019.119603] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 10/11/2019] [Accepted: 11/04/2019] [Indexed: 01/05/2023]

Affiliation(s)

Karim Ben M'Barek INSERM U861, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France; UEVE U861, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France; CECS, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France
Stéphane Bertin CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DGOS CIC 1423, Paris, France
Elena Brazhnikova Institut de la Vision, Sorbonne Université, INSERM, CNRS, F-75012, Paris, France
Céline Jaillard Institut de la Vision, Sorbonne Université, INSERM, CNRS, F-75012, Paris, France
Walter Habeler INSERM U861, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France; UEVE U861, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France; CECS, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France
Alexandra Plancheron INSERM U861, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France; UEVE U861, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France; CECS, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France
Claire-Maëlle Fovet CEA-MIRCen, 92260 FAR, France
Joanna Demilly CEA-MIRCen, 92260 FAR, France
Mohamed Jarraya Banque de Tissus Humain, Hôpital Saint Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
Ana Bejanariu CECS, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France
José-Alain Sahel CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DGOS CIC 1423, Paris, France; Institut de la Vision, Sorbonne Université, INSERM, CNRS, F-75012, Paris, France; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
Marc Peschanski INSERM U861, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France; UEVE U861, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France; CECS, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France
Olivier Goureau Institut de la Vision, Sorbonne Université, INSERM, CNRS, F-75012, Paris, France.
Christelle Monville INSERM U861, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France; UEVE U861, I-Stem, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 91100, Corbeil-Essonnes, France.

Collapse

Lojudice FH, Fernandes RAB, Innocenti F, Franciozi CE, Cristovam P, Maia M, Sogayar MC, Junior RB. In vitro differentiation of cGMP-grade retinal pigmented epithelium from human embryonic stem cells. Int J Retina Vitreous 2019;5:45. [PMID: 31646003 PMCID: PMC6802162 DOI: 10.1186/s40942-019-0194-7] [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: 07/19/2019] [Accepted: 10/10/2019] [Indexed: 11/15/2022] Open

Abstract

Background

The World Health Organization (WHO) estimates that the number of individuals who lose their vision due to retinal degeneration is expected to reach 6 million annually in 2020. The retinal degenerative diseases affect the macula, which is responsible for central and detailed vision. Most macular degeneration, i.e., age-related macular degeneration (AMD) develops in the elderly; however, certain hereditary diseases, such as the Stargardt disease, also affect young people. This degeneration begins with loss of retinal pigmented epithelium (RPE) due to formation of drusen (atrophic) or abnormal vessels (exudative). In wet AMD, numerous drugs are available to successful treat the disease; however, no proven therapy currently is available to treat dry AMD or Stargardt. Since its discovery, human embryonic stem cells (hESCs) have been considered a valuable therapeutic tool. Some evidence has shown that transplantation of RPEs differentiated from hESCs cells can result in recovery of both RPE and photoreceptors and prevent visual loss.

Methods

The human embryonic WA-09 stem cell lineage was cultured under current Good Manufacturing Practices (cGMP) conditions using serum-free media and supplements. The colonies were isolated manually and allowed to spontaneously differentiate into RPE cells.

Results

This simple and effective protocol required minimal manipulation and yielded more than 10e8 RPE cells by the end of the differentiation and enrichment processes, with cells exhibiting a cobblestone morphology and displaying cellular markers and a gene expression profile typical of mature RPE cells. Moreover, the differentiated cells displayed phagocytic activity and only a small percentage of the total cells remained positive for the Octamer-binding transcriptions factor 4 (OCT-4) pluripotency cell marker.

Conclusions

These results showed that functional RPE cells can be produced efficiently and suggested the possibility of scaling-up to aim at therapeutic protocols for retinal diseases associated with RPE degeneration.

Collapse

Mazzilli JL, Snook JD, Simmons K, Domozhirov AY, Garcia CA, Wetsel RA, Zsigmond EM, Westenskow PD. A Preclinical Safety Study of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells for Macular Degeneration. J Ocul Pharmacol Ther 2019;36:65-69. [PMID: 31596637 DOI: 10.1089/jop.2019.0039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open

Kretschmer V, Patnaik SR, Kretschmer F, Chawda MM, Hernandez-Hernandez V, May-Simera HL. Progressive Characterization of Visual Phenotype in Bardet-Biedl Syndrome Mutant Mice. Invest Ophthalmol Vis Sci 2019;60:1132-1143. [PMID: 30901771 DOI: 10.1167/iovs.18-25210] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open

Alsaeedi HA, Koh AEH, Lam C, Rashid MBA, Harun MHN, Saleh MFBM, Teh SW, Luu CD, Ng MH, Isa HM, Leow SN, Then KY, Bastion MLC, Mok PL, Muthuvenkatachalam BS, Samrot AV, Swamy KB, Nandakumar J, Kumar SS. Dental pulp stem cells therapy overcome photoreceptor cell death and protects the retina in a rat model of sodium iodate-induced retinal degeneration. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2019;198:111561. [PMID: 31352000 DOI: 10.1016/j.jphotobiol.2019.111561] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 06/10/2019] [Accepted: 07/15/2019] [Indexed: 12/11/2022]

Affiliation(s)

