Survey of Ophthalmology
Volume 44, Issue 5 , Pages 415-425 , March 2000

Limbal Stem Cells of the Corneal Epithelium

  • Harminder S Dua, MD, MS, FRCS, FRCOphth, PhD

      Affiliations

    • Queen's Medical Centre, University of Nottingham, Nottingham, UK
    • Corresponding Author InformationReprint address: Professor Harminder S. Dua, Department of Ophthalmology, B-Floor, South Block, Queen's Medical Centre, University Hospital, Nottingham, NG7 2UH, England, UK.
    • ,
  • Augusto Azuara-Blanco, MD, PhD

      Affiliations

    • Queen's Medical Centre, University of Nottingham, Nottingham, UK
    • Princess Alexandra Eye Pavilion, University of Edinburgh, Edinburgh, UK

References 

  1. Azuara-Blanco A, Dua HS, Sloper M. Treatment of corneal stem cell deficiency. Invest Ophthalmol Vis Sci. 1999;40(Suppl):336
  2. Barros EJ, Santos OF, Matsumoto K, et al.  Differential tubulogenic and branching morphogenetic activities of growth factors (implications for epithelial tissue development). Proc Natl Acad Sci U S A. 1995;92:4412–4416
  3. Beyer EC, Kistler J, Paul DL, Goodenough DA. Antisera directed against connexin43 peptides react with a 43-kD protein localized to gap junctions in myocardium and other tissues. J Cell Biol. 1989;108:595–605
  4. Buck RC. Ultrastructure of conjunctival epithelium replacing corneal epithelium. Curr Eye Res. 1986;5:149–159
  5. Chen JJ, Tseng SC. Abnormal corneal epithelial wound healing in partial-thickness removal of limbal epithelium. Invest Ophthalmol Vis Sci. 1991;32:2219–2233
  6. Chen JJ, Tseng SC. Corneal epithelial wound healing in partial limbal deficiency. Invest Ophthalmol Vis Sci. 1990;31:1301–1314
  7. Chen WY, Mui MM, Kao WW, et al.  Conjunctival epithelial cells do not transdifferentiate in organotypic cultures (expression of K12 keratin is restricted to corneal epithelium). Curr Eye Res. 1994;13:765–778
  8. Chiou AG, Florakis GJ, Kazim M. Management of conjunctival cicatrizing diseases and severe ocular surface dysfunction. Surv Ophthalmol. 1998;43:19–46[see comments]
  9. Chung EH, DeGregorio PG, Wasson M, Zieske JD. Epithelial regeneration after limbus-to-limbus debridement. Expression of alpha-enolase in stem and transient amplifying cells. Invest Ophthalmol Vis Sci. 1995;36:1336–1343
  10. Clinch TE, Goins KM, Cobo LM. Treatment of contact lens-related ocular surface disorders with autologous conjunctival transplantation. Ophthalmology. 1992;99:634–638
  11. Cooper D, Schermer A, Sun TT. Classification of human epithelia and their neoplasms using monoclonal antibodies to keratins (strategies, applications, and limitations). Lab Invest. 1985;52:243–256
  12. Copeland RA, Char DH. Limbal autograft reconstruction after conjunctival squamous cell carcinoma. Am J Ophthalmol. 1990;110:412–415
  13. Coster DJ, Aggarwal RK, Williams KA. Surgical management of ocular surface disorders using conjunctival and stem cell allografts. Br J Ophthalmol. 1995;79:977–982
  14. Cotsarelis G, Cheng SZ, Dong G, et al.  Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate (implications on epithelial stem cells). Cell. 1989;57:201–209
  15. Davanger M, Evensen A. Role of the pericorneal papillary structure in renewal of corneal epithelium. Nature. 1971;229:560–561
  16. Dong Y, Roos M, Gruijters T, et al.  Differential expression of two gap junction proteins in corneal epithelium. Eur J Cell Biol. 1994;64:95–100
  17. Dua HS. The conjunctiva in corneal epithelial wound healing. Br J Ophthalmol. 1998;82:1407–1411
  18. Dua HS. Stem cells of the ocular surface (scientific principles and clinical applications). Br J Ophthalmol. 1995;79:968–969
  19. Dua HS, Azuara-Blanco A. Allo-limbal transplantation in patients with limbal stem cell deficiency. Br J Ophthalmol. 1999;83:414–419
  20. Dua HS, Azuara-Blanco A: Auto-limbal transplantation in patients with unilateral corneal stem cell deficiency. Br J Ophthalmol (In Press)
