Skip to main content

Adult Human Corneal Epithelial Stem Cells

  • Chapter
  • First Online:
Book cover Adult Stem Cells

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

The cornea’s accessibility and visualization with minimally invasive techniques renders it an ideal organ to study SC and their differentiated progeny. The limbus houses, nurtures, and protects a rare population of epithelial stem cells which play a critical role in the long-term maintenance of the cornea. Despite the absence of an exclusive marker that identifies these cells with pinpoint accuracy, significant advances have been made towards identifying, isolating, cultivating, and transplanting limbal epithelial stem cells (LESC) for corneal reconstruction. However, determining the signals, factors, and mechanisms that maintain their “stemness” in vitro and in situ has proven major obstacles in progressing the field. Knowledge of the key molecules that comprise the niche and the signaling pathways and genetic programs that dictate LESC quiescence and differentiation is essential to improve current and develop effective next-generation cell-based therapies. This chapter will highlight limitations and controversies in the field and summarize the key concepts and experimental paradigms that have inspired researchers to develop cell therapies for patients with blinding corneal disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

BM:

Basement membrane

CK:

Cytokeratins

ECM:

Extracellular membrane

ESC:

Epithelial stem cells

FACS:

Fluorescent-activated cell sorting

HAM:

Human amniotic membrane

iPSC:

Induced pluripotent stem cells

LESC:

Limbal epithelial stem cells

LSCD:

Limbal stem cell deficiency

SC:

Stem cells

SP:

Side population

TAC:

Transient amplifying cells

TDC:

Terminally differentiated cells

VN:

Vitronectin

References

  1. Mann I (1944) A study of epithelial regeneration in the living eye. Br J Ophthalmol 28:26–40

    PubMed Central  PubMed  CAS  Google Scholar 

  2. Davanger M, Evensen A (1971) Role of the pericorneal papillary structure in renewal of corneal epithelium. Nature 229:560–561

    PubMed  CAS  Google Scholar 

  3. Goldberg MF (1982) Limbal of Vogt. Trans Am Ophthalmol Soc 80:155–171

    PubMed Central  PubMed  CAS  Google Scholar 

  4. Townsend WM (1991) The limbal palisades of Vogt. Trans Am Ophthalmol Soc 89:721–755

    PubMed Central  PubMed  CAS  Google Scholar 

  5. Kenyon KR, Tseng SCG (1989) Limbal autograft transplantation for ocular surface disorders. Ophthalmology 96:709–723

    PubMed  CAS  Google Scholar 

  6. Pellegrini G, Traverso CE, Franzi AT, Zingirian M, Cancedda R, De Luca M (1997) Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 349:990–993

    PubMed  CAS  Google Scholar 

  7. Shortt AJ, Secker GA, Notara MD et al (2007) Transplantation of ex vivo cultured limbal epithelial stem cells: a review of techniques and clinical results. Surv Ophthalmol 52:483–502

    PubMed  Google Scholar 

  8. Shortt AJ, Tuft SJ, Daniels JT (2010) Ex vivo cultured limbal epithelial transplantation. A clinical perspective. Ocul Surf 8:80–90

    PubMed  Google Scholar 

  9. Rama P, Bonini S, Lambiase A et al (2001) Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency. Transplantation 72:1478–1485

    PubMed  CAS  Google Scholar 

  10. Rama PP, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G (2010) Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med 363:147–155

    PubMed  CAS  Google Scholar 

  11. Di Iorio E, Ferrari S, Fasolo A, Bohm E, Ponzin D, Barbaro V (2010) Techniques for culture and assessment of limbal stem cell grafts. Ocul Surf 8:146–153

    PubMed  Google Scholar 

  12. Burman S, Sangwan V (2008) Cultivated limbal stem cell transplantation for ocular surface reconstruction. Clin Ophthalmol 3:489–502

    Google Scholar 

  13. Baylis O, Figueirdo F, Henein C, Lako M, Ahmad S (2011) 13 years of cultured epithelial cell therapy: a review of the outcomes. J Cell Biochem 112:993–1002

    PubMed  CAS  Google Scholar 

  14. Sangwan VS, Basu S, Vemuganti GK et al (2011) Clinical outcomes of xeno-free autologous cultivated limbal epithelial transplantation: a 10-year study. Br J Ophthalmol 95:1525–1529

