The retinal pigment epithelium (RPE) forms an important cellular monolayer, which contributes to the normal physiology of the eye. Damage to the RPE leads to the development of degenerative diseases, such as age-related macular degeneration (AMD). Apart from acting as a physical barrier between the retina and choroidal blood vessels, the RPE is crucial in maintaining photoreceptor (PR) and visual functions. Current clinical intervention to treat early stages of AMD includes stem cell-derived RPE transplantation, which is still in its early stages of evolution. Therefore, it becomes essential to derive RPEs which are functional and exhibit features as observed in native human RPE cells. The conventional strategy is to use the knowledge obtained from developmental studies using various animal models and stem cell-based exploratory studies to understand RPE biogenies and developmental trajectory. This article emphasises such studies and aims to present a comprehensive understanding of the basic biology, including the genetics and molecular pathways of RPE development. It encompasses basic developmental biology and stem cell-based developmental studies to uncover RPE differentiation. Knowledge of the in utero developmental cues provides an inclusive methodology required for deriving RPEs using stem cells.

Center for Eye Research and Innovative Diagnostics Department of Ophthalmology Institute for Clinical Medicine Faculty of Medicine University of Oslo 0450 Oslo Norway

Department of Medical Biochemistry Institute of Clinical Medicine University of Oslo 0372 Oslo Norway

Department of Ophthalmology Justus Liebig University Giessen University Hospital Giessen and Marburg GmbH 35392 Giessen Germany

Department of Ophthalmology Oslo University Hospital 0450 Oslo Norway

Department of Ophthalmology University of Split School of Medicine and University Hospital Centre 21000 Split Croatia

Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic 27721 Libechov Czech Republic

Institute of Experimental Medicine Academy of Sciences of the Czech Republic 11720 Prague Czech Republic

Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic 16206 Prague Czech Republic

Karl Landsteiner Institute for Retinal Research and Imaging 1030 Vienna Austria

Ocular and Stem Cell Translational Research Section NEI NIH Bethesda MD 20892 USA

Research Center Principe Felipe Stem Cell Therapies in Neurodegenerative Diseases Laboratory 46012 Valencia Spain

Zobrazit více v PubMed

Jager R.D., Mieler W.F., Miller J.W. Age-Related Macular Degeneration. N. Engl. J. Med. 2008;358:2606–2617. doi: 10.1056/NEJMra0801537. PubMed DOI

Heesterbeek T.J., Lorés-Motta L., Hoyng C.B., Lechanteur Y.T.E., den Hollander A.I. Risk factors for progression of age-related macular degeneration. Ophthalmic Physiol. Opt. 2020;40:140–170. doi: 10.1111/opo.12675. PubMed DOI PMC

Cachafeiro M., Bemelmans A.-P., Samardzija M., Afanasieva T., Pournaras J.-A., Grimm C., Kostic C., Philippe S., Wenzel A., Arsenijevic Y. Hyperactivation of retina by light in mice leads to photoreceptor cell death mediated by VEGF and retinal pigment epithelium permeability. Cell Death Dis. 2013;4:e781. doi: 10.1038/cddis.2013.303. PubMed DOI PMC

McLeod D.S., Grebe R., Bhutto I., Merges C., Baba T., Lutty G.A. Relationship between RPE and Choriocapillaris in Age-Related Macular Degeneration. Investig. Ophthalmol. Vis. Sci. 2009;50:4982–4991. doi: 10.1167/iovs.09-3639. PubMed DOI PMC

Pugazhendhi A., Hubbell M., Jairam P., Ambati B. Neovascular Macular Degeneration: A Review of Etiology, Risk Factors, and Recent Advances in Research and Therapy. Int. J. Mol. Sci. 2021;22:1170. doi: 10.3390/ijms22031170. PubMed DOI PMC

Yang S., Zhou J., Li D. Functions and Diseases of the Retinal Pigment Epithelium. Front. Pharmacol. 2021;12:1170. doi: 10.3389/fphar.2021.727870. PubMed DOI PMC

Kim S.-Y., Kim Y., Oh Y. Inflammatory pathways in pathological neovascularization in retina and choroid: A narrative review on the inflammatory drug target molecules in retinal and choroidal neovascularization. Ann. Eye Sci. 2021;6:1–17. doi: 10.21037/aes-21-4. DOI

Zarbin M. Cell-Based Therapy for Degenerative Retinal Disease. Trends Mol. Med. 2016;22:115–134. doi: 10.1016/j.molmed.2015.12.007. PubMed DOI