Hiba Amer Alsaeedi Department of Medical Microbiology and Parasitology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
Avin Ee-Hwan Koh Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
Chenshen Lam Department of Ophthalmology, Faculty of Medicine, UKM Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia
Munirah Binti Abd Rashid Department of Ophthalmology, Faculty of Medicine, UKM Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia
Mohd Hairul Nizam Harun Department of Ophthalmology, Faculty of Medicine, UKM Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia.
Muhamad Fakhri Bin Mohd Saleh Department of Pathology, Faculty of Medicine, UKM Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia
Seoh Wei Teh Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
Chi D Luu Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, Melbourne 3002, Australia; Department of Surgery (Ophthalmology), the University of Melbourne, Melbourne 3010, Australia.
Min Hwei Ng Tissue Engineering Centre, Universiti Kebangsaan Malaysia Medical Center, 56000 Cheras, Kuala Lumpur, Malaysia
Hazlita Mohd Isa Department of Ophthalmology, Faculty of Medicine, UKM Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia
Sue Ngein Leow Department of Ophthalmology, Hospital Sultanah Aminah, 80100 Johor Bahru, Johor, Malaysia
Kong Yong Then Department of Ophthalmology, Faculty of Medicine, UKM Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia
Mae-Lynn Catherine Bastion Department of Ophthalmology, Faculty of Medicine, UKM Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia
Pooi Ling Mok Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Genetics and Regenerative Medicine Research Center, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Department of Clinical Laboratory Sciences, College of Applied Medical Science, Jouf University, Sakaka, P.O Box 2014, Aljouf Province, Saudi Arabia.
Bala Sundaram Muthuvenkatachalam Department of Biochemistry, Faculty of Medicine, AIMST University, Jalan Bedong-Semeling, 08100 Bedong, Kedah, Malaysia
Antony V Samrot Department of Biotechnology, School of Bio and Chemical Engineering, Sathyabama Institute of Science and Technology, Jeppiaar Nagar, Rajiv Gandhi Salai, Sholinganallur, Chennai 600119, Tamil Nadu, India; Department of Biomedical Sciences, Faculty of Medicine and Biomedical Sciences, MAHSA University, Jalan SP2, Bandar Saujana Putra, 42810 Jenjarom, Selangor, Malaysia
K B Swamy Faculty of Medicine, Lincoln University College, Wisma Lincoln, No. 12-18, Jalan SS 6/12, 47301 Petaling Jaya, Selangor Darul Ehsan, Malaysia
Jaikumar Nandakumar Department of Microbiology, Karpagam University, Eachanari, Coimbatore 641021, Tamil Nadu, India
Suresh Subbiah Kumar Department of Medical Microbiology and Parasitology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Genetics and Regenerative Medicine Research Center, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Department of Cancer, Institute of Bioscience, Universiti Putra Malaysia, Malaysia.

Collapse

Gu J, Wang Y, Cui Z, Li H, Li S, Yang X, Yan X, Ding C, Tang S, Chen J. The Construction of Retinal Pigment Epithelium Sheets with Enhanced Characteristics and Cilium Assembly Using iPS Conditioned Medium and Small Incision Lenticule Extraction Derived Lenticules. Acta Biomater 2019;92:115-131. [PMID: 31075513 DOI: 10.1016/j.actbio.2019.05.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 04/18/2019] [Accepted: 05/06/2019] [Indexed: 01/06/2023]

Abstract

In vitro generation of a functional retinal pigment epithelium (RPE) monolayer sheet is useful and promising for RPE cell therapy. Here, for the first time, we used induced pluripotent stem (iPS) supernatant as the conditioned medium (iPS-CM) and femtosecond laser intrastromal lenticule (FLI-lenticule) as a scaffold to construct an engineered RPE sheet. There are significant enhancements in RPE cell density, transepithelial electrical resistance (TER) and inhibitions of ultraviolet C (UVC)-irradiated apoptosis when RPE cells are cultured in iPS supernatant/Dulbecco's modified Eagle's medium (DMEM)-F12 of 1/2 (iPS-CM) compared with those in normal medium (NM, DMEM-F12). Using the assay of a panel of cytokines, combined with transcriptome and protein analyses, we discover that iPS-CM contains high levels of platelet-derived growth factor AA (PDGF-AA), insulin-like growth factor binding protein (IGFBP)-2, transforming growth factor (TGF)-α and IGFBP-6, which are responsible for the upregulation of gene and protein markers with RPE phenotypes and downregulation of gene and protein markers with epithelial-mesenchymal transition (EMT) phenotypes for RPE cells in iPS-CM when compared to those in NM. Moreover, compared to cultures on tissue culture plates (TCP), RPE cells on FLI-lenticule display more microvilli and cilium in accordance with the results in terms of RNA-Seq data, quantitative polymerase chain reaction (qPCR) expression, immunofluorescence staining, and western blot assays. Furthermore, acellular FLI-lenticule exhibits biocompatibility after rabbit subretinal implantation by 30 days through electroretinography and histological examination. Thus, we determined that engineered RPE sheets treated by iPS-CM in conjunction with FLI-lenticule scaffold aid in enhanced RPE characteristics and cilium assembly. Such a strategy to construct RPE sheets is a promising avenue for developing RPE cell therapy, disease models and drug screening tools. STATEMENT OF SIGNIFICANCE: In vitro generation of a functional RPE monolayer sheet is useful and promising for RPE cell therapy. Here, we constructed engineered RPE sheets treated by iPS-CM in conjunction with FLI-lenticule scaffolds to help in enhanced RPE characteristics and cilium assembly. Such a strategy to generate RPE sheets is a promising avenue for developing RPE cell therapy, disease models and drug screening tools.

Collapse

McGill TJ, Osborne L, Lu B, Stoddard J, Huhn S, Tsukamoto A, Capela A. Subretinal Transplantation of Human Central Nervous System Stem Cells Stimulates Controlled Proliferation of Endogenous Retinal Pigment Epithelium. Transl Vis Sci Technol 2019;8:43. [PMID: 31245172 PMCID: PMC6586077 DOI: 10.1167/tvst.8.3.43] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 03/26/2019] [Indexed: 12/03/2022] Open