The Current Status of Corneal Limbal Stem Cell Transplantation in Humans

  • Roy S. Chuck
  • Alexandra A. Herzlich
  • Philip Niles
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


The cornea provides an accessible source of adult stem cells for cell-based therapies. Corneal stem cells have been discovered in the three primary strata—epithelium, stroma, and endothelium—of the cornea. Limbal epithelial stem cells are found on the surface and are able to differentiate into transient amplifying cells, which can regenerate epithelial tissues. Limbal stem cell deficiencies can result in epithelial defects, ulceration, corneal vascularization, chronic inflammation, scarring, and conjunctivalization of the cornea. Stromal stem cells share many properties with bone marrow-derived stem cells. Though stromal stem cell research is in the early stages, these cells may one day provide bio-prosthetic stromal material. Endothelial stem cells may be of particular importance due to endothelial cell damage during common surgeries and degenerative diseases. Current stem cell therapies focus on regeneration of the corneal surface by replacing limbal epithelial stem cells with corneal-derived cells, other adult stem cells or embryonic stem cells. Advances in cell culturing will hopefully soon be translated from bench to bedside to help in the treatment of severe ocular surface disease.


Amniotic Membrane Corneal Endothelial Cell Conjunctival Epithelium Limbal Stem Cell Stromal Stem Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Hollingsworth J et al (2001) A population study of the normal cornea using in vivo, slit-scanning confocal microscope. Optom Vis Sci 78:706–711PubMedCrossRefGoogle Scholar
  2. 2.
    Eagle RC (2011) Cornea and sclera. Eye pathology: an atlas and text. Lippincott Williams and Wilkins, Philadelphia, PA, pp 77–105Google Scholar
  3. 3.
    Takacs L et al (2009) Stem cells of the adult cornea: from cytometric markers to therapeutic applications. Cytometry A 75A:54–6CrossRefGoogle Scholar
  4. 4.
    DelMonte DW, Kim T (2011) Anatomy and physiology of the cornea. J Cataract Refract Surg 37(3):588–598PubMedCrossRefGoogle Scholar
  5. 5.
    Sun TT, Lavker RM (2004) Corneal epithelial stem cells: past, present and future. J Invest Dermatol Symp Proc 9:202–207CrossRefGoogle Scholar
  6. 6.
    Sevel D, Isaacs R (1998) A re-evaluation of corneal development. Trans Am Ophthal Soc 86:178–207Google Scholar
  7. 7.
    Amann J et al (2003) Increased endothelial cell density in the paracentral peripheral regions of the human cornea. Am J Opthalmol 15(5):584–590CrossRefGoogle Scholar
  8. 8.
    Maurice DM (1972) The location of the fluid pump in the cornea. J Physiol 221:43–54PubMedGoogle Scholar
  9. 9.
    Alison MR et al (2002) An introduction to stem cells. J Pathol 197:419–423PubMedCrossRefGoogle Scholar
  10. 10.
    Moller-Pedersen T et al (1998) Confocal microscopic characterization of wound repair after PRK. Invest Opthalmol Vis Sci 39:487–501Google Scholar
  11. 11.
    Garana RM et al (1992) Radial keratotomy. II. Role of myofibroblast in corneal wound contraction. Invest Opthalmol Vis Sci 33:3271–3282Google Scholar
  12. 12.
    Engelmann K et al (1988) Isolation and long-term cultivation of human corneal endothelial cells. Invest Opthalmol Vis Sci 29(11):1656–1662Google Scholar
  13. 13.
    McGowann SL et al (2007) Stem cells markers in the human posterior limbus and corneal endothelium of the unwounded and wounded corneas. Mol Vis 13:1984–2000Google Scholar
  14. 14.
    Davanger M, Evenson A (1971) Role of pericorneal papillary structure in renewal of corneal epithelium. Nature 229:560–561PubMedCrossRefGoogle Scholar
  15. 15.
    Buck RC (1985) Measurement of centripetal migration of normal corneal epithelial cells in the mouse. Invest Opthalmol Vis Sci 26(5):1296–1299Google Scholar
  16. 16.
    Cotsarelis G et al (1989) Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 57:201–209PubMedCrossRefGoogle Scholar
  17. 17.
    Lavker RM et al (1991) Relative proliferative rates of limbal and corneal epithelia. Implications of corneal epithelial migration, circadian rhythm, and suprabasally located DNA-synthesizing keratinocytes. Invest Opthalmol Vis Sci 32:1864–1875Google Scholar
  18. 18.
    Dua HS, Forrester JV (1990) The corneoscleral limbus in human corneal epithelial wound healing. Am J Opthalmol 110:646–656Google Scholar
  19. 19.
    Schermer A et al (1986) 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 103:49–62PubMedCrossRefGoogle Scholar
  20. 20.
    Pelligrini G et al (2001) p63 identifies keratinocyte stem cell. Proc Natl Acad Sci USA 98:3156–3161CrossRefGoogle Scholar
  21. 21.
    Pelligrini G et al (1999) Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface. J Cell Biol 145:769CrossRefGoogle Scholar
  22. 22.