    PubMed  Google Scholar 

  15. Wei ZG, Cotsarelis G, Sun TT, Lavker RM (1995) Label-retaining cells are preferentially located in fornical epithelium: implications on conjunctival epithelial homeostasis. Invest Ophthalmol Vis Sci 36:236–246

    PubMed  CAS  Google Scholar 

  16. Pellegrini G, Golisano O, Paterna P et al (1999) Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface. J Cell Biol 145:769–782

    PubMed Central  PubMed  CAS  Google Scholar 

  17. Seigel GM, Sun W, Salvi R, Campbell LM, Sullivan S, Reidy JJ (2003) Human corneal stem cells display functional neuronal properties. Mol Vis 9:159–163

    PubMed  CAS  Google Scholar 

  18. Zhao X, Das AV, Bhattacharya S et al (2008) Derivation of neurons with functional properties from adult limbal epithelium: implications in autologous cell therapy for photoreceptor degeneration. Stem Cells 26:939–949

    PubMed  CAS  Google Scholar 

  19. Thoft RA, Friend J (1983) The X, Y, Z hypothesis of corneal epithelial maintenance. Invest Ophthalmol Vis Sci 24:1442–1443

    PubMed  CAS  Google Scholar 

  20. Buck RC (1985) Measurement of centripetal migration of normal corneal epithelial cells in the mouse. Invest Ophthalmol Vis Sci 26:1296–1299

    PubMed  CAS  Google Scholar 

  21. Sharma A, Coles WH (1989) Kinetics of corneal epithelial maintenance and graft loss. Invest Ophthalmol Vis Sci 30:1962–1971

    PubMed  CAS  Google Scholar 

  22. Friedenwald JS, Buschke W (1944) Some factors concerned in the mitotic and wound-healing activities of the corneal epithelium. Trans Am Ophthalmol Soc 42:371–383

    PubMed Central  PubMed  CAS  Google Scholar 

  23. Hanna C, O’Brien JE (1960) Cell production and migration in the epithelial layer of the cornea. Arch Ophthalmol 64:536–539

    PubMed  CAS  Google Scholar 

  24. Hanna C (1966) Proliferation and migration of epithelial cells during corneal wound repair in the rabbit and rat. Am J Ophthalmol 61:55–63

    PubMed  CAS  Google Scholar 

  25. Srinivasan BD, Eakins KE (1979) The reepithelialization of rabbit cornea following single and multiple denudation. Exp Eye Res 29:595–600

    PubMed  CAS  Google Scholar 

  26. Chen JJY, Tseng SCG (1991) Abnormal corneal epithelial wound healing in partial-thickness removal of limbal epithelium. Invest Ophthalmol Vis Sci 32:2219–2233

    PubMed  CAS  Google Scholar 

  27. Huang AJW, Tseng SCG (1991) Corneal epithelial wound healing in the absence of limbal epithelium. Invest Ophthalmol Vis Sci 32:96–105

    PubMed  CAS  Google Scholar 

  28. Cotsarelis G, Cheng S-Z, Dong G, Sun T-T, Lavker RM (1989) Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 57:201–209

    PubMed  CAS  Google Scholar 

  29. Schermer A, Galvin S, Sun T-T (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 103:49–62

    PubMed  CAS  Google Scholar 

  30. Kurpakus MA, Stock EL, Jones JCR (1990) Expression of the 55-kD/64-kD corneal keratins in ocular surface epithelium. Invest Ophthalmol Vis Sci 31:448–456

    PubMed  CAS  Google Scholar 

  31. Kinoshita S, Friend J, Thoft RA (1981) Sex chromatin of donor corneal epithelium in rabbits. Invest Ophthalmol Vis Sci 21:434–441

    PubMed  CAS  Google Scholar 

  32. Chui J, Coroneo MT, Crouch R, Wakefield D, Di Girolamo N (2011) Ophthalmic pterygia: a stem cell disorder with pre-neoplastic features. Am J Pathol 178:817–827

    PubMed Central  PubMed  Google Scholar 

  33. Grossniklaus HE, Green WR, Luckenbach M, Chan CC (1987) Conjunctival lesions in adults: a clinical and histopathological review. Cornea 6:78–116

    PubMed  CAS  Google Scholar 

  34. Garner A (1989) The pathology of tumours at the limbus. Eye 3:210–217

    PubMed  Google Scholar 

  35. McNairn AJ, Guasch G (2011) Epithelial transition zones: merging microenvironments, niches, and cellular transformation. Eur J Dermatol 21(Suppl 2):21–28