Cai J., Nelson K.C., Wu M., Sternberg P., Jones D.P. Oxidative damage and protection of the RPE. Prog. Retin. Eye Res. 2000;19:205–221. doi: 10.1016/S1350-9462(99)00009-9. PubMed DOI

Whitmore S.S., Sohn E.H., Chirco K.R., Drack A.V., Stone E.M., Tucker B.A., Mullins R.F. Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy. Prog. Retin. Eye Res. 2015;45:1–29. doi: 10.1016/j.preteyeres.2014.11.005. PubMed DOI PMC

Feher J., Kovacs I., Artico M., Cavallotti C., Papale A., Balacco Gabrieli C. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol. Aging. 2006;27:983–993. doi: 10.1016/j.neurobiolaging.2005.05.012. PubMed DOI

Brown E.E., DeWeerd A.J., Ildefonso C.J., Lewin A.S., Ash J.D. Mitochondrial oxidative stress in the retinal pigment epithelium (RPE) led to metabolic dysfunction in both the RPE and retinal photoreceptors. Redox Biol. 2019;24:101201. doi: 10.1016/j.redox.2019.101201. PubMed DOI PMC

Strauss O. The Retinal Pigment Epithelium in Visual Function. Physiol. Rev. 2005;85:845–881. doi: 10.1152/physrev.00021.2004. PubMed DOI

Somasundaran S., Constable I.J., Mellough C.B., Carvalho L.S. Retinal pigment epithelium and age-related macular degeneration: A review of major disease mechanisms. Clin. Experiment. Ophthalmol. 2020;48:1043–1056. doi: 10.1111/ceo.13834. PubMed DOI PMC

Sharma R., Bose D., Maminishkis A., Bharti K. Retinal Pigment Epithelium Replacement Therapy for Age-Related Macular Degeneration: Are We There Yet? Annu. Rev. Pharmacol. Toxicol. 2020;60:553–572. doi: 10.1146/annurev-pharmtox-010919-023245. PubMed DOI PMC

Fuhrmann S., Zou C., Levine E.M. Retinal pigment epithelium development, plasticity, and tissue homeostasis. Exp. Eye Res. 2014;123:141–150. doi: 10.1016/j.exer.2013.09.003. PubMed DOI PMC

Holz F.G., Schmitz-Valckenberg S., Fleckenstein M. Recent developments in the treatment of age-related macular degeneration. J. Clin. Investig. 2014;124:1430–1438. doi: 10.1172/JCI71029. PubMed DOI PMC

Ammar M.J., Hsu J., Chiang A., Ho A.C., Regillo C.D. Age-related macular degeneration therapy: A review. Curr. Opin. Ophthalmol. 2020;31:215–221. doi: 10.1097/ICU.0000000000000657. PubMed DOI

Zarbin M., Sugino I., Townes-Anderson E. Concise Review: Update on Retinal Pigment Epithelium Transplantation for Age-Related Macular Degeneration. Stem Cells Transl. Med. 2019;8:466–477. doi: 10.1002/sctm.18-0282. PubMed DOI PMC

Fernández-Robredo P., Sancho A., Johnen S., Recalde S., Gama N., Thumann G., Groll J., García-Layana A. Current Treatment Limitations in Age-Related Macular Degeneration and Future Approaches Based on Cell Therapy and Tissue Engineering. J. Ophthalmol. 2014;2014:510285. doi: 10.1155/2014/510285. PubMed DOI PMC

Baradaran-Rafii A., Sarvari M., Alavi-Moghadam S., Payab M., Goodarzi P., Aghayan H.R., Larijani B., Rezaei-Tavirani M., Biglar M., Arjmand B. Cell-based approaches towards treating age-related macular degeneration. Cell Tissue Bank. 2020;21:339–347. doi: 10.1007/s10561-020-09826-3. PubMed DOI

Forest D.L., Johnson L.V., Clegg D.O. Cellular models and therapies for age-related macular degeneration. Dis. Model. Mech. 2015;8:421–427. doi: 10.1242/dmm.017236. PubMed DOI PMC

Schwartz S.D., Hubschman J.-P., Heilwell G., Franco-Cardenas V., Pan C.K., Ostrick R.M., Mickunas E., Gay R., Klimanskaya I., Lanza R. Embryonic stem cell trials for macular degeneration: A preliminary report. Lancet. 2012;379:713–720. doi: 10.1016/S0140-6736(12)60028-2. PubMed DOI