    Majo F et al (2008) Oligopotent stem cells are distributed throughout the mammalian ocular surface. Nature 456:250–255PubMedCrossRefGoogle Scholar
  23. 23.
    Dua HS et al (2009) The role of limbal stem cells in corneal epithelial maintenance: testing the dogma. Ophthalmology 116(5):856–63PubMedCrossRefGoogle Scholar
  24. 24.
    Yang X, Moldovan NI, Zhao Q et al (2008) Reconstruction of damaged cornea by autologous transplantation of epidermal adult stem cells. Mol Vis 14:1064–1070PubMedGoogle Scholar
  25. 25.
    Ang LPK, Tan DTH (2004) Ocular surface stem cells and disease: current concepts and clinical applications. Ann Acad Med Singapore 33:576–580PubMedGoogle Scholar
  26. 26.
    Huang AJ, Tseng SC (1991) Corneal epithelial wound healing in the absence of limbal epithelium. Invest Opthalmol Vis Sci 32(1):96–105Google Scholar
  27. 27.
    Park KS et al (2006) The side population cells in the rabbit limbus sensitively increased in the response to the central cornea wounding. Invest Opthalmol Vis Sci 47(3):892–900CrossRefGoogle Scholar
  28. 28.
    Du Y et al (2005) Multipotent stem cells in the human corneal stroma. Stem Cells 23(9):1266–75PubMedCrossRefGoogle Scholar
  29. 29.
    Funderburgh ML et al (2005) PAX6 expression identifies progenitor cells for corneal keratocytes. FASEB J 10:1096Google Scholar
  30. 30.
    Yoshida S et al (2005) Serum-free spheroid culture of mouse corneal keratocytes. Invest Opthalmol Vis Sci 46(5):1653–1658CrossRefGoogle Scholar
  31. 31.
    Du Y et al (2007) Secretion and organization of a cornea-like tissue in vitro by stem cells from human corneal stroma. Invest Opthalmol Vis Sci 48:5038–5045CrossRefGoogle Scholar
  32. 32.
    Whikehart DR et al (2005) Evidence suggesting the existence of stem cells for the human corneal endothelium. Mol Vis 11:816–824PubMedGoogle Scholar
  33. 33.
    Joyce NC et al (2002) Mechanisms of mitotic inhibition in corneal endothelium: contact inhibition and TGF-beta2. Invest Opthalmol Vis Sci 43(7):2152–2159Google Scholar
  34. 34.
    Reneker LW et al (2010) Induction of corneal myofibroblasts by lens-derived transforming growth factor beta1: a transgenic mouse model. Brain Res Bull 81(2–3):287–296PubMedCrossRefGoogle Scholar
  35. 35.
    Sumioka T et al (2008) Inhibitory effect of blocking TGF-beta/Smad signal on injury-induced fibrosis of corneal endothelium. Mol Vis 14:2272–2281PubMedGoogle Scholar
  36. 36.
    Matsubara M, Tanishima T (1982) Wound healing of the corneal endothelium in the monkey: a morphometric study. Jpn J Ophthalmol 26(3):264–273PubMedGoogle Scholar
  37. 37.
    Ignacio TS et al (2005) A technique to harvest Descemet’s membrane with viable endothelial cells for selective transplantation. Am J Ophthalmol 139(2):325–330PubMedCrossRefGoogle Scholar
  38. 38.
    Kenyon KR, Tseng SC (1989) Limbalautograft transplantation for ocular surface disorders. Ophthalmology 96:709–23PubMedGoogle Scholar
  39. 39.
    Holland EJ, Schwartz GS (2004) The patron lecture ocular surface transplantation: 10 years’ experience. Cornea 23:425–31PubMedCrossRefGoogle Scholar
  40. 40.
    Pauklin M et al (2009) Characterization of the corneal surface in limbal stem cell deficiency and after transplantation of cultivated limbal epithelium. Ophthalmology 116:1048–1056PubMedCrossRefGoogle Scholar
  41. 41.
    Dua HS, Azuara-Blanco A (1999) Allo-limbal transplantation in patients with limbal stem cell deficiency. Br J Opthalmol 83(11):1266–1269Google Scholar
  42. 42.
    Bakhtiari P, Djalilian A (2010) Update on limbal stem cell transplantation. Middle East Afr J Ophthalmol 17:9–14PubMedGoogle Scholar
  43. 43.
    Tsubota K et al (1995) Reconstruction of the corneal epithelium by limbal allograft transplantation for severe ocular surface disorders. Ophthalmology 102:1486–1495PubMedGoogle Scholar
  44. 44.
    Holland EJ (1996) Epithelial transplantation for the management of severe ocular surface disease. Trans Am Ophthalmol Soc 94:677–743PubMedGoogle Scholar
  45. 45.
    Holland EJ et al (2003) Management of Aniridickeratopathy with keratolimbal allograft: a limbal stem cell transplantation technique. Ophthalmology 110:125–130PubMedCrossRefGoogle Scholar
  46. 46.
    Pelligrini G et al (1997) Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 349:990–993CrossRefGoogle Scholar
  47. 47.