    PubMed  CAS  Google Scholar 

  36. Smith GT, Deutsch GP, Cree IA, Liu CSC (2000) Permanent corneal limbal stem cell dysfunction following radiotherapy for orbital lymphoma. Eye 14:905–907

    PubMed  CAS  Google Scholar 

  37. Ellies P, Anderson DF, Touhami A, Tseng SCG (2001) Limbal stem cell deficiency arising from systemic chemotherapy. Br J Ophthalmol 85:373–374

    PubMed  CAS  Google Scholar 

  38. Schofield R (1983) The stem cell system. Biomed Pharmacother 37:375–380

    PubMed  CAS  Google Scholar 

  39. Zheng T, Xu J (2008) Age-related changes of human limbus on in vivo confocal microscopy. Cornea 27:782–786

    PubMed  Google Scholar 

  40. Mort RL, Ramaesh T, Kleinjan DA, Morley SD, West JD (2009) Mosaic analysis of stem cell function and wound healing in the mouse corneal epithelium. BMC Dev Biol 9:4

    PubMed Central  PubMed  Google Scholar 

  41. Notara M, Shortt AJ, O’Callaghan AR, Daniels JT (2013) The impact of age on the physical and cellular properties of the human limbal stem cell niche. Age (Dordr) 35(2):289–300

    CAS  Google Scholar 

  42. Douvaras P, Webb S, Whitaker DA et al (2012) Rare corneal clones in mice suggest an age-related decrease of stem cell activity and supports the limbal epithelial stem cell hypothesis. Stem Cell Res 8:109–119

    PubMed  CAS  Google Scholar 

  43. Higa K, Shimmura S, Miyashita H, Shimazaki J, Tsubota K (2005) Melanocytes in the corneal limbus interact with K19-positive basal epithelial cells. Exp Eye Res 81:218–223

    PubMed  CAS  Google Scholar 

  44. Coroneo MT, Muller-Stolzenburg NW, Ho A (1991) Peripheral light focusing by the anterior eye and the ophthalmohelioses. Ophthalmic Surg 22:705–711

    PubMed  CAS  Google Scholar 

  45. Vantrappen L, Geboes K, Missotten L, Maudgal PC, Desmet V (1985) Lymphocytes and Langerhans cells in the normal human cornea. Invest Ophthalmol Vis Sci 26:220–225

    PubMed  CAS  Google Scholar 

  46. Schlotzer-Schrehardt U, Kruse FE (2005) Identification and characterization of limbal stem cells. Exp Eye Res 81:247–264

    PubMed  Google Scholar 

  47. Chen Z, De Paiva CS, Luo L, Kretzer FL, Pfugfelder SC, Li D-Q (2004) Characterization of putative stem cell phenotype in human limbal epithelia. Stem Cells 22:355–366

    PubMed Central  PubMed  Google Scholar 

  48. der Merwe V, Kidson SH (2010) Advances in imaging the blood and aqueous vessels of the outer limbus. Exp Eye Res 91:118–126

    PubMed  Google Scholar 

  49. Pinnamaneni N, Funderburgh JL (2012) Stem cells in the corneal stroma. Stem Cells 30:1059–1063

    PubMed Central  PubMed  CAS  Google Scholar 

  50. Marfurt CF, Cox J, Deek S, Dvorscak L (2010) Anatomy of the human corneal innervation. Exp Eye Res 90:478–492

    PubMed  CAS  Google Scholar 

  51. Auran JD, Koester CJ, Kleiman NJ et al (1995) Scanning slit confocal microscope observation of cell morphology and movement within the normal human anterior cornea. Ophthalmology 102:33–41

    PubMed  CAS  Google Scholar 

  52. Chui J, Di Girolamo N, Coroneo MT, Wakefield D (2007) The role of substance P in the pathogenesis of pterygia. Invest Ophthalmol Vis Sci 48:4482–4489

    PubMed  Google Scholar 

  53. Dua HS, Shanmuganathan VA, Powell-Richards AO, Tighe PJ, Joseph A (2005) Limbal epithelial crypts: a novel anatomical structure and a putative limbal stem cell niche. Br J Ophthalmol 89:529–532

    PubMed Central  PubMed  CAS  Google Scholar 

  54. Shanmuganathan VA, Foster T, Kulkarni BB et al (2007) Morphological characteristics of the limbal epithelial crypt. Br J Ophthalmol 91:514–519

