Ageing of the retinal pigment epithelium: implications for transplantation

Review

Abstract

This review will discuss some of the implications for using cells from aged donors for retinal pigment epithelium (RPE) transplantation. It will consider age-related changes in the structure and function of RPE cells and the accumulation of potentially damaging photoreactive constituents. The review will focus on the role of the ocular pigments lipofuscin and melanin in respect to age-related changes in composition, photoreactivity and potential role in retinal ageing and age-related macular degeneration. The article concludes by considering the suitability of senescent RPE cells for transplantation and whether such cells can be rejuvenated.

References

  1. 1.
    Abe T, Durlu Y, Tamai M (1996) The properties of retinal pigment epithelial cells in proliferative vitreoretinopathy compared with cultured retinal pigment epithelial cells. Exp Eye Res 63:201–210CrossRefPubMedGoogle Scholar
  2. 2.
    Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, Pearce-Kelling SE, Anand V, Zeng Y, Maguire AM, Jacobson SG, Hauswirth WW, Bennett J (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92–95CrossRefPubMedGoogle Scholar
  3. 3.
    Algvere P, Gouras P, Dafgard Kopp E (1999) Long-term outcome of RPE allografts in non-immunosuppressed patients with AMD. Eur J Ophthalmol 9:217–230PubMedGoogle Scholar
  4. 4.
    Beatty S, Koh H-H, Henson D, Boulton M (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45:115–134CrossRefPubMedGoogle Scholar
  5. 5.
    Ben-Shabat S, Parish CA, Hashimoto M, Liu J, Nakanishi K, Sparrow JR (2001) Fluorescent pigments of the retinal pigment epithelium and age-related macular degeneration. Bioorg Med Chem Lett 11:1533–1540CrossRefPubMedGoogle Scholar
  6. 6.
    Binder S, Stolba U, Krebs I, Kellner L, Jahn C, Feichtinger H, Povelka M, Frohner U, Kruger A, Hilgers RD, Krugluger W (2002) Transplantation of autologous retinal pigment epithelium in eyes with foveal neovascularization resulting from age-related macular degeneration: a pilot study. Am J Ophthalmol 133:215–225PubMedGoogle Scholar
  7. 7.
    Boulton M (1991) Ageing of the retinal pigment epithelium. In: Osborne N, Chader G, (eds) Progress in retinal research. Pergamon, Oxford, pp 125–151Google Scholar
  8. 8.
    Boulton M (1998) The role of melanin in the RPE. In: Marmor M, Wolfensberger T, (eds) The retinal pigment epithelium. Oxford University Press, Oxford, pp 68–85Google Scholar
  9. 9.
    Boulton M (2004) The importance of maintaining the RPE phenotype in retinal transplantation. In: Binder S (ed) The macula. Springer, Vienna New York (in press)Google Scholar
  10. 10.
    Boulton M, Dayhaw-Barker P (2001) The role of the retinal pigment epithelium: topographical variation and ageing changes. Eye 15:384–389PubMedGoogle Scholar
  11. 11.
    Boulton M, Dontsov A, Jarvis-Evans J, Ostrovsky M, Svistunenko D (1993) Lipofuscin is a photoinducible free radical generator. Photochem Photobiol B: Biol 19:201–204Google Scholar
  12. 12.
    Boulton M, Różanowska M, Różanowski B (2001) Retinal photodamage. J Photochem Photobiol B 64:144–161CrossRefPubMedGoogle Scholar
  13. 13.
    Brizee KR, Ordy JM (1981) Cellular features, regional accommodation, and prospects of modification of age pigments in mammals. In: Sohal RS (ed) Age pigments. Elsevier/North Holland, Amsterdam, pp 101–154Google Scholar
  14. 14.
    Cai J, Nelson K, Wu M, Sternberg P, Jones D (2000) Oxidative damage and protection of the RPE. Prog Ret Res 19:205–221CrossRefGoogle Scholar
  15. 15.
    Cantrell A, McGarvey DJ, Roberts J, Sarna T, Truscott TG (2001) Photochemical studies of A2-E. Photochem Photobiol B: Biol 64:162–165Google Scholar
  16. 16.
    Clancy CMR, Krogmeier JR, et al (2000) Atomic force microscopy and near-field scanning optical microscopy measurements of single human retinal lipofuscin granules. J Phys Chem B 104:12098–12101CrossRefGoogle Scholar
  17. 17.