Mandai M., Watanabe A., Kurimoto Y., Hirami Y., Morinaga C., Daimon T., Fujihara M., Akimaru H., Sakai N., Shibata Y., et al. Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration. N. Engl. J. Med. 2017;376:1038–1046. doi: 10.1056/NEJMoa1608368. PubMed DOI

van Meurs J.C., ter Averst E., Hofland L.J., van Hagen P.M., Mooy C.M., Baarsma G.S., Kuijpers R.W., Boks T., Stalmans P. Autologous peripheral retinal pigment epithelium translocation in patients with subfoveal neovascular membranes. Br. J. Ophthalmol. 2004;88:110–113. doi: 10.1136/bjo.88.1.110. PubMed DOI PMC

Binder S., Krebs I., Hilgers R.-D., Abri A., Stolba U., Assadoulina A., Kellner L., Stanzel B.V., Jahn C., Feichtinger H. Outcome of Transplantation of Autologous Retinal Pigment Epithelium in Age-Related Macular Degeneration: A Prospective Trial. Investig. Ophthalmol. Vis. Sci. 2004;45:4151–4160. doi: 10.1167/iovs.04-0118. PubMed DOI

Knoernschild T., Grasbon T., Wilsch C., Kampik A., Lütjen-Drecoll E. RPE cell transplants to non-immune-privileged sites of the eye transform into fibroblast-like cells. Curr. Eye Res. 2003;27:25–34. doi: 10.1076/ceyr.27.2.25.15453. PubMed DOI

Lytvynchuk L., Ebbert A., Studenovska H., Nagymihály R., Josifovska N., Rais D., Popelka Š., Tichotová L., Nemesh Y., Čížková J., et al. Subretinal Implantation of Human Primary RPE Cells Cultured on Nanofibrous Membranes in Minipigs. Biomedicines. 2022;10:669. doi: 10.3390/biomedicines10030669. PubMed DOI PMC

Xiang P., Wu K.-C., Zhu Y., Xiang L., Li C., Chen D.-L., Chen F., Xu G., Wang A., Li M., et al. A novel Bruch’s membrane-mimetic electrospun substrate scaffold for human retinal pigment epithelium cells. Biomaterials. 2014;35:9777–9788. doi: 10.1016/j.biomaterials.2014.08.040. PubMed DOI

Kashani A.H., Lebkowski J.S., Rahhal F.M., Avery R.L., Salehi-Had H., Dang W., Lin C.-M., Mitra D., Zhu D., Thomas B.B., et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Sci. Transl. Med. 2018;10:eaao4097. doi: 10.1126/scitranslmed.aao4097. PubMed DOI

Sharma R., Khristov V., Rising A., Jha B.S., Dejene R., Hotaling N., Li Y., Stoddard J., Stankewicz C., Wan Q., et al. Clinical-grade stem cell–derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs. Sci. Transl. Med. 2019;11:eaat5580. doi: 10.1126/scitranslmed.aat5580. PubMed DOI PMC

Kuroda T., Ando S., Takeno Y., Kishino A., Kimura T. Robust induction of retinal pigment epithelium cells from human induced pluripotent stem cells by inhibiting FGF/MAPK signaling. Stem Cell Res. 2019;39:101514. doi: 10.1016/j.scr.2019.101514. PubMed DOI

Choudhary P., Booth H., Gutteridge A., Surmacz B., Louca I., Steer J., Kerby J., Whiting P.J. Directing Differentiation of Pluripotent Stem Cells Toward Retinal Pigment Epithelium Lineage. Stem Cells Transl. Med. 2017;6:490–501. doi: 10.5966/sctm.2016-0088. PubMed DOI PMC

Boulton M., Dayhaw-Barker P. The role of the retinal pigment epithelium: Topographical variation and ageing changes. Eye. 2001;15:384–389. doi: 10.1038/eye.2001.141. PubMed DOI

Adler R., Canto-Soler M.V. Molecular mechanisms of optic vesicle development: Complexities, ambiguities and controversies. Dev. Biol. 2007;305:1–13. doi: 10.1016/j.ydbio.2007.01.045. PubMed DOI PMC

Zaghloul N.A., Yan B., Moody S.A. Step-wise specification of retinal stem cells during normal embryogenesis. Biol. Cell. 2005;97:321–337. doi: 10.1042/BC20040521. PubMed DOI

Zuber M.E., Gestri G., Viczian A.S., Barsacchi G., Harris W.A. Specification of the vertebrate eye by a network of eye field transcription factors. Development. 2003;130:5155–5167. doi: 10.1242/dev.00723. PubMed DOI