    PubMed Central  PubMed  Google Scholar 

  55. Shortt AJ, Secker GA, Munro PM, Khaw PT, Tuft SJ, Daniels JT (2007) Characterization of the limbal epithelial stem cell niche: novel imaging techniques permit in vivo observation and targeted biopsy of limbal epithelial stem cells. Stem Cells 25:1402–1409

    PubMed  Google Scholar 

  56. Majo F, Rochat A, Nicolas M, Jaoude GA, Barrandon Y (2008) Oligopotent stem cells are distributed throughout the mammalian ocular surface. Nature 456:250–254

    PubMed  CAS  Google Scholar 

  57. Chang CY, McGhee JJ, Green CR, Sherwin T (2011) Comparison of stem cell properties in cell populations isolated from human central and limbal corneal epithelium. Cornea 30:1155–1162

    PubMed  Google Scholar 

  58. Dua HS, Miri A, Alomar T, Yeung AM, Said DG (2009) The role of limbal stem cells in corneal epithelial maintenance. Ophthalmology 116:856–863

    PubMed  Google Scholar 

  59. Chang CY, Green CR, McGhee JJ, Sherwin T (2008) Acute wound healing in the human central corneal epithelium appears to be independent of limbal stem cell influence. Invest Ophthalmol Vis Sci 49:5279–5286

    PubMed  Google Scholar 

  60. Duke-Elder S, Cook C (1963) Normal and abnormal development. Part 1: Embryology. In: Duke-Elder S (ed) System of ophthalmology. Henry Kimpton, London

    Google Scholar 

  61. Mann I (1964) The development of the human eye. British Medical Association, London

    Google Scholar 

  62. Sevel D, Isaacs R (1988) A re-evaluation of corneal development. Trans Am Ophthalmol Soc 86:178–207

    PubMed Central  PubMed  CAS  Google Scholar 

  63. Zhao XC, Yee RW, Norcom E et al (2006) The zebrafish cornea: structure and development. Invest Ophthalmol Vis Sci 47:4341–4348

    PubMed  Google Scholar 

  64. Hay ED (1997) Development of the vertebrate cornea. Int Rev Cytol 63:263–322

    Google Scholar 

  65. Zieske JD (2004) Corneal development associated with eyelid opening. Int J Dev Biol 48:903–911

    PubMed  Google Scholar 

  66. Davies S, Chui J, Madigan MC, Provis JM, Wakefield D, Di Girolamo N (2009) Stem cell activity in the developing human cornea. Stem Cells 27:2781–2792

    PubMed  CAS  Google Scholar 

  67. Dora N, Ou J, Kucerova R, Parisi I, West JD, Collinson JM (2008) Pax6 dosage effects on corneal development, growth, and wound healing. Dev Dyn 237:1295–1306

    PubMed Central  PubMed  CAS  Google Scholar 

  68. Fokina VM, Frolova EI (2006) Expression patterns of wnt genes during development of anterior part of the chicken eye. Dev Dyn 235:496–505

    PubMed Central  PubMed  CAS  Google Scholar 

  69. O’Rahilly R (1975) The prenatal development of the human eye. Exp Eye Res 21:93–112

    PubMed  Google Scholar 

  70. Graw J (2010) Eye development. Curr Top Dev Biol 90:343–386

    PubMed  Google Scholar 

  71. Watt FM, Hogan BLM (2000) Out of Eden: stem cells and their niches. Science 287:1427–1430

    PubMed  CAS  Google Scholar 

  72. Iozzo RV, Zoeller JJ, Nystrom A (2009) Basement membrane proteoglycans: modulators par excellence of cancer growth and angiogenesis. Mol Cells 27:503–513

    PubMed  CAS  Google Scholar 

  73. Kurpakus MA, Stock EL, Jones JC (1992) The role of the basement membrane in differential expression of keratin proteins in epithelial cells. Dev Biol 150:243–255

    PubMed  CAS  Google Scholar 

  74. Gipson IK (1989) The epithelial basement membrane zone of the limbus. Eye 3(Pt 2):132–140

    PubMed  Google Scholar 

  75. Ljubimov AV, Burgeson RE, Butkowski RJ, Michael AF, Sun T-T, Kenney MC (1995) Human corneal basement membrane heterogeneity: topographical differences in the expression of type IV collagen and laminin isoforms. Lab Invest 72:461–473