    Kim JY et al (2003) Ocular surface reconstruction: limbal stem cell transplantation. Ophthalmol Clin N Am 16:67–77CrossRefGoogle Scholar
  48. 48.
    Rama P et al (2010) Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med 363(2):147–155PubMedCrossRefGoogle Scholar
  49. 49.
    de Roth A (1940) Plastic repair of conjunctival defects with fetal membrane. Arch Ophthalmol 23:522–525CrossRefGoogle Scholar
  50. 50.
    Chuck RS et al (2004) Biomechanical characterization of human amniotic membrane preparations for ocular surface reconstruction. Ophthalmic Res 36:341–348PubMedCrossRefGoogle Scholar
  51. 51.
    Kim JC, Tseng SCG (1995) Transplantation of preserved human amniotic membrane for surface reconstruction in severely damaged rabbit corneas. Cornea 14:473–484PubMedCrossRefGoogle Scholar
  52. 52.
    Tseng SC et al (1998) Amniotic membrane transplantation with and without limbal allografts for corneal surface reconstruction in patients with limbal stem cell deficiency. Arch Ophthalmol 116(4):431–441PubMedGoogle Scholar
  53. 53.
    Tsubota K et al (1999) Treatment of severe ocular surface disorders with corneal epithelial stem-cell transplantation. N Engl J Med 340:1697–1703PubMedCrossRefGoogle Scholar
  54. 54.
    Tsubota K et al (1996) Surgical reconstruction of the ocular surface in advanced ocular cicatricial pemphigoid and Stevens-Johnson syndrome. Am J Opthalmol 122:38–52Google Scholar
  55. 55.
    Koizumi N et al (2001) Cultivated corneal epithelial stem cell transplantation in ocular surface disorders. Ophthalmology 108:1569–1574PubMedCrossRefGoogle Scholar
  56. 56.
    Schwab IR et al (2000) Successful transplantation of bioengineered tissue replacements in patients with ocular surface disease. Cornea 19:421–426PubMedCrossRefGoogle Scholar
  57. 57.
    Tsai RJF et al (2000) Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells. N Engl J Med 343(2):86–93PubMedCrossRefGoogle Scholar
  58. 58.
    Meller D (2002) Ex vivo preservation and expansion of human limbal epithelial stem cells on amniotic membrane cultures. Br J Opthalmol 86:463–471CrossRefGoogle Scholar
  59. 59.
    Miri A et al (2011) Donor site complications in autolimbal and living related allolimbal transplantation. Ophthalmology 118:1265–1271PubMedGoogle Scholar
  60. 60.
    Daya SM et al (2005) Outcomes and DNA analysis of ex vivo expanded stem cell allograft for ocular surface reconstruction. Ophthalmology 112(3):470–477PubMedCrossRefGoogle Scholar
  61. 61.
    Griffith M et al (2002) Artificial human corneas: scaffolds for transplantation and host regeneration. Cornea 21(7 Suppl):S54–S61PubMedCrossRefGoogle Scholar
  62. 62.
    Monteiro BG et al (2009) Human immature dental pulp stem cells share key characteristic features with limbal stem cells. Cell Prolif 42:587–594PubMedCrossRefGoogle Scholar
  63. 63.
    Kim JH et al (2010) Ocular surface reconstruction with autologous nasal mucosa in cicatricial ocular surface disease. Am J Opthalmol 149:45–53CrossRefGoogle Scholar
  64. 64.
    Meyer-Blazejewska EA et al (2011) From hair to cornea: toward the therapeutic use of hair follicle-derived stem cells in the treatment of limbal stem cell deficiency. Stem Cells 29:57–66PubMedCrossRefGoogle Scholar
  65. 65.
    Nakamura T et al (2011) Long-term results of autologous cultivated oral mucosal epithelial transplantation in the scar phase of severe ocular surface disorders. Br J Opthalmol 95(7):942–946CrossRefGoogle Scholar
  66. 66.
    Ang LPK et al (2006) Autologous serum-derived cultivated oral epithelial transplants for severe ocular surface disease. Arch Ophthalmol 124:1543–1551PubMedCrossRefGoogle Scholar
  67. 67.
    Satake Y et al (2008) Barrier function and cytologic features of the ocular surface epithelium after autologous cultivated oral mucosal epithelial transplantation. Arch Ophthalmol 126(1):23–28PubMedCrossRefGoogle Scholar
  68. 68.
    Ahmad S et al (2007) Differentiation of human embryonic stem cells into corneal epithelial-like cells by in vitro replication of the corneal epithelial stem cell niche. Stem Cells 25(5):1145–1155PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Roy S. Chuck
    • 1
    • 2
  • Alexandra A. Herzlich
    • 3
  • Philip Niles
    • 4
  1. 1.Department of Ophthalmology & Visual Sciences, Montefiore Medical CenterAlbert Einstein College of MedicineBronxUSA
  2. 2.Department of Genetics, Montefiore Medical CenterAlbert Einstein College of MedicineBronxUSA
  3. 3.Montefiore Medical CenterAlbert Einstein College of MedicineBronxUSA
  4. 4.Case Western Medical SchoolClevelandUSA

Personalised recommendations