Kwan K.M., Otsuna H., Kidokoro H., Carney K.R., Saijoh Y., Chien C.-B. A complex choreography of cell movements shapes the vertebrate eye. Development. 2012;139:359–372. doi: 10.1242/dev.071407. PubMed DOI PMC

England S.J., Blanchard G.B., Mahadevan L., Adams R.J. A dynamic fate map of the forebrain shows how vertebrate eyes form and explains two causes of cyclopia. Development. 2006;133:4613–4617. doi: 10.1242/dev.02678. PubMed DOI

Muranishi Y., Terada K., Furukawa T. An essential role for Rax in retina and neuroendocrine system development. Dev. Growth Differ. 2012;54:341–348. doi: 10.1111/j.1440-169X.2012.01337.x. PubMed DOI

Mathers P.H., Grinberg A., Mahon K.A., Jamrich M. The Rx homeobox gene is essential for vertebrate eye development. Nature. 1997;387:603–607. doi: 10.1038/42475. PubMed DOI

Voronina V.A., Kozhemyakina E.A., O’Kernick C.M., Kahn N.D., Wenger S.L., Linberg J.V., Schneider A.S., Mathers P.H. Mutations in the human RAX homeobox gene in a patient with anophthalmia and sclerocornea. Hum. Mol. Genet. 2004;13:315–322. doi: 10.1093/hmg/ddh025. PubMed DOI

Liu W., Lagutin O., Swindell E., Jamrich M., Oliver G. Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate. J. Clin. Investig. 2010;120:3568–3577. doi: 10.1172/JCI43219. PubMed DOI PMC

Lagutin O.V., Zhu C.C., Kobayashi D., Topczewski J., Shimamura K., Puelles L., Russell H.R.C., McKinnon P.J., Solnica-Krezel L., Oliver G. Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development. Genes Dev. 2003;17:368–379. doi: 10.1101/gad.1059403. PubMed DOI PMC

Loosli F., Winkler S., Wittbrodt J. Six3 overexpression initiates the formation of ectopic retina. Genes Dev. 1999;13:649–654. doi: 10.1101/gad.13.6.649. PubMed DOI PMC

Fuhrmann S. Chapter Three–Eye Morphogenesis and Patterning of the Optic Vesicle. In: Cagan R.L., Reh T.A., editors. Current Topics in Developmental Biology. Volume 93. Academic Press; Cambridge, MA, USA: 2010. pp. 61–84. PubMed PMC

Bharti K., Nguyen M.-T.T., Skuntz S., Bertuzzi S., Arnheiter H. The other pigment cell: Specification and development of the pigmented epithelium of the vertebrate eye. Pigment Cell Res. 2006;19:380–394. doi: 10.1111/j.1600-0749.2006.00318.x. PubMed DOI PMC

Amram B., Cohen-Tayar Y., David A., Ashery-Padan R. The retinal pigmented epithelium–from basic developmental biology research to translational approaches. Int. J. Dev. Biol. 2017;61:225–234. doi: 10.1387/ijdb.160393ra. PubMed DOI

Cohen-Tayar Y., Cohen H., Mitiagin Y., Abravanel Z., Levy C., Idelson M., Reubinoff B., Itzkovitz S., Raviv S., Kaestner K.H., et al. Pax6 regulation of Sox9 in the mouse retinal pigmented epithelium controls its timely differentiation and choroid vasculature development. Development. 2018;145:dev163691. doi: 10.1242/dev.163691. PubMed DOI

Bharti K., Liu W., Csermely T., Bertuzzi S., Arnheiter H. Alternative promoter use in eye development: The complex role and regulation of the transcription factor MITF. Development. 2008;135:1169–1178. doi: 10.1242/dev.014142. PubMed DOI PMC

Cavodeassi F., Bovolenta P. New functions for old genes: Pax6 and Mitf in eye pigment biogenesis. Pigment Cell Melanoma Res. 2014;27:1005–1007. doi: 10.1111/pcmr.12308. PubMed DOI

Raviv S., Bharti K., Rencus-Lazar S., Cohen-Tayar Y., Schyr R., Evantal N., Meshorer E., Zilberberg A., Idelson M., Reubinoff B., et al. PAX6 Regulates Melanogenesis in the Retinal Pigmented Epithelium through Feed-Forward Regulatory Interactions with MITF. PLoS Genet. 2014;10:e1004360. doi: 10.1371/journal.pgen.1004360. PubMed DOI PMC

Ramón Martínez-Morales J., Rodrigo I., Bovolenta P. Eye development: A view from the retina pigmented epithelium. BioEssays. 2004;26:766–777. doi: 10.1002/bies.20064. PubMed DOI