    Curcio CA, Medeiros NE, Millican CL (1996) Photoreceptor loss in age-related macular degeneration. Invest Ophthalmol Vis Sci 37:1236–1249PubMedGoogle Scholar
  18. 18.
    Davies S, Elliott MH, Floor E, Truscott TG, Zareba M, Sarna T, Shamsi FA. Boulton M (2001) Photocytotoxicity of lipofuscin in human retinal pigment epithelial cells. Free Radic Biol Med 31:256–265CrossRefPubMedGoogle Scholar
  19. 19.
    Dayhaw-Barker P, Davies S, Shamsi F, Różanowska M, Rozanowski B, Boulton M (2001) The phototoxicity of aged RPE melanosomes. Invest Ophthalmol Vis Sci 42:S755Google Scholar
  20. 20.
    Delori FC, Goger DG, Dorey CK (2001) Age-related accumulation and spatial distribution of lipofuscin in RPE of normal subjects. Invest Ophthalmol Vis Sci 42:1855–1866PubMedGoogle Scholar
  21. 21.
    Eldred GE (1998) Lipofuscin and other lysosomal storage deposits in the retinal pigment epithelium. In: Marmor M, Wolfensberger T (eds) The retinal pigment epithelium. Oxford University Press, Oxford, pp 651–668Google Scholar
  22. 22.
    Eldred GE, Katz ML (1988) Fluorophores of the human retinal pigment epithelium: separation and spectral characterization. Exp Eye Res 47:71–86PubMedGoogle Scholar
  23. 23.
    Eldred GE, Lasky M (1993) Retinal age pigments generated by self-assembling lysosomotropic detergents. Nature 361:724–726PubMedGoogle Scholar
  24. 24.
    Feeney-Burns L, Hilderbrand E, Eldridge S (1984) Aging human RPE: morphometric analysis of macular, equatorial and peripheral cells. Invest Ophthalmol Vis Sci 25:195–200PubMedGoogle Scholar
  25. 25.
    Friedrichson T, Kalbach H, Buck P, van Kuijk F (1995) Vitamin E in macular and peripheral tissues of the human eye. Curr Eye Res 14:693–701Google Scholar
  26. 26.
    Gaillard ER, Atherton SJ, Eldred GE, Dillon J (1995) Photophysical studies on human retinal lipofuscin. Photochem Photobiol 61:448–453PubMedGoogle Scholar
  27. 27.
    Gaillard ER, Hill C, Griffiths TD (2003) UVC and visible light damage to re-pigmented RPE cells. Invest Ophthalmol Vis Sci Abstract 377Google Scholar
  28. 28.
    Gouras P, Kong J, Tsang SH (2002) Retinal degeneration and RPE transplantation in Rpe65(-/-) mice. Invest Ophthalmol Vis Sci 43:3307–3311PubMedGoogle Scholar
  29. 29.
    Guymer R, Bird AC (1998) Bruch’s membrane, drusen, and age-related macular degeneration. In: Marmor M, Wolfensberger T (eds) The retinal pigment epithelium. Oxford University Press, Oxford, pp 693–705Google Scholar
  30. 30.
    Hageman GS, Luthert PJ, Victor Chong NH, Johnson L, Anderson DH, Mullins RF (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE–Bruch’s membrane interface in aging and age-related macular degeneration. Prog Ret Eye Res 20:705–732CrossRefGoogle Scholar
  31. 31.
    Haralampus-Grynaviski NM, Lamb LE, Simon JD, Krogmeier JR, Dunn RC, Pawlak A, Różanowska M, Sarna T, Burke JM (2001) Probing the spatial dependence of the emission spectrum of single human retinal lipofuscin granules using near-field scanning optical microscopy. Photochem Photobiol 74:364–368PubMedGoogle Scholar
  32. 32.
    Haralampus-Grynaviski NM, Lamb LE, Clancy CM, Skumatz C, Burke JM, Sarna T, Simon JD (2003) Spectroscopic and morphological studies of human retinal lipofuscin granules. Proc Natl Acad Sci U S A 100:3179–3184CrossRefPubMedGoogle Scholar
  33. 33.
    Hjelmeland L (1999) Senescence of the retinal pigmented epithelium. Invest Ophthalmol Vis Sci 40:1–2PubMedGoogle Scholar
  34. 34.
    Hogan M, Alvarado J, Weddell J (1971) Histology of the human eye. Saunders, PhiladelphiaGoogle Scholar
  35. 35.
    Holz FG, Bellman C, Staudt S, Schutt F, Volcker HE (2001) Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci 42:1051–1056Google Scholar
  36. 36.
    Holz FG, Schutt F, Kopitz J, Eldred GE, Kruse FE, Volcker HE, Cantz M (1999) Inhibition of lysosomal degradative functions in RPE cells by a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci 41:2303–2308Google Scholar
  37. 37.
    Kayatz P, Thumann G, Luther TT, Jordan JF, Bartz-Schmidt KU, Esser PJ, Schraermeyer U (2001) Oxidation causes melanin fluorescence. Invest Ophthalmol Vis Sci 42:241–246PubMedGoogle Scholar
  38. 38.
    Korte GE, Reppucci V, Henkind P (1984) RPE destruction causes choriocapillary atrophy. Invest Ophthalmol Vis Sci 25:1135–1145Google Scholar
  39. 39.
    Krogmeier JR, Clancy CM, Pawlak A, Różanowska M, Sarna T, Simon JD, Dunn RC (2001) Mapping the distribution of emissive molecules in human ocular lipofuscin granules with near-field scanning optical microscopy. J Microsc 202:386–390CrossRefPubMedGoogle Scholar
  40. 40.
    Lamb LE, Ye T, et al (2001) Primary photophysical properties of A2E in solution. J Phys Chem B 105:11507–11512CrossRefGoogle Scholar
  41. 41.
    Lamb LE, Zareba M, Plakoudas SN, Sarna T, Simon JD (2001) Retinyl palmitate and the blue-light-induced phototoxicity of human ocular lipofuscin. Arch Biochem Biophys 393:316–320CrossRefPubMedGoogle Scholar
  42. 42.
    Liles M, Newsome D, Oliver P (1991) Antioxidant enzymes in the aging human retinal pigment epithelium. Arch Ophthalmol 109:1285–1288PubMedGoogle Scholar
  43. 43.
    Lois N, Owens SL, Coco R, Hopkins J, Fitzke FW, Bird A (2002) Fundus autofluorescence in patients with age-related macular degeneration and high risk of visual loss. Am J Ophthalmol 133:341–349CrossRefPubMedGoogle Scholar
  44. 44.
    Lund R, Adamson P, Sauve Y, Keegan D, Girman S, Wang S, Winton H, Kanuga N, Kwan A, Beauchene L, Zerbib A, Hetherington L, Couraud P, Coffey P, Greenwood J (2001) Subretinal transplantation of genetically modified human cell lines attenuates loss of visual function in dystrophic rats. Proc Natl Acad Sci USA 98:9942–9947CrossRefPubMedGoogle Scholar
  45. 45.
    Lund RD, Kwan AS, Keegan DJ, Sauve Y, Coffey PJ, Lawrence JM (2001) Cell transplantation as a treatment for retinal disease. Prog Ret Eye Res 20:415–449CrossRefGoogle Scholar
  46. 46.
    Mahaffy H, McFarlane S, Simpson D, Curry W, Stitt A (2003) Advanced glycation endproducts accumulate in RPE lysosomal compartments and induce widespread alteration in gene expression: possible role in age-related dysfunction. Invest Ophthalmol Vis Sci Abstract 2274Google Scholar
  47. 47.
    Marmor M, Wolfensberger T (1998) The retinal pigment epithelium. Oxford University Press, OxfordGoogle Scholar
  48. 48.
    Marshall J (1987) The ageing retina: physiology or pathology? Eye 1:282–295PubMedGoogle Scholar
  49. 49.
    Marshall J, Hussain AA, Starita A, Moore DJ, Patmore AL (1998) Aging and Bruch’s membrane. In: Marmor M, Wolfensberger T (eds) The retinal pigment epithelium. Oxford University Press, Oxford, pp 669–692Google Scholar
  50. 50.
    Mata NL, Weng J, Travis GH (2000) Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci U S A 20:7154–7159CrossRefGoogle Scholar
  51. 51.
    Matsunaga H, Handa JT, Aotaki-Keen A, Sherwood SW, West MD, Hjelmeland LM (1999) Beta-galactosidase histochemistry and telomere loss in senescent retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 40:197–202PubMedGoogle Scholar
  52. 52.
    Narfstrom K, Katz ML, Ford M, Redmond TM, Rakoczy E, Bragadottir R (2003) In vivo gene therapy in young and adult RPE65-/- dogs produces long-term visual improvement. J Hered 94:31–37CrossRefPubMedGoogle Scholar
  53. 53.
    Panda-Jonas S, Jonas J, Jakobczyk-Kmija M (1996) Retinal pigment epithelial cell count distribution, and correlations in normal eyes. Am J Ophthalmol 121:181–189PubMedGoogle Scholar
  54. 54.
    Parish CA, Hashimoto M, Nakanishi K, Dillon J, Sparrow JR (1998) Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium. Proc Natl Acad Sci U S A 95:14609–14613CrossRefPubMedGoogle Scholar
  55. 55.
    Pawlak A, Różanowska M, Zareba M, Lamb LE, Simon JD, Sarna T. (2002) Action spectra for the photoconsumption of oxygen by human ocular lipofuscin and lipofuscin extracts. Arch Biochem Biophys 403:59–62CrossRefPubMedGoogle Scholar
  56. 56.
    Pawlak A, Wrona M, Różanowska M, Zareba M, Lamb LE, Roberts JE, Simon JD, Sarna T (2003) Comparison of the aerobic photoreactivity of A2E with its precursor retinal. Photochem Photobiol 77:253–258PubMedGoogle Scholar
  57. 57.
    Różanowska M, Boulton M, Burke J, Korytowski W, Jarvis-Evans J, Sarna T (1995) Blue light-induced reactivity of retinal age pigment. J Biol Chem 270:18825–18830Google Scholar
  58. 58.
    Różanowska M, Wessels J, Boulton M, Burke J, Rodgers M, Truscott T, Sarna T (1998) Blue light-induced singlet oxygen generation by retinal lipofuscin in non-polar media. Free Radic Biol Med 24:1107–1112Google Scholar
  59. 59.
    Różanowska M, Korytowski W, Różanowski B, Skumatz C, Boulton M, Burke J, Sarna T (2002) Photoreactivity of aged human RPE melanosomes: a comparison with lipofuscin. Invest Ophthalmol Vis Sci 43:2088–2096Google Scholar
  60. 60.
    Różanowska M, Pawlak A, Różanowski B, Skumatz C, Zareba M, Boulton M, Burke JM, Sarna T, Simon J (2004) Age-related changes in the photoreactivity of retinal lipofuscin granules: role of chloroform insoluble components. Invest Ophthalmol Vis Sci Abstract 678Google Scholar
  61. 61.
    Sakai N, Decatur J, Nakanishi K, Eldred GE (1996) Ocular age pigment A2E: an unprecedented pyridinum bisretinoid. J Am Chem Soc 118:1559–1560CrossRefGoogle Scholar
  62. 62.
    Sarna T (1992) Properties and function of the ocular melanin—a photophysical view. J Photochem Photobiol B: Biol 12:215–258Google Scholar
  63. 63.
    Sarna T, Burke JM, Korytowski W, Różanowska M, Skumatz CM, Zareba A, Zareba M (2003) Loss of melanin from human RPE with aging: possible role of melanin photooxidation. Exp Eye Res 76:89–98CrossRefPubMedGoogle Scholar
  64. 64.
    Schutt F, Davies S, Kopitz J, Holz FG, Boulton M (2000) Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci 41:2303–2308Google Scholar
  65. 65.
    Schutt F, Ueberle B, Schnölzer M, Holz FG, Kopitz J (2002) Proteome analysis of lipofuscin in human retinal pigment epithelial cells. FEBS Lett 528:217–221CrossRefPubMedGoogle Scholar
  66. 66.
    Schutt F, Bergmann M, Holz FG, Kopitz J (2002) Isolation of intact lysosomes from human RPE cells and effects of A2-E on the integrity of the lysosomal and other cellular membranes. Graefes Arch Clin Exp Ophthalmol 240:983–988PubMedGoogle Scholar
  67. 67.
    Schutt F, Bergmann M, Holz FG, Kopitz J (2003) Proteins modified by malondialdehyde, 4-hydroxynonenal, or advanced glycation end products in lipofuscin of human retinal pigment epithelium. Invest Ophthalmol Vis Sci 44:3663–3668CrossRefPubMedGoogle Scholar
  68. 68.
    Shamsi FA, Boulton M (2001) Inhibition of RPE lysosomal and antioxidant activity by the age pigment lipofuscin. Invest Ophthalmol Vis Sci 42:3041–3046PubMedGoogle Scholar
  69. 69.
    Simovich MJ, Miller B, Ezzeldin H, Kirkland BT, McLeod G, Fulmer C, Nathans J, Jacobson SG, Pittler SJ (2001) Four novel mutations in the RPE65 gene in patients with Leber congenital anaurosis. Hum Mutat 18:164CrossRefGoogle Scholar
  70. 70.
    Smith AJ, Schlichtenbrede FC, Tschernutter M, Bainbridge JW, Thrasher AJ, Ali RR (2003) AAV-mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa. Mol Ther 8:188–195CrossRefPubMedGoogle Scholar
  71. 71.
    Sohal RS (1981) Age pigments. Elsevier/North Holland, AmsterdamGoogle Scholar
  72. 72.
    Sparrow JR, Cai B (2001) Blue light-induced apoptosis of A2E-containing RPE: involvement of caspase-3 and protection by Bcl-2. Invest Ophthalmol Vis Sci 42:1356–1362Google Scholar
  73. 73.
    Sparrow JR, Nakanishi K, Parish CA (2000) The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci 41:1981–1989Google Scholar
  74. 74.
    Sparrow JR, Zhou J, Ben-Shabat S, Vollmer H, Itagal Nakanishi K (2002) Involvement of oxidative mechanisms in blue-light-induced damage to A2E-laden RPE. Invest Ophthalmol Vis Sci 43:1222–1227PubMedGoogle Scholar
  75. 75.
    Sparrow JR, Vollmer-Snarr HR, Zhou J, Jang YP, Jockusch S, Itagaki Y, Nakanishi K (2003) A2E-epoxides damage DNA in retinal pigment epithelial cells. J Biol Chem 278:18207–18213CrossRefPubMedGoogle Scholar
  76. 76.
    Sparrow JR, Zhou J, Cai B (2003) DNA is a target of the photodynamic effects elicited in A2E-laden RPE by blue-light illumination. Invest Ophthalmol Vis Sci 44:2245–2251CrossRefPubMedGoogle Scholar
  77. 77.
    Suter M, Reme C, Grimm C, Wenzel A, Jaattela M, Esser P, Kociok N, Leist M, Richter C (2000) Age-related macular degeneration. The lipofusion component N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells. J Biol Chem 275:39625–39630PubMedGoogle Scholar
  78. 78.
    Thompson DA, McHenry CL, Li Y, Richards JE, Othman MI, Schwinger E, Vollrath D, Jacobson SG, Gal A (2002) Retinal dystrophy due to paternal isodisomy for chromosome 1 or chromosome 2, with homoallelism for mutations in RPE65 or MERTK, respectively. Am J Hum Genet 70:224–229CrossRefPubMedGoogle Scholar
  79. 79.
    Wang Q, Chen Q, Zhao K, Wang L, Wang L, Traboulsi E (2001) Update on the molecular genetics of retinitis pigmentosa. Ophthalmic Genet 22:133–154CrossRefPubMedGoogle Scholar
  80. 80.
    Wassell J, Davies S, Bardsley W, Boulton M (1999) Photoreactivity of the retinal age pigment lipofuscin. J Biol Chem 274:23828–23832PubMedGoogle Scholar
  81. 81.
    Weiter J, Delori F, Wing G, Fitch K (1986) Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes. Invest Ophthalmol Vis Sci 27:145–152PubMedGoogle Scholar
  82. 82.
    Wing G, Blanchard G, Weiter J (1978) The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 17:601–607PubMedGoogle Scholar
  83. 83.
    Winkler BS, Boulton M, Gottsch JD, Sternberg P (1999) Oxidative damage and age-related macular degeneration. Mol Vis 5:32PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Mike Boulton
    • 1
  • Malgorzata Różanowska
    • 1
  • Tim Wess
    • 1
  1. 1.School of Optometry and Vision SciencesCardiff UniversityCardiffUK

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