    PubMed  CAS  Google Scholar 

  76. Cleutjens JPM, Havenith MG, Kasper M, Vallinga M, Bosman FT (1990) Absence of type IV collagen in the centre of the corneal epithelial basement membrane. Histochem J 22:688–694

    PubMed  CAS  Google Scholar 

  77. Tuori A, Uusitalo H, Burgeson RE, Terttunen J, Virtanen I (1996) The immunohistochemical composition of the human corneal basement membrane. Cornea 15:286–294

    PubMed  CAS  Google Scholar 

  78. Schlotzer-Schrehardt U, Dietrich T, Saito K et al (2007) Characterization of extracellular matrix components in the limbal epithelial stem cell compartment. Exp Eye Res 85:845–860

    PubMed  CAS  Google Scholar 

  79. Kabosova A, Azar DT, Bannikov GA et al (2007) Compositional differences between infant and adult human corneal basement membranes. Invest Ophthalmol Vis Sci 48:4989–4999

    PubMed Central  PubMed  Google Scholar 

  80. Echevarria T, Chow S, Watson S, Wakefield D, Di Girolamo N (2011) Vitronectin: a matrix support factor for human limbal epithelial progenitor cells. Invest Ophthalmol Vis Sci 52:8138–8147

    PubMed  CAS  Google Scholar 

  81. Braam SR, Zeinstra L, Litjens S et al (2008) Recombinant vitronectin is a functionally defined substrate that supports human embryonic stem cells self-renewal via αvβ5 integrin. Stem Cells 26:2257–2265

    PubMed  CAS  Google Scholar 

  82. Li D-Q, Tseng SCG (1995) Three patterns of cytokine expression potentially involved in epithelial-fibroblast interactions of human ocular surface. J Cell Physiol 163:61–79

    PubMed  CAS  Google Scholar 

  83. Qi H, Chuang EY, Yoon K-C et al (2007) Patterned expression of neurotrophic factors and receptors in human limbal and corneal regions. Mol Vis 13:1934–1941

    PubMed Central  PubMed  CAS  Google Scholar 

  84. Touhami A, Grueterich M, Tseng SCG (2002) The role of NGF signaling in human limbal epithelium expanded by amniotic membrane culture. Invest Ophthalmol Vis Sci 43:987–994

    PubMed  Google Scholar 

  85. Di Girolamo N, Sarris M, Chiu J, Cheema H, Coroneo MT, Wakefield D (2008) Localization of the low affinity nerve growth factor receptor p75 in human limbal epithelial cells. J Cell Mol Med 12:2799–2811

    PubMed  Google Scholar 

  86. Mukhopadhyay M, Gorivodsky M, Shtrom S et al (2006) DKK2 plays and essential role in the corneal fate of the ocular surface epithelium. Development 133:2149–2154

    PubMed  CAS  Google Scholar 

  87. Espana EM, Kawakita T, Romano A et al (2003) Stromal niche controls the plasticity of limbal and corneal epithelial differentiation in a rabbit model of recombined tissue. Invest Ophthalmol Vis Sci 44:5130–5135

    PubMed  Google Scholar 

  88. Notara M, Shortt AJ, Galatowicz G, Calder V, Daniels JT (2010) IL-6 and the human limbal stem cell niche: a mediator of epithelial-stromal interaction. Stem Cell Res 5:188–200

    PubMed  CAS  Google Scholar 

  89. Xie H-T, Chen S-Y, Li G-G, Tseng SCG (2011) Limbal epithelial stem/progenitor cells attract stromal niche cells by SDF-1/CXCR4 signaling to prevent differentiation. Stem Cells 29:1874–1885

    PubMed  CAS  Google Scholar 

  90. Amad S, Stewart R, Yung 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 25:1145–1155

    Google Scholar 

  91. Blazejewska EA, Schlotzer-Schrehardt U, Zenkel M et al (2009) Corneal limbal microenvironment can induce transdifferentiation of hair follicle stem cells into corneal epithelial-like cells. Stem Cells 27:642–652

    PubMed Central  PubMed  CAS  Google Scholar 

  92. Ferraris C, Chevalier G, Favier B, Jahoda CAB, Dhouailly D (2000) Adult corneal epithelium basal cells possess the capacity to activate epidermal, pilosebaceous and sweat gland genetic programs in response to embryonic dermal stimuli. Development 127:5487–5495

    PubMed  CAS  Google Scholar 

  93. Pearton DJ, Ferraris C, Dhouailly D (2004) Transdifferentiation of corneal epithelium: evidence for a linkage between the segregation of epidermal stem cells and the induction of hair follicles during embryogenesis. Int J Dev Biol 48:197–201

