{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T09:53:27Z","timestamp":1772272407031,"version":"3.50.1"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T00:00:00Z","timestamp":1605225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Science &amp; Technology Project of Guangdong Province","award":["2017B020230003"],"award-info":[{"award-number":["2017B020230003"]}]},{"name":"the National Key R&amp;D Program of China","award":["2017YFA0104100; 2016YFC1101103"],"award-info":[{"award-number":["2017YFA0104100; 2016YFC1101103"]}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970842, 81570874"],"award-info":[{"award-number":["81970842, 81570874"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Science &amp; Technology Project of Guangzhou","award":["201803010078"],"award-info":[{"award-number":["201803010078"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Retinal degenerative disorders (RDs) are the main cause of blindness without curable treatment. Our previous studies have demonstrated that human-induced pluripotent stem cells can differentiate into retinal organoids with all subtypes of retina, which provides huge promise for treating these diseases. Before these methods can be realized, RD animal models are required to evaluate the safety and efficacy of stem cell therapy and to develop the surgical tools and procedures for cell transplantation in patients. This study involved the development of a monkey model of RD with controllable lesion sites, which can be rapidly prepared for the study of preclinical stem cell therapy among other applications. Methods: Sodium nitroprusside (SNP) in three doses was delivered into the monkey eye by subretinal injection (SI), and normal saline was applied as control. Structural and functional changes of the retinas were evaluated via multimodal imaging techniques and multifocal electroretinography (mfERG) before and after the treatment. Histological examination was performed to identify the target layer of the affected retina. The health status of monkeys was monitored during the experiment. Results: Well-defined lesions with various degrees of retinal degeneration were induced at the posterior pole of retina as early as 7 days after SNP SI. The damage of SNP was dose dependent. In general, 0.05 mM SNP caused mild structural changes in the retina; 0.1 mM SNP led to the loss of outer retinal layers, including the outer plexiform layer (OPL), outer nuclear layer (ONL), and retinal pigment epithelium (RPE); while 0.2 mM SNP impacted the entire layer of the retina and choroid. MfERG showed reduced amplitude in the damaged region. The structural and functional damages were not recovered at 7-month follow-up. Conclusion: A rapidly induced lesion site-controllable retinal degeneration monkey model was established by the subretinal administration of SNP, of which the optimal dose is 0.1 mM. This monkey model mimics the histological changes of advanced RDs and provides a valuable platform for preclinical assessment of stem cell therapy for RDs.<\/jats:p>","DOI":"10.3390\/cells9112468","type":"journal-article","created":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T08:44:02Z","timestamp":1605257042000},"page":"2468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Establishment of a Rapid Lesion-Controllable Retinal Degeneration Monkey Model for Preclinical Stem Cell Therapy"],"prefix":"10.3390","volume":"9","author":[{"given":"Guanjie","family":"Gao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liwen","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengxu","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dandan","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojing","family":"Song","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3115-8930","authenticated-orcid":false,"given":"Minzhong","family":"Yu","sequence":"additional","affiliation":[{"name":"Electrophysiology Laboratory, Department of Ophthalmology, University Hospitals, Case Western Reserve University, Cleveland, OH 44101, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangwei","family":"Luo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiufeng","family":"Zhong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","article-title":"Age-related macular degeneration","volume":"392","author":"Mitchell","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.preteyeres.2018.03.005","article-title":"Non-syndromic retinitis pigmentosa","volume":"66","author":"Verbakel","year":"2018","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/eye.2016.286","article-title":"Effectiveness and safety of nutritional supplements in the treatment of hereditary retinal dystrophies: A systematic review","volume":"31","author":"Coco","year":"2017","journal-title":"Eye"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1080\/02713683.2016.1270326","article-title":"Advances in Retinal Prosthetic Research: A Systematic Review of Engineering and Clinical Characteristics of Current Prosthetic Initiatives","volume":"42","author":"Cheng","year":"2017","journal-title":"Curr. Eye Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ydbio.2017.09.028","article-title":"Organoid technology for retinal repair","volume":"433","author":"Llonch","year":"2018","journal-title":"Dev. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"ORSFg1","DOI":"10.1167\/iovs.15-17659","article-title":"Photoreceptor Transplantation in Late Stage Retinal Degeneration","volume":"57","author":"Reh","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preteyeres.2019.03.001","article-title":"Photoreceptor cell replacement in macular degeneration and retinitis pigmentosa: A pluripotent stem cell-based approach","volume":"71","author":"Gagliardi","year":"2019","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preteyeres.2018.11.001","article-title":"Transplantation of photoreceptors into the degenerative retina: Current state and future perspectives","volume":"69","author":"Gasparini","year":"2019","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1126\/science.282.5391.1145","article-title":"Embryonic stem cell lines derived from human blastocysts","volume":"282","author":"Thomson","year":"1998","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.stem.2012.05.009","article-title":"Self-formation of optic cups and storable stratified neural retina from human ESCs","volume":"10","author":"Nakano","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4047","DOI":"10.1038\/ncomms5047","article-title":"Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs","volume":"5","author":"Zhong","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4968658","DOI":"10.1155\/2018\/4968658","article-title":"Generation of Retinal Organoids with Mature Rods and Cones from Urine-Derived Human Induced Pluripotent Stem Cells","volume":"2018","author":"Li","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41421-018-0053-y","article-title":"Human embryonic stem cell-derived retinal pigment epithelium transplants as a potential treatment for wet age-related macular degeneration","volume":"4","author":"Liu","year":"2018","journal-title":"Cell Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9428176","DOI":"10.1155\/2017\/9428176","article-title":"Assessment of Safety and Functional Efficacy of Stem Cell-Based Therapeutic Approaches Using Retinal Degenerative Animal Models","volume":"2017","author":"Lin","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1293\/tox.2015-0037","article-title":"Characteristics of structures and lesions of the eye in laboratory animals used in toxicity studies","volume":"28","author":"Shibuya","year":"2015","journal-title":"J. Toxicol. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1017\/S0952523808080401","article-title":"Long-term cellular and regional specificity of the photoreceptor toxin, iodoacetic acid (IAA), in the rabbit retina","volume":"25","author":"Liang","year":"2008","journal-title":"Vis. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.exer.2011.06.017","article-title":"Anatomical evidence of photoreceptor degeneration induced by iodoacetic acid in the porcine eye","volume":"93","author":"Scott","year":"2011","journal-title":"Exp. Eye Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E81","DOI":"10.1073\/pnas.1512590113","article-title":"Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration","volume":"113","author":"Shirai","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.preteyeres.2009.11.004","article-title":"Retinal light damage: Mechanisms and protection","volume":"29","author":"Organisciak","year":"2010","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.exer.2015.07.005","article-title":"Damage threshold in adult rabbit eyes after scleral cross-linking by riboflavin\/blue light application","volume":"139","author":"Iseli","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"352","DOI":"10.2174\/1566524018666181113104023","article-title":"Establishment of Retinal Degeneration Model in Rat and Monkey by Intravitreal Injection of Sodium Iodate","volume":"18","author":"Ou","year":"2018","journal-title":"Curr. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s00417-016-3531-7","article-title":"Photoreceptor degeneration by intravitreal injection of N-methyl-N-nitrosourea (MNU) in rabbits: A pilot study","volume":"255","author":"Rosch","year":"2017","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.exer.2005.08.002","article-title":"Behavioral and anatomical abnormalities in a sodium iodate-induced model of retinal pigment epithelium degeneration","volume":"82","author":"Enzmann","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1007\/s11427-013-4483-3","article-title":"Functional evaluation of iodoacetic acid induced photoreceptor degeneration in the cat","volume":"56","author":"Nan","year":"2013","journal-title":"Sci. China Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1016\/0042-6989(96)00017-X","article-title":"Nitric oxide: A review of its role in retinal function and disease","volume":"36","author":"Goldstein","year":"1996","journal-title":"Vis. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Isago, H., Sugano, E., Murayama, N., Tamai, M., and Tomita, H. (2013). Establishment of monocular-limited photoreceptor degeneration models in rabbits. BMC Ophthalmol., 13.","DOI":"10.1186\/1471-2415-13-19"},{"key":"ref_28","first-page":"235","article-title":"Generation of an acute retinal photoreceptor degeneration model in rabbits","volume":"10","author":"Li","year":"2018","journal-title":"Am. J. Transl. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1136\/bjo.2003.037879","article-title":"Effects of melatonin on the nitric oxide treated retina","volume":"88","author":"Siu","year":"2004","journal-title":"Br. J. Ophthalmol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1159\/000165916","article-title":"Indocyanine green angiography in experimental choroidal circulatory disturbance","volume":"41","author":"Nishikawa","year":"2009","journal-title":"Ophthalmic Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10633-011-9296-8","article-title":"ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition)","volume":"124","author":"Hood","year":"2012","journal-title":"Doc. Ophthalmol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.vascn.2010.06.008","article-title":"Evaluation of a convenient method of assessing rodent visual function in safety pharmacology studies: Effects of sodium iodate on visual acuity and retinal morphology in albino and pigmented rats and mice","volume":"63","author":"Redfern","year":"2011","journal-title":"J Pharm. Toxicol. Methods"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.exer.2013.12.019","article-title":"N -methyl- N -nitrosourea-induced retinal degeneration in mice","volume":"121","author":"Chen","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1007\/s10384-016-0429-1","article-title":"Monocular retinal degeneration induced by intravitreal injection of sodium iodate in rabbit eyes","volume":"60","author":"Cho","year":"2016","journal-title":"Jpn J. Ophthalmol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.brainres.2006.06.037","article-title":"A new model of retinal photoreceptor cell degeneration induced by a chemical hypoxia-mimicking agent, cobalt chloride","volume":"1109","author":"Hara","year":"2006","journal-title":"Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1136\/bjo.43.3.177","article-title":"Iodoacetate poisoning of the rat retina. I. Production of retinal degeneration","volume":"43","author":"Graymore","year":"1959","journal-title":"Br. J. Ophthalmol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.exer.2011.12.018","article-title":"Iodoacetic acid, but not sodium iodate, creates an inducible swine model of photoreceptor damage","volume":"97","author":"Noel","year":"2012","journal-title":"Exp. Eye Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/s41591-020-0763-1","article-title":"Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR","volume":"26","author":"Xue","year":"2020","journal-title":"Nat. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/aos.13384","article-title":"Nitric oxide in the pathophysiology of retinopathy: Evidences from preclinical and clinical researches","volume":"96","author":"Opatrilova","year":"2018","journal-title":"Acta Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4075","DOI":"10.1097\/00001756-200112210-00043","article-title":"Sodium nitroprusside selectively induces apoptotic cell death in the outer retina of the rat","volume":"12","author":"Ju","year":"2001","journal-title":"Neuroreport"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5659","DOI":"10.1167\/iovs.17-23613","article-title":"Self-Formation of RPE Spheroids Facilitates Enrichment and Expansion of hiPSC-Derived RPE Generated on Retinal Organoid Induction Platform","volume":"59","author":"Liu","year":"2018","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1002\/stem.2890","article-title":"An Optimized System for Effective Derivation of Three-Dimensional Retinal Tissue via Wnt Signaling Regulation","volume":"36","author":"Luo","year":"2018","journal-title":"Stem Cells"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/11\/2468\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:32:46Z","timestamp":1760178766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/11\/2468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,13]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["cells9112468"],"URL":"https:\/\/doi.org\/10.3390\/cells9112468","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-59826\/v1","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,13]]}}}