Fan Y., Nikitina T., Zhao J., Fleury T.J., Bhattacharyya R., Bouhassira E.E., Stein A., Woodcock C.L., Skoultchi A.I. Histone H1 Depletion in Mammals Alters Global Chromatin Structure but Causes Specific Changes in Gene Regulation. Cell. 2005;123:1199–1212. doi: 10.1016/j.cell.2005.10.028. PubMed DOI

Fyodorov D.V., Zhou B.-R., Skoultchi A.I., Bai Y. Emerging roles of linker histones in regulating chromatin structure and function. Nat. Rev. Mol. Cell Biol. 2018;19:192–206. doi: 10.1038/nrm.2017.94. PubMed DOI PMC

Luz-Madrigal A., Grajales-Esquivel E., Tangeman J., Kosse S., Liu L., Wang K., Fausey A., Liang C., Tsonis P.A., Del Rio-Tsonis K. DNA demethylation is a driver for chick retina regeneration. Epigenetics. 2020;15:998–1019. doi: 10.1080/15592294.2020.1747742. PubMed DOI PMC

Raeisossadati R., Ferrari M.F.R., Kihara A.H., AlDiri I., Gross J.M. Epigenetic regulation of retinal development. Epigenetics Chromatin. 2021;14:11. doi: 10.1186/s13072-021-00384-w. PubMed DOI PMC

Dvoriantchikova G., Seemungal R.J., Ivanov D. The epigenetic basis for the impaired ability of adult murine retinal pigment epithelium cells to regenerate retinal tissue. Sci. Rep. 2019;9:3860. doi: 10.1038/s41598-019-40262-w. PubMed DOI PMC

Wang J., Zibetti C., Shang P., Sripathi S.R., Zhang P., Cano M., Hoang T., Xia S., Ji H., Merbs S.L., et al. ATAC-Seq analysis reveals a widespread decrease of chromatin accessibility in age-related macular degeneration. Nat. Commun. 2018;9:1364. doi: 10.1038/s41467-018-03856-y. PubMed DOI PMC

Kim Y., Jeong Y., Kwon K., Ismail T., Lee H.-K., Kim C., Park J.-W., Kwon O.-S., Kang B.-S., Lee D.-S., et al. Physiological effects of KDM5C on neural crest migration and eye formation during vertebrate development. Epigenetics Chromatin. 2018;11:72. doi: 10.1186/s13072-018-0241-x. PubMed DOI PMC

Karg M., Lu Y., Hoffmann E., Philipose H., Sinclair D., Ksander B., Saint-Geniez M. In vivo epigenetic reprogramming reverses the age-induced morphological decline of retinal pigment epithelial cells. Investig. Ophthalmol. Vis. Sci. 2021;62:3283.

Rai K., Chidester S., Zavala C.V., Manos E.J., James S.R., Karpf A.R., Jones D.A., Cairns B.R. Dnmt2 functions in the cytoplasm to promote liver, brain, and retina development in zebrafish. Genes Dev. 2007;21:261–266. doi: 10.1101/gad.1472907. PubMed DOI PMC

Nasonkin I.O., Merbs S.L., Lazo K., Oliver V.F., Brooks M., Patel K., Enke R.A., Nellissery J., Jamrich M., Le Y.Z., et al. Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis. Development. 2013;140:1330–1341. doi: 10.1242/dev.086603. PubMed DOI PMC

Adil A., Kumar V., Jan A.T., Asger M. Single-Cell Transcriptomics: Current Methods and Challenges in Data Acquisition and Analysis. Front. Neurosci. 2021;15:591122. doi: 10.3389/fnins.2021.591122. PubMed DOI PMC

Hu Y., Wang X., Hu B., Mao Y., Chen Y., Yan L., Yong J., Dong J., Wei Y., Wang W., et al. Dissecting the transcriptome landscape of the human fetal neural retina and retinal pigment epithelium by single-cell RNA-seq analysis. PLoS Biol. 2019;17:e3000365. doi: 10.1371/journal.pbio.3000365. PubMed DOI PMC

Booij J.C., van Soest S., Swagemakers S.M.A., Essing A.H.W., Verkerk A.J.M.H., van der Spek P.J., Gorgels T.G.M.F., Bergen A.A.B. Functional annotation of the human retinal pigment epithelium transcriptome. BMC Genom. 2009;10:164. doi: 10.1186/1471-2164-10-164. PubMed DOI PMC