    PubMed  CAS  Google Scholar 

  94. Du Y, Funderburgh ML, Mann MM, SundarRaj N, Funderburgh JL (2005) Multipotent stem cells in human corneal stroma. Stem Cells 23:1266–1275

    PubMed Central  PubMed  Google Scholar 

  95. Li GG, Zhu YT, Xie HT, Chen SY, Tseng SC (2012) Mesenchymal stem cells derived from human limbal niche cells. Invest Ophthalmol Vis Sci 53:5686–5697

    PubMed Central  PubMed  CAS  Google Scholar 

  96. Branch MJ, Hashmani K, Dhillon P, Jones DRE, Dua HS, Hopkinson A (2012) Mesenchymal stem cells in the human corneal limbal stroma. Invest Ophthalmol Vis Sci 53:5109–5116

    PubMed  Google Scholar 

  97. Yoshida S, Shimmura S, Nagoshi N et al (2006) Isolation of multipotent neural crest-derived stem cells from the adult mouse cornea. Stem Cells 24:2714–2722

    PubMed  CAS  Google Scholar 

  98. Nakamura T, Ishikawa F, Sonoda K-h et al (2005) Characterization and distribution of bone marrow-derived cells in mouse cornea. Invest Ophthalmol Vis Sci 46:497–503

    PubMed  Google Scholar 

  99. Ye J, Lee SY, Hoon K, Yao K (2008) Bone marrow-derived progenitor cells promote corneal wound healing following alkali injury. Graefes Arch Clin Exp Ophthalmol 246:217–222

    PubMed  Google Scholar 

  100. Kim HS, Song XJ, De Paiva CS, Chen Z, Pfugfelder SC, Li D-Q (2004) Phenotypic characterization of human corneal epithelial cells expanded ex vivo from limbal explants and single cell cultures. Exp Eye Res 79:41–49

    PubMed Central  PubMed  CAS  Google Scholar 

  101. De Paiva CS, Pflugfelder SC, Li D-Q (2006) Cell size correlates with phenotype and proliferative capacity in human corneal epithelial cells. Stem Cells 24:368–375

    PubMed Central  PubMed  Google Scholar 

  102. Boehlke CS, Yuan C, Kao WW, Huang AJ (2004) Cytokeratin 12 in human ocular surface epithelia is the antigen reactive with a commercial anti-Galpha q antibody. Mol Vis 10:867–873

    PubMed  CAS  Google Scholar 

  103. Sun L, Sun T-T Lavker RM (2000) CLED: a calcium-linked protein associated with early epithelial differentiation. Exp Cell Res 259:96–106

    PubMed  CAS  Google Scholar 

  104. Matic M, Petrov IN, Chen S, Wang C, Dimitrijevich SD, Wolosin JM (1997) Stem cells of the corneal epithelium lack connexins and metabolite transfer capacity. Differentiation 61:251–260

    PubMed  CAS  Google Scholar 

  105. Wolosin JM, Schutte M, Zieske JD, Budak MT (2002) Changes in connexin 43 in early ocular surface development. Curr Eye Res 24:430–438

    PubMed  Google Scholar 

  106. Chen Z, Evans WH, Pflugfelder SC, Li D-Q (2006) Gap junction protein connexin 43 serves as a negative marker for a stem cell-containing population of human limbal epithelial cells. Stem Cells 24:1265–1273

    PubMed Central  PubMed  CAS  Google Scholar 

  107. Ahmad S, Kolli S, Li D-Q et al (2008) A putative role for RHAMM/HMMR as a negative marker of stem cell-containing population of human limbal epithelial cells. Stem Cells 26:1609–1619

    PubMed  CAS  Google Scholar 

  108. Kim M, Turnquist H, Jackson J et al (2002) The multidrug resistance transported ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res 8:22–28

    PubMed  CAS  Google Scholar 

  109. Zhou S, Schuetz JD, Bunting KD et al (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7:1028–1034

    PubMed  CAS  Google Scholar 

  110. Watanabe K, Nishida K, Yamato M et al (2004) Human limbal epithelium contains side population cells expressing the ATP-binding cassette transporter ABCG2. FEBS Lett 565:6–10