  21. Dua HS, Forrester JV. The corneoscleral limbus in human corneal epithelial wound healing. Am J Ophthalmol. 1990;110:646–656
  22. Dua HS, Forrester JV. Clinical patterns of corneal epithelial wound healing. Am J Ophthalmol. 1987;104:481–489
  23. Dua HS, Gomes JA, Singh A. Corneal epithelial wound healing. Br J Ophthalmol. 1994;78:401–408
  24. Ebato B, Friend J, Thoft RA. Comparison of limbal and peripheral human corneal epithelium in tissue culture. Invest Ophthalmol Vis Sci. 1988;29:1533–1537
  25. Egbert PR, Lauber S, Maurice DM. A simple conjunctival biopsy. Am J Ophthalmol. 1977;84:798–801
  26. Friend J, Thoft RA. Functional competence of regenerating ocular surface epithelium. Invest Ophthalmol Vis Sci. 1978;17:134–139
  27. Frucht-Pery J, Siganos CS, Solomon A, et al.  Limbal cell autograft transplantation for severe ocular surface disorders. Graefes Arch Clin Exp Ophthalmol. 1998;236:582–587
  28. Fujishima H, Shimazaki J, Tsubota K. Temporary corneal stem cell dysfunction after radiation therapy. Br J Ophthalmol. 1996;80:911–914
  29. Gipson IK. The epithelial basement membrane zone of the limbus. Eye. 1989;3:132–140
  30. Hall PA, Watt FM. Stem cells (the generation and maintenance of cellular diversity). Development. 1989;106:619–633
  31. Hanna C, O'Brien JE. Cell production and migration in the epithelial layer of the cornea. Arch Ophthalmol. 1960;64:536–539
  32. Harris TM, Berry ER, Pakurar AS, et al.  Biochemical transformation of bulbar conjunctiva into corneal epithelium (an electrophoretic analysis). Exp Eye Res. 1985;41:597–605
  33. Hayashi K, Kenyon KR. Increased cytochrome oxidase activity in alkali-burned corneas. Curr Eye Res. 1988;7:131–138
  34. Herman WK, Doughman DJ, Lindstrom RL. Conjunctival autograft transplantation for unilateral ocular surface diseases. Ophthalmology. 1983;90:1121–1126
  35. Hogan MJ, Alvarado JA, Weddell JE: Histology of the human eye, in Hogan MJ, Alvarado JA, Weddell JE (eds), Philadelphia, PA, Saunders Co, 1971, pp 112–26
  36. Holland EJ. Epithelial transplantation for the management of severe ocular surface disease. Trans Am Ophthalmol Soc. 1996;94:677–743
  37. Holland EJ, Schwartz GS. The evolution of epithelial transplantation for severe ocular surface disease and a proposed classification system. Cornea. 1996;15:549–556
  38. Huang AJ, Tseng SC. Corneal epithelial wound healing in the absence of limbal epithelium. Invest Ophthalmol Vis Sci. 1991;32:96–105
  39. Jenkins C, Tuft S, Liu C, Buckley R. Limbal transplantation in the management of chronic contact-lens- associated epitheliopathy. Eye. 1993;7:629–633
  40. Kasper M, Moll R, Stosiek P, Karsten U. Patterns of cytokeratin and vimentin expression in the human eye. Histochemistry. 1988;89:369–377
  41. Kenyon KR, Rapoza PA. Limbal allograft transplantation for ocular surface disorders. Ophthalmology. 1995;102(Suppl):S101–S102
  42. Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders. Ophthalmology. 1989;96:709–722discussion 722–3
  43. Kim JC, Tseng SC. Transplantation of preserved human amniotic membrane for surface reconstruction in severely damaged rabbit corneas. Cornea. 1995;14:473–484
  44. Kinoshita S: New approaches to human ocular surface epithelium. From basic understanding to clinical applications. in: Kinoshita S, Ohashi Y (eds), 1st Annual Meeting of the Kyoto Cornea Club, Amsterdam/New York, Kugler Publications, 1995
  45. Kinoshita S, Friend J, Thoft RA. Biphasic cell proliferation in transdifferentiation of conjunctival to corneal epithelium in rabbits. Invest Ophthalmol Vis Sci. 1983;24:1008–1014
  46. Kolega J, Manabe M, Sun TT. Basement membrane heterogeneity and variation in corneal epithelial differentiation. Differentiation. 1989;42:54–63
  47. Kruse FE. Stem cells and corneal epithelial regeneration. Eye. 1994;8:170–183
  48. Kruse FE, Chen JJ, Tsai RJ, Tseng SC. Conjunctival transdifferentiation is due to the incomplete removal of limbal basal epithelium. Invest Ophthalmol Vis Sci. 1990;31:1903–1913