Lidgerwood G.E., Senabouth A., Smith-Anttila C.J.A., Gnanasambandapillai V., Kaczorowski D.C., Amann-Zalcenstein D., Fletcher E.L., Naik S.H., Hewitt A.W., Powell J.E., et al. Transcriptomic Profiling of Human Pluripotent Stem Cell-derived Retinal Pigment Epithelium over Time. Genom. Proteom. Bioinform. 2021;19:223–242. doi: 10.1016/j.gpb.2020.08.002. PubMed DOI PMC

Voigt A.P., Mulfaul K., Mullin N.K., Flamme-Wiese M.J., Giacalone J.C., Stone E.M., Tucker B.A., Scheetz T.E., Mullins R.F. Single-cell transcriptomics of the human retinal pigment epithelium and choroid in health and macular degeneration. Proc. Natl. Acad. Sci. USA. 2019;116:24100–24107. doi: 10.1073/pnas.1914143116. PubMed DOI PMC

Whitmore S.S., Wagner A.H., DeLuca A.P., Drack A.V., Stone E.M., Tucker B.A., Zeng S., Braun T.A., Mullins R.F., Scheetz T.E. Transcriptomic analysis across nasal, temporal, and macular regions of human neural retina and RPE/choroid by RNA-Seq. Exp. Eye Res. 2014;129:93–106. doi: 10.1016/j.exer.2014.11.001. PubMed DOI PMC

West K.A., Yan L., Shadrach K., Sun J., Hasan A., Miyagi M., Crabb J.S., Hollyfield J.G., Marmorstein A.D., Crabb J.W. Protein Database, Human Retinal Pigment Epithelium. Mol. Cell. Proteom. 2003;2:37–49. doi: 10.1074/mcp.D200001-MCP200. PubMed DOI

Hongisto H., Jylhä A., Nättinen J., Rieck J., Ilmarinen T., Veréb Z., Aapola U., Beuerman R., Petrovski G., Uusitalo H., et al. Comparative proteomic analysis of human embryonic stem cell-derived and primary human retinal pigment epithelium. Sci. Rep. 2017;7:6016. doi: 10.1038/s41598-017-06233-9. PubMed DOI PMC

Pelkonen L., Sato K., Reinisalo M., Kidron H., Tachikawa M., Watanabe M., Uchida Y., Urtti A., Terasaki T. LC–MS/MS Based Quantitation of ABC and SLC Transporter Proteins in Plasma Membranes of Cultured Primary Human Retinal Pigment Epithelium Cells and Immortalized ARPE19 Cell Line. Mol. Pharm. 2017;14:605–613. doi: 10.1021/acs.molpharmaceut.6b00782. PubMed DOI

Pfeffer B.A., Fliesler S.J. Reassessing the suitability of ARPE-19 cells as a valid model of native RPE biology. Exp. Eye Res. 2022;219:109046. doi: 10.1016/j.exer.2022.109046. PubMed DOI

Zhou M., Geathers J.S., Grillo S.L., Weber S.R., Wang W., Zhao Y., Sundstrom J.M. Role of Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium Dysfunction. Front. Cell Dev. Biol. 2020;8:501. doi: 10.3389/fcell.2020.00501. PubMed DOI PMC

Alge C.S., Suppmann S., Priglinger S.G., Neubauer A.S., May C.A., Hauck S., Welge-Lussen U., Ueffing M., Kampik A. Comparative Proteome Analysis of Native Differentiated and Cultured Dedifferentiated Human RPE Cells. Investig. Ophthalmol. Vis. Sci. 2003;44:3629–3641. doi: 10.1167/iovs.02-1225. PubMed DOI

An E., Lu X., Flippin J., Devaney J.M., Halligan B., Hoffman E., Csaky K., Hathout Y. Secreted Proteome Profiling in Human RPE Cell Cultures Derived from Donors with Age Related Macular Degeneration and Age Matched Healthy Donors. J. Proteome Res. 2006;5:2599–2610. doi: 10.1021/pr060121j. PubMed DOI

Lee R.C., Feinbaum R.L., Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-4. Cell. 1993;75:843–854. doi: 10.1016/0092-8674(93)90529-Y. PubMed DOI

Wightman B., Ha I., Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-4 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75:855–862. doi: 10.1016/0092-8674(93)90530-4. PubMed DOI

Ha M., Kim V.N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 2014;15:509–524. doi: 10.1038/nrm3838. PubMed DOI

Treiber T., Treiber N., Meister G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat. Rev. Mol. Cell Biol. 2019;20:5–20. doi: 10.1038/s41580-018-0059-1. PubMed DOI