    PubMed  CAS  Google Scholar 

  111. De Pavia CS, Chen Z, Corrales RM, Pflugfelder SC, Li D-Q (2005) ABCG2 transporter identifies a population of clonogenic human limbal epithelial cells. Stem Cells 23:63–73

    Google Scholar 

  112. Budak MT, Alpdogan OS, Zhou M, Lavker RM, Akinci MAM, Wolosin JM (2005) Ocular surface epithelia contain ABCG2-dependent side population cells exhibiting features associated with stem cells. J Cell Sci 118:1715–1724

    PubMed Central  PubMed  CAS  Google Scholar 

  113. Umemoto T, Yamato M, Nishida K, Yang J, Tano Y, Okano T (2006) Limbal epithelial side-population cells have stem cell-like properties, including quiescent state. Stem Cells 24:86–94

    PubMed  Google Scholar 

  114. Umemoto T, Yamato M, Nishida K et al (2005) Rat limbal epithelial side population cells exhibit expression of stem cell markers that are lacking in side population cells from the central cornea. FEBS Lett 579:6569–6574

    PubMed  CAS  Google Scholar 

  115. Chen W, Hara K, Tian Q, Zhao K, Yoshitomi T (2007) Existence of small slow-cycling Langerhans cells in the limbal basal epithelium that express ABCG2. Exp Eye Res 84:626–634

    PubMed  CAS  Google Scholar 

  116. Wolosin JM, Akinci M, Taveras M, Turner H (2006) Intraepithelial lymphocytes are a major component of ocular surface epithelial side populations. ARVO Abstr 47:3954

    Google Scholar 

  117. Kubota M, Shimmura S, Miyashita H, Kawashima M, Kawakita T, Tsubota K (2010) The anti-oxidative role of ABCG2 in corneal epithelial cells. Invest Ophthalmol Vis Sci 51:5617–5622

    PubMed  Google Scholar 

  118. Jonker JW, Buitelaar M, Wagenaar E et al (2002) The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protophorphyria. Proc Natl Acad Sci U S A 99:15649–15654

    PubMed Central  PubMed  CAS  Google Scholar 

  119. Zieske JD, Bukusoglu G, Yankaukas MA, Wasson ME, Keutmann HT (1992) Alpha-enolase is restricted to basal cells of stratified squamous epithelium. Dev Biol 151:18–26

    PubMed  CAS  Google Scholar 

  120. Zieske JD (1994) Perpetuation of stem cells in the eye. Eye 8:163–169

    PubMed  Google Scholar 

  121. Chung E-H, DeGregorio PG, Wasson ME, Zieske JD (1995) Epithelial regeneration after limbus-to-limbus debridement. Invest Ophthalmol Vis Sci 36:1336–1343

    PubMed  CAS  Google Scholar 

  122. Barnard Z, Apel AJG, Harkin DG (2001) Phenotypic analysis of limbal epithelial cell cultures derived from donor corneoscleral rims. Clin Exp Ophthalmol 29:138–142

    CAS  Google Scholar 

  123. Figueira EC, Di Girolamo N, Coroneo MT, Wakefield D (2007) The phenotype of limbal epithelial stem cells. Invest Ophthalmol Vis Sci 48:144–156

    PubMed  Google Scholar 

  124. Nieto-Miguel T, Calonge M, de la Mata A et al (2011) A comparison of stem cell-related gene expression in the progenitor-rich limbal epithelium and the differentiating central corneal epithelium. Mol Vis 17:2102–2117

    PubMed Central  PubMed  CAS  Google Scholar 

  125. Yoshida S, Shimmura S, Kawakita T et al (2006) Cytokeratin 15 can be used to identify the limbal phenotype in normal and diseased ocular surfaces. Invest Ophthalmol Vis Sci 47:4780–4786

    PubMed  Google Scholar 

  126. Kasper M (1992) Patterns of cytokeratins and vimentin in guinea pig and mouse eye tissue; evidence for regional variations in intermediate filament expression in limbal epithelium. Acta Histochem 92:319–332

    Google Scholar 

  127. Lauweryns B, van den Oord JJ, De Vos R, Missotten L (1993) A new epithelial cell type in the human cornea. Invest Ophthalmol Vis Sci 34:1983–1990

    PubMed  CAS  Google Scholar 

  128. Lu H, Zimek A, Chen J et al (2006) Keratin 5 knockout mice reveal plasticity of keratin expression in the corneal epithelium. Eur J Cell Biol 85:803–811

