Retinal Pigment Epithelium Transplantation: Past, Present, and Future


Retinal pigment epithelium (RPE) is a monolayer of cells situated between photoreceptors and the underlying choroid. It is essential for normal retinal function. Damaged RPE is associated with diseases such as age-related macular degeneration, Stargardt’s macular dystrophy, and retinitis pigmentosa. RPE cells can easily be visualized in vivo, sustainable in vitro, and differentiated from stem cells with a relatively straightforward protocol. Due to these properties and the clinical significance of this epithelium in various retinal diseases, RPE transplantation as a treatment modality has gained considerable interest in the last decade. This paper presents the main techniques for RPE transplantation and discusses recent clinically relevant publications.


Retinal Pigment Epithelium, Retinal Pigment Epithelium Transplantation, Regenerative Medicine, Vitreoretinal Surgery, Tissue Engineering

1. Klettner AK, Dithmar S. Retinal pigment epithelium in health and disease. Springer International Publishing; 2020.

2. Strauss O. The retinal pigment epithelium in visual function. Physiol Rev 2005;85:845–881.

3. Khandhadia S, Cherry J, Lotery AJ. Age-related macular degeneration. In: Ahmad SI, editor. Neurodegenerative diseases [Internet]. New York, NY: Springer; 2012. p. 15– 36.

4. Spraul CW, Lang GE, Grossniklaus HE, Lang GK. Histologic and morphometric analysis of the choroid, Bruch’s membrane, and retinal pigment epithelium in postmortem eyes with age-related macular degeneration and histologic examination of surgically excised choroidal neovascular membranes. Surv Ophthalmol 1999;44:S10– 32.

5. Al-Hussaini H, Schneiders M, Lundh P, Jeffery G. Drusen are associated with local and distant disruptions to human retinal pigment epithelium cells. Exp Eye Res 2009;88:610–612.

6. Li ZY, Possin DE, Milam AH. Histopathology of bone spicule pigmentation in retinitis pigmentosa. Ophthalmology 1995;102:805–816.

7. Snead DR, James S, Snead MP. Pathological changes in the vitreoretinal junction 1: Epiretinal membrane formation. Eye 2008;22:1310–1317.

8. Machemer R, Laqua H. Pigment epithelium proliferation in retinal detachment (massive periretinal proliferation). Am J Ophthalmol 1975;80:1–23.

9. Fahl E, Jaissle GB, May CA. Pavert Svd, Wenzel A, Claes E, et al. Bone spicule formation in retinitis pigmentosa: Insights from a mouse model. Invest Ophthalmol Vis Sci 2008;49:2199–2199.

10. Flood MT, Gouras P, Kjeldbye H. Growth characteristics and ultrastructure of human retinal pigment epithelium in vitro. Invest Ophthalmol Vis Sci 1980;19:1309–1320.

11. Gouras P, Flood MT, Kjeldbye H. Transplantation of cultured human retinal cells to monkey retina. An Acad Bras Cienc 1984;56:431–443.

12. Li LX, Turner JE. Inherited retinal dystrophy in the RCS rat: Prevention of photoreceptor degeneration by pigment epithelial cell transplantation. Exp Eye Res 1988;47:911– 917.

13. Lopez R, Gouras P, Brittis M, Kjeldbye H. Transplantation of cultured rabbit retinal epithelium to rabbit retina using a closed-eye method. Invest Ophthalmol Vis Sci 1987;28:1131–1137.

14. Lopez R, Gouras P, Kjeldbye H, Sullivan B, Reppucci V, Brittis M, et al. Transplanted retinal pigment epithelium modifies the retinal degeneration in the RCS rat. Invest Ophthalmol Vis Sci 1989;30:586–588.

15. Sheedlo HJ, Li L, Turner JE. Photoreceptor cell rescue in the RCS rat by RPE transplantation: A therapeutic approach in a model of inherited retinal dystrophy. Prog Clin Biol Res 1989;314:645–658.

16. Algvere PV, Berglin L, Gouras P, Sheng Y, Kopp ED. Transplantation of RPE in age-related macular degeneration: Observations in disciform lesions and dry RPE atrophy. Graefes Arch Clin Exp Ophthalmol 1997;235:149–158.

17. Algvere PV, Berglin L, Gouras P, Sheng Y. Transplantation of fetal retinal pigment epithelium in age-related macular degeneration with subfoveal neovascularization. Graefes Arch Clin Exp Ophthalmol 1994;232:707–716.

18. Del Priore LV, Kaplan HJ, Tezel TH, Hayashi N, Berger AS, Green WR. Retinal pigment epithelial cell transplantation after subfoveal membranectomy in age-related macular degeneration: Clinicopathologic correlation. Am J Ophthalmol 2001;131:472–480.

19. Peyman GA, Blinder KJ, Paris CL, Alturki W, Nelson NC Jr, Desai U. A technique for retinal pigment epithelium transplantation for age-related macular degeneration secondary to extensive subfoveal scarring. Ophthalmic Surg 1991;22:102–108.