  49. Kruse FE, Tseng SC. A tumor promoter-resistant subpopulation of progenitor cells is larger in limbal epithelium than in corneal epithelium. Invest Ophthalmol Vis Sci. 1993;34:2501–2511
  50. Kruse FE, Tseng SC. Retinoic acid regulates clonal growth and differentiation of cultured limbal and peripheral corneal epithelium. Invest Ophthalmol Vis Sci. 1994;35:2405–2420
  51. Kruse FE, Tseng SC. Growth factors modulate clonal growth and differentiation of cultured rabbit limbal and corneal epithelium. Invest Ophthalmol Vis Sci. 1993;34:1963–1976
  52. Kurpakus MA, Stock EL, Jones JC. Expression of the 55-kD/64-kD corneal keratins in ocular surface epithelium. Invest Ophthalmol Vis Sci. 1990;31:448–456
  53. Kwitko S, Marinho D, Barcaro S, et al.  Allograft conjunctival transplantation for bilateral ocular surface disorders. Ophthalmology. 1995;102:1020–1025
  54. Lajtha LG. Stem cell concepts. Differentiation. 1979;14:23–34
  55. Lauweryns B, van den Oord JJ, Missotten L. The transitional zone between limbus and peripheral cornea. An immunohistochemical study. Invest Ophthalmol Vis Sci. 1993;34:1991–1999
  56. Lavker RM, Dong G, Cheng SZ, et al.  Relative proliferative rates of limbal and corneal epithelia. Implications of corneal epithelial migration, circadian rhythm, and suprabasally located DNA-synthesizing keratinocytes. Invest Ophthalmol Vis Sci. 1991;32:1864–1875
  57. Leblond CP. The life history of cells in renewing systems. Am J Anat. 1981;160:114–158
  58. Lehrer MS, Sun TT, Lavker RM. Strategies of epithelial repair (modulation of stem cell and transit amplifying cell proliferation). J Cell Sci. 1998;111:2867–2875
  59. Li DQ, Tseng SC. Differential regulation of keratinocyte growth factor and hepatocyte growth factor/scatter factor by different cytokines in human corneal and limbal fibroblasts. J Cell Physiol. 1997;172:361–372
  60. Li DQ, Tseng SCG. Cytokine network between human limbal or corneal epithelium and fibroblasts. Invest Ophthalmol Vis Sci. 1993;34(Suppl):S1011
  61. Lindberg K, Brown ME, Chaves HV, et al.  In vitro propagation of human ocular surface epithelial cells for transplantation. Invest Ophthalmol Vis Sci. 1993;34:2672–2679
  62. Lutjen-Drecoll E, Steuhl P, Arnold WH: Morphologische besonderheiten der conjunctiva bulbi. in Marquardt R (ed): Chronische conjunctivitis-trockenes Auge. Berlin, Springer, 1982, pp 25–34
  63. Mashima Y, Yamada M, Yamada H. Limbal autograft transplantations for chronic ocular surface failures. Jpn J Clin Ophthalmol. 1993;47:607
  64. Matic M, Petrov IN, Chen S, et al.  Stem cells of the corneal epithelium lack connexins and metabolite transfer capacity. Differentiation. 1997;61:251–260
  65. Miller SJ, Lavker RM, Sun TT. Keratinocyte stem cells of cornea, skin, and hair follicle (common and distinguishing features). Semin Dev Biol. 1993;4:217–240
  66. Moll R, Franke WW, Schiller DL, et al.  The catalog of human cytokeratins (patterns of expression in normal epithelia, tumors and cultured cells). Cell. 1982;31:11–24
  67. Morgan S, Murray A. Limbal autotransplantation in the acute and chronic phases of severe chemical injuries. Eye. 1996;10:349–354
  68. Morrison SJ, Shah NM, Anderson DJ. Regulatory mechanisms in stem cell biology. Cell. 1997;88:287–298
  69. Moyer PD, Kaufman AH, Zhang Z, et al.  Conjunctival epithelial cells can resurface denuded cornea, but do not transdifferentiate to express cornea-specific keratin 12 following removal of limbal epithelium in mouse. Differentiation. 1996;60:31–38
  70. Nishida K, Kinoshita S, Ohashi Y, et al.  Ocular surface abnormalities in aniridia. Am J Ophthalmol. 1995;120:368–375
  71. Pellegrini G, Traverso CE, Franzi AT, et al.  Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet. 1997;349:990–993[see comments]
  72. Pels E, van der Gaag R. HLA-A,B,C, and HLA-DR antigens and dendritic cells in fresh and organ culture preserved corneas. Cornea. 1984;3:231–239