Wang H.-C., Greene W.A., Kaini R.R., Shen-Gunther J., Chen H.-I.H., Car H., Wang Y. Profiling the microRNA Expression in Human iPS and iPS-derived Retinal Pigment Epithelium. Cancer Inform. 2014;13:CIN-S14074. doi: 10.4137/CIN.S14074. PubMed DOI PMC

Hu G., Huang K., Yu J., Gopalakrishna-Pillai S., Kong J., Xu H., Liu Z., Zhang K., Xu J., Luo Y., et al. Identification of miRNA Signatures during the Differentiation of hESCs into Retinal Pigment Epithelial Cells. PLoS ONE. 2012;7:e37224. doi: 10.1371/journal.pone.0037224. PubMed DOI PMC

Davis N., Mor E., Ashery-Padan R. Roles for Dicer1 in the patterning and differentiation of the optic cup neuroepithelium. Development. 2011;138:127–138. doi: 10.1242/dev.053637. PubMed DOI

Sundermeier T.R., Sakami S., Sahu B., Howell S.J., Gao S., Dong Z., Golczak M., Maeda A., Palczewski K. MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice. J. Biol. Chem. 2017;292:3366–3378. doi: 10.1074/jbc.M116.770024. PubMed DOI PMC

Iacovelli J., Zhao C., Wolkow N., Veldman P., Gollomp K., Ojha P., Lukinova N., King A., Feiner L., Esumi N., et al. Generation of Cre Transgenic Mice with Postnatal RPE-Specific Ocular Expression. Investig. Ophthalmol. Vis. Sci. 2011;52:1378–1383. doi: 10.1167/iovs.10-6347. PubMed DOI PMC

Ohana R., Weiman-Kelman B., Raviv S., Tamm E.R., Pasmanik-Chor M., Rinon A., Netanely D., Shamir R., Solomon A.S., Ashery-Padan R. MicroRNAs are essential for differentiation of the retinal pigmented epithelium and maturation of adjacent photoreceptors. Development. 2015;142:2487–2498. doi: 10.1242/jcs.177584. PubMed DOI

Du S.W., Palczewski K. MicroRNA regulation of critical retinal pigment epithelial functions. Trends Neurosci. 2022;45:78–90. doi: 10.1016/j.tins.2021.10.008. PubMed DOI PMC

Adijanto J., Castorino J.J., Wang Z.-X., Maminishkis A., Grunwald G.B., Philp N.J. Microphthalmia-associated Transcription Factor (MITF) Promotes Differentiation of Human Retinal Pigment Epithelium (RPE) by Regulating microRNAs-204/211 Expression. J. Biol. Chem. 2012;287:20491–20503. doi: 10.1074/jbc.M112.354761. PubMed DOI PMC

Jiang C., Qin B., Liu G., Sun X., Shi H., Ding S., Liu Y., Zhu M., Chen X., Zhao C. MicroRNA-184 promotes differentiation of the retinal pigment epithelium by targeting the AKT2/mTOR signaling pathway. Oncotarget. 2016;7:52340–52353. doi: 10.18632/oncotarget.10566. PubMed DOI PMC

Choi S.W., Kim J.-J., Seo M.-S., Park S.-B., Kang T.-W., Lee J.Y., Lee B.-C., Kang I., Shin T.-H., Kim H.-S., et al. miR-410 Inhibition Induces RPE Differentiation of Amniotic Epithelial Stem Cells via Overexpression of OTX2 and RPE65. Stem Cell Rev. Rep. 2015;11:376–386. doi: 10.1007/s12015-014-9568-2. PubMed DOI

Harhaj N.S., Antonetti D.A. Regulation of tight junctions and loss of barrier function in pathophysiology. Int. J. Biochem. Cell Biol. 2004;36:1206–1237. doi: 10.1016/j.biocel.2003.08.007. PubMed DOI

Wang F.E., Zhang C., Maminishkis A., Dong L., Zhi C., Li R., Zhao J., Majerciak V., Gaur A.B., Chen S., et al. MicroRNA-204/211 alters epithelial physiology. FASEB J. 2010;24:1552–1571. doi: 10.1096/fj.08-125856. PubMed DOI PMC

Takayama K., Kaneko H., Hwang S.-J., Ye F., Higuchi A., Tsunekawa T., Matsuura T., Iwase T., Asami T., Ito Y., et al. Increased Ocular Levels of MicroRNA-148a in Cases of Retinal Detachment Promote Epithelial–Mesenchymal Transition. Investig. Ophthalmol. Vis. Sci. 2016;57:2699–2705. doi: 10.1167/iovs.15-18660. PubMed DOI