20. Tezel TH, Del Priore LV, Berger AS, Kaplan HJ. Adult retinal pigment epithelial transplantation in exudative age-related macular degeneration. Am J Ophthalmol 2007;143:584–595.

21. Binder S, Krebs I, Hilgers RD, Abri A, Stolba U, Assadoulina A, et al. Outcome of transplantation of autologous retinal pigment epithelium in age-related macular degeneration: A prospective trial. Invest Ophthalmol Vis Sci 2004;45:4151–4160.

22. Binder S, Stolba U, Krebs I, Kellner L, Jahn C, Feichtinger H, et al. Transplantation of autologous retinal pigment epithelium in eyes with foveal neovascularization resulting from age-related macular degeneration: A pilot study. Am J Ophthalmol 2002;133:215–225.

23. Treumer F, Bunse A, Klatt C, Roider J. Autologous retinal pigment epithelium-choroid sheet transplantation in age related macular degeneration: morphological and functional results. Br J Ophthalmol 2007;91:349–353.

24. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 2017;376:1038–1046.

25. Song WK, Park KM, Kim HJ, Lee JH, Choi J, Chong SY, et al. Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: Preliminary results in Asian patients. Stem Cell Reports 2015;4:860–872.

26. da Cruz L, Fynes K, Georgiadis O, Kerby J, Luo YH, Ahmado A, et al. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol 2018;36:328–337.

27. Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ, Gregori NZ, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: Follow-up of two open-label phase 1/2 studies. Lancet 2015;385:509–516.

28. Panopoulos AD, Ruiz S, Izpisua Belmonte JC. iPSCs: Induced back to controversy. Cell Stem Cell 2011;8:347– 348.

29. Almond B. Using and misusing embryos: The ethical debates. In: King-Tak IP, editor. The bioethics of regenerative medicine. Springer Dordrecht: Springer; 2009. p. 77–92.

30. Blackford R. Stem cell research on other worlds, or why embryos do not have a right to life. J Med Ethics 2006;32:177–180.

31. Mcgee G. Trading lives or changing human nature: The strange dilemma of embryo-based regenerative medicine. In: King-Tak IP, editor. The bioethics of regenerative medicine. Springer Dordrecht: Springer; 2009. p. 93–106.

32. Buchholz DE, Hikita ST, Rowland TJ, Friedrich AM, Hinman CR, Johnson LV, et al. Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells. Stem Cells 2009;27:2427–2434.

33. Hirami Y, Osakada F, Takahashi K, Okita K, Yamanaka S, Ikeda H, et al. Generation of retinal cells from mouse and human induced pluripotent stem cells. Neurosci Lett 2009;458:126–131.

34. Kawasaki H, Suemori H, Mizuseki K, Watanabe K, Urano F, Ichinose H, et al. Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity. Proc Natl Acad Sci USA 2002;99:1580–1585.

35. Osakada F, Ikeda H, Mandai M, Wataya T, Watanabe K, Yoshimura N, et al. Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nat Biotechnol 2008;26:215–224.

36. van Zeeburg EJ, Maaijwee KJ, Missotten TO, Heimann H, van Meurs JC. A free retinal pigment epithelium–choroid graft in patients with exudative age-related macular degeneration: Results up to 7 years. Am J Ophthalmol 2012;153:120–127.e122.

37. van Meurs JC, Van Den Biesen PR. Autologous retinal pigment epithelium and choroid translocation in patients with exudative age-related macular degeneration: Shortterm follow-up. Am J Ophthalmol 2003;136:688–695.

38. John S, Natarajan S, Parikumar P, Shanmugam P M, Senthilkumar R, Green DW, et al. Choice of cell source in cell-based therapies for retinal damage due to agerelated macular degeneration: A review. J Ophthalmol 2013;2013:465169.

39. Stanga PE, Kychenthal A, Fitzke FW, Halfyard AS, Chan R, Bird AC, et al. Retinal pigment epithelium translocation after choroidal neovascular membrane removal in age-related macular degeneration. Ophthalmology 2002;109:1492–1498.

40. Kashani AH, Lebkowski JS, Rahhal FM, Avery RL, Salehi-Had H, Dang W, et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Sci Transl Med 2018;10(435):eaao4097.

41. Kashani AH, Uang J, Mert M, Rahhal F, Chan C, Avery RL, et al. Surgical method for implantation of a biosynthetic retinal pigment epithelium monolayer for geographic atrophy: Experience from a phase 1/2a study. Ophthalmol Retina 2020;4:264–273.

42. Falkner-Radler CI, Krebs I, Glittenberg C, Povazay B, Drexler W, Graf A, et al. Human retinal pigment epithelium (RPE) transplantation: Outcome after autologous RPEchoroid sheet and RPE cell-suspension in a randomised clinical study. Br J Ophthalmol 2011;95:370–375.

43. Schwartz SD, Hubschman JP, Heilwell G, Franco- Cardenas V, Pan CK, Ostrick RM, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 2012;379:713–720.