    PubMed  CAS  Google Scholar 

  129. Yang A, Schweitzer R, Sun D et al (1999) p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398:714–718

    PubMed  CAS  Google Scholar 

  130. Mills AA, Zheng B, Wang X-J, Vogel H, Roop DR, Bradley A (1999) p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398:708–713

    PubMed  CAS  Google Scholar 

  131. Pellegrini G, Dellambra E, Golisano O et al (2001) p63 identifies keratinocyte stem cells. Proc Natl Acad Sci U S A 98:3156–3161

    PubMed Central  PubMed  CAS  Google Scholar 

  132. Dua HS, Joseph A, Shanmuganathan VA, Jones RE (2003) Stem cell differentiation and the effects of deficiency. Eye 17:877–885

    PubMed  CAS  Google Scholar 

  133. Chee KYH, Kicic A, Wiffen SJ (2006) Limbal stem cells: the search for a marker. Clin Exp Ophthalmol 34:64–73

    Google Scholar 

  134. Di Iorio E, Barbaro V, Ruzza A, Ponzin D, Pellegrini G, De Luca M (2005) Isoforms of ΔNp63 and the migration of ocular limbal cells in human corneal regeneration. Proc Natl Acad Sci U S A 102:9523–9528

    PubMed Central  PubMed  Google Scholar 

  135. Harkin DG, Barnard Z, Gillies P, Ainscough SL, Apel AJG (2004) Analysis of p63 and cytokeratin expression in a cultivated limbal autograft used in the treatment of limbal stem cell deficiency. Br J Ophthalmol 88:1154–1158

    PubMed Central  PubMed  CAS  Google Scholar 

  136. Carter RT (2009) The role of integrins in corneal wound healing. Vet Ophthalmol 12(Suppl 1):2–9

    PubMed  CAS  Google Scholar 

  137. Stepp MA (2006) Corneal integrins and their functions. Exp Eye Res 83:3–15

    PubMed  CAS  Google Scholar 

  138. Braam SR, Zientra L, Litjens S et al (2008) Recombinant vitronectin is a functionally defined substrate that supports human embryonic stem cell self-renewal via αvβ5 integrin. Stem Cell 26:2257–2265

    CAS  Google Scholar 

  139. Pajoohesh-Ganji A, Ghosh SP, Stepp MA (2004) Regional distribution of α9β1 integrin within the limbus of the mouse ocular surface. Dev Dyn 230:518–528

    PubMed  CAS  Google Scholar 

  140. Maseruka H, Ridgway A, Tullo A, Bonshek R (2000) Developmental changes in patterns of expression of Tenascin-C variants in the human cornea. Invest Ophthalmol Vis Sci 41:4101–4107

    PubMed  CAS  Google Scholar 

  141. Pajoohesh-Ganji A, Ghosh SP, Simmens SJ, Stepp MA (2006) Integrins in slow-cycling corneal epithelial cells at the limbus in the mouse. Stem Cells 24:1075–1086

    PubMed  CAS  Google Scholar 

  142. Li A, Simmons PJ, Kaur P (1998) Identification and isolation of candidate human keratinocyte stem cells based on cell surface phenotype. Proc Natl Acad Sci U S A 95:3902–3907

    PubMed Central  PubMed  CAS  Google Scholar 

  143. Tani H, Morris RJ, Kaur P (2000) Enrichment for murine keratinocyte stem cells based on cell surface phenotype. Proc Natl Acad Sci U S A 97:10960–10965

    PubMed Central  PubMed  CAS  Google Scholar 

  144. Croagh D, Phillips WA, Redvers R, Thomas RJS, Kaur P (2007) Identification of candidate murine esophageal stem cells using a combination of cell kinetics studies and cell surface markers. Stem Cells 25:313–318

    PubMed  CAS  Google Scholar 

  145. Hayashi R, Yamato M, Saito T et al (2008) Enrichment of corneal epithelial stem/progenitor cells using cell surface markers, integrin α6 and CD71. Biochem Biophys Res Commun 367:256–263

    PubMed  CAS  Google Scholar 

  146. Hayashi R, Yamato M, Sugiyama H et al (2007) N-Cadherin is expressed by putative stem/progenitor cells and melanocytes in the human epithelial stem cell niche. Stem Cells 25:289–296

    PubMed  CAS  Google Scholar 

  147. Higa K, Shimmura S, Miyashita H et al (2009) N-cadherin in the maintenance of human corneal limbal epithelial progenitor cells in vitro. Invest Ophthalmol