  73. Pfister RR. Corneal stem cell disease (concepts, categorization, and treatment by auto- and homotransplantation of limbal stem cells). CLAO J. 1994;20:64–72
  74. Pizzarello LD, Jakobiec FA: Bowen's disease of the conjunctiva, in Jakobiec FA (ed): Ocular and Adnexal Tumors, Birmingham, Aexculapius, 1978, pp 553–71
  75. Potten CS, Loeffler M. Stem cells (attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt). Development. 1990;110:1001–1020
  76. Potten CS, Morris RJ. Epithelial stem cells in vivo. J Cell Sci. 1988;10(Suppl):S45–S62
  77. Potten SC, Loeffler M. Epidermal cell proliferation. I. Changes with time in the proportion of isolated, paried and clustered labeled cells in sheets of murine epidermis. Virchows Arch. 1987;53:286–300
  78. Prabhasawat P, Tseng SC. Impression cytology study of epithelial phenotype of ocular surface reconstructed by preserved human amniotic membrane. Arch Ophthalmol. 1997;115:1360–1367
  79. Puangsricharern V, Tseng SC. Cytologic evidence of corneal diseases with limbal stem cell deficiency. Ophthalmology. 1995;102:1476–1485
  80. Rao SK, Rajagopal R, Sitalakshmi G, Padmanabhan P. Limbal allografting from related live donors for corneal surface reconstruction. Ophthalmology. 1999;106:822–828
  81. Ren H, Wilson G. Apoptosis in the corneal epithelium. Invest Ophthalmol Vis Sci. 1996;37:1017–1025
  82. Schermer A, Galvin S, Sun TT. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells. J Cell Biol. 1986;103:49–62
  83. Schofield R. The stem cell system. Biomed Pharmacother. 1983;37:375–380
  84. Sharma A, Coles WH. Kinetics of corneal epithelial maintenance and graft loss. A population balance model. Invest Ophthalmol Vis Sci. 1989;30:1962–1971
  85. Shimazaki J, Yang HY, Tsubota K. Amniotic membrane transplantation for ocular surface reconstruction in patients with chemical and thermal burns. Ophthalmology. 1997;104:2068–2076
  86. Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the treatment of posterior uveitis refractory to cyclosporine. Ophthalmology. 1999;106:723–728
  87. Steuhl K-P, Thiel H-J. Histochemical and morphological study of the regenerating corneal epithelium after limbus to limbus denudation. Graefe's Arch Clin Exp Ophthalmol. 1987;225:53–58
  88. Sundmacher R, Reinhard T: [Homologous lamellar central limbokeratoplasty in severe limbal stem cell deficiency]. Klin Monatsbl Augenheilkd 213: 254–5, 1998
  89. Sundmacher R, Reinhard T. Central corneolimbal transplantation under systemic ciclosporin A cover for severe limbal stem cell insuficiency. Graefe's Arch Clin Exp Ophthalmol. 1996;234(Suppl):S122–S125
  90. Sundmacher R, Reinhard T, Althaus C. [Homologous central limbo-keratoplasty in limbus stem cell damage. Retrospective study of. 1997;3(years experience]. Ophthalmologe 94):897–901
  91. Tan DT, Ficker LA, Buckley RJ. Limbal transplantation. Ophthalmology. 1996;103:29–36
  92. Theng JT, Tan DT. Combined penetrating keratoplasty and limbal allograft transplantation for severe corneal burns. Ophthalmic Surg Lasers. 1997;28:765–768
  93. Thoft RA. Keratoepithelioplasty. Am J Ophthalmol. 1984;97:1–6
  94. Thoft RA. Conjunctival transplantation. Arch Ophthalmol. 1977;95:1425–1427
  95. Thoft RA, Friend J. The X, Y, Z hypothesis of corneal epithelial maintenance. Invest Ophthalmol Vis Sci. 1983;24:1442–1443[letter]
  96. Thoft RA, Friend J. Biochemical transformation of regenerating ocular surface epithelium. Invest Ophthalmol Vis Sci. 1977;16:14–20
  97. Tsai RJ, Sun TT, Tseng SC. Comparison of limbal and conjunctival autograft transplantation in corneal surface reconstruction in rabbits. Ophthalmology. 1990;97:446–455
  98. Tsai RJF. The morphologic studies of organotypic cultures of ocular surface epithelium on amniotic membrane. Invest Ophthalmol Vis Sci. 1999;40(Suppl):S578
  99. Tsai RJF. Corneal surfaces reconstruction by amniotic membrane with cultivated autologous limbo-corneal epithelium. Invest Ophthalmol Vis Sci. 1998;39(Suppl):S429