Zhang C., Miyagishima K.J., Dong L., Rising A., Nimmagadda M., Liang G., Sharma R., Dejene R., Wang Y., Abu-Asab M., et al. Regulation of phagolysosomal activity by miR-204 critically influences structure and function of retinal pigment epithelium/retina. Hum. Mol. Genet. 2019;28:3355–3368. doi: 10.1093/hmg/ddz171. PubMed DOI PMC

Murad N., Kokkinaki M., Gunawardena N., Gunawan M.S., Hathout Y., Janczura K.J., Theos A.C., Golestaneh N. miR-184 regulates ezrin, LAMP-1 expression, affects phagocytosis in human retinal pigment epithelium and is downregulated in age-related macular degeneration. FEBS J. 2014;281:5251–5264. doi: 10.1111/febs.13066. PubMed DOI

Choi S.W., Kim J.-J., Seo M.-S., Park S.-B., Shin T.-H., Shin J.-H., Seo Y., Kim H.-S., Kang K.-S. Inhibition by miR-410 facilitates direct retinal pigment epithelium differentiation of umbilical cord blood-derived mesenchymal stem cells. J. Vet. Sci. 2017;18:59–65. doi: 10.4142/jvs.2017.18.1.59. PubMed DOI PMC

Cui L., Lyu Y., Jin X., Wang Y., Li X., Wang J., Zhang J., Deng Z., Yang N., Zheng Z., et al. miR-194 suppresses epithelial-mesenchymal transition of retinal pigment epithelial cells by directly targeting ZEB1. Ann. Transl. Med. 2019;7:751. doi: 10.21037/atm.2019.11.90. PubMed DOI PMC

Zhang J., Wang J., Zheng L., Wang M., Lu Y., Li Z., Lian C., Mao S., Hou X., Li S., et al. miR-25 Mediates Retinal Degeneration Via Inhibiting ITGAV and PEDF in Rat. Curr. Mol. Med. 2017;17:359–374. doi: 10.2174/1566524018666171205122540. PubMed DOI

Zhang K., Ding S. Stem Cells and Eye Development. N. Engl. J. Med. 2011;365:370–372. doi: 10.1056/NEJMcibr1105280. PubMed DOI PMC

Sonoda S., Spee C., Barron E., Ryan S.J., Kannan R., Hinton D.R. A protocol for the culture and differentiation of highly polarized human retinal pigment epithelial cells. Nat. Protoc. 2009;4:662–673. doi: 10.1038/nprot.2009.33. PubMed DOI PMC

Limnios I.J., Chau Y.-Q., Skabo S.J., Surrao D.C., O’Neill H.C. Efficient differentiation of human embryonic stem cells to retinal pigment epithelium under defined conditions. Stem Cell Res. Ther. 2021;12:248. doi: 10.1186/s13287-021-02316-7. PubMed DOI PMC

Zahabi A., Shahbazi E., Ahmadieh H., Hassani S.-N., Totonchi M., Taei A., Masoudi N., Ebrahimi M., Aghdami N., Seifinejad A., et al. A New Efficient Protocol for Directed Differentiation of Retinal Pigmented Epithelial Cells from Normal and Retinal Disease Induced Pluripotent Stem Cells. Stem Cells Dev. 2011;21:2262–2272. doi: 10.1089/scd.2011.0599. PubMed DOI

Greber B., Coulon P., Zhang M., Moritz S., Frank S., Müller-Molina A.J., Araúzo-Bravo M.J., Han D.W., Pape H.-C., Schöler H.R. FGF signalling inhibits neural induction in human embryonic stem cells. EMBO J. 2011;30:4874–4884. doi: 10.1038/emboj.2011.407. PubMed DOI PMC

Sun C., Zhou J., Meng X. Primary cilia in retinal pigment epithelium development and diseases. J. Cell. Mol. Med. 2021;25:9084–9088. doi: 10.1111/jcmm.16882. PubMed DOI PMC

Fuhrmann S., Levine E.M., Reh T.A. Extraocular mesenchyme patterns the optic vesicle during early eye development in the embryonic chick. Development. 2000;127:4599–4609. doi: 10.1242/dev.127.21.4599. PubMed DOI

Buse E., de Groot H. Generation of developmental patterns in the neuroepithelium of the developing mammalian eye: The pigment epithelium of the eye. Neurosci. Lett. 1991;126:63–66. doi: 10.1016/0304-3940(91)90372-Z. PubMed DOI