  100. Tseng SC. Regulation and clinical implications of corneal epithelial stem cells. Mol Biol Rep. 1996;23:47–58
  101. Tseng SC, Farazdaghi M, Rider AA. Conjunctival transdifferentiation induced by systemic vitamin A deficiency in vascularized rabbit corneas. Invest Ophthalmol Vis Sci. 1987;28:1497–1504
  102. Tseng SC, Hirst LW, Farazdaghi M, Green WR. Goblet cell density and vascularization during conjunctival transdifferentiation. Invest Ophthalmol Vis Sci. 1984;25:1168–1176
  103. Tseng SC, Li DQ. Comparison of protein kinase C subtype expression between normal and aniridic human ocular surfaces (implications for limbal stem cell dysfunction in aniridia). Cornea. 1996;15:168–178
  104. Tseng SC, Prabhasawat P, Barton K, et al.  Amniotic membrane transplantation with or without limbal allografts for corneal surface reconstruction in patients with limbal stem cell deficiency. Arch Ophthalmol. 1998;116:431–441
  105. Tseng SC, Tsai RJ. Limbal transplantation for ocular surface reconstruction–a review. Fortschr Ophthalmol. 1991;88:236–242
  106. Tseng SC, Tsubota K. Important concepts for treating ocular surface and tear disorders. Am J Ophthalmol. 1997;124:825–835
  107. Tseng SC, Zhang SH. Limbal epithelium is more resistant to 5-fluorouracil toxicity than corneal epithelium. Cornea. 1995;14:394–401
  108. Tseng SCG, et al.  Concept and application of limbal stem cells. Eye. 1989;57:201–209
  109. Tseng SCG: Conjunctival grafting for corneal diseases. in: Tasman W, Jaeger EA (eds): Duane's Clinical Ophthalmology, vol. 6 Chap 34, Philadelphia, JB Lippincott, 1994, pp 1–11
  110. Tseng SCG, Chen JJY, Huang AJW, et al.  Classification of conjunctival surgeries for corneal disease based on stem cell concept. Ophthalmol Clin North Am. 1990;3:595–610
  111. Tseng SCG, Sun TT: Stem cells: ocular surface maintenance. in: Brightbill FS (ed) Corneal Surgery: Theory, Technique and Tissue, St. Louis, Mosby, 1999, ed 3, chap. 2
  112. Tsubota K, Satake Y, Kaido M, et al.  Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation. N Engl J Med. 1999;340:1697–1703[see comments]
  113. Tsubota K, Satake Y, Ohyama M, et al.  Surgical reconstruction of the ocular surface in advanced ocular cicatricial pemphigoid and Stevens-Johnson syndrome. Am J Ophthalmol. 1996;122:38–52[see comments]
  114. Tsubota K, Satake Y, Shimazaki J. Treatment of severe dry eye. Lancet. 1996;348:123
  115. Tsubota K, Toda I, Saito H, et al.  Reconstruction of the corneal epithelium by limbal allograft transplantation for severe ocular surface disorders. Ophthalmology. 1995;102:1486–1496
  116. Wei ZG, Sun TT, Lavker RM. Rabbit conjunctival and corneal epithelial cells belong to two separate lineages. Invest Ophthalmol Vis Sci. 1996;37:523–533
  117. Wei ZG, Wu RL, Lavker RM, Sun TT. In vitro growth and differentiation of rabbit bulbar, fornix, and palpebral conjunctival epithelia. Implications on conjunctival epithelial transdifferentiation and stem cells. Invest Ophthalmol Vis Sci. 1993;34:1814–1828
  118. Williams KA, Brereton HM, Aggarwal R, et al.  Use of DNA polymorphisms and the polymerase chain reaction to examine the survival of a human limbal stem cell allograft. Am J Ophthalmol. 1995;120:342–350
  119. Williams KA, Coster DJ. Rethinking immunological privilege (implications for corneal and limbal stem cell transplantation). Mol Med Today. 1997;3:495–501
  120. Zieske JD. Perpetuation of stem cells in the eye. Eye. 1994;8:163–169
  121. Zieske JD, Bukusoglu G, Yankauckas MA. Characterization of a potential marker of corneal epithelial stem cells. Invest Ophthalmol Vis Sci. 1992;33:143–152
  122. Zieske JD, Wasson M. Regional variation in distribution of EGF receptor in developing and adult corneal epithelium. J Cell Sci. 1993;106:145–152

☆ The authors have no commercial or proprietary interest in any product or concept discussed in this article.

PII: S0039-6257(00)00109-0

Survey of Ophthalmology
Volume 44, Issue 5 , Pages 415-425 , March 2000

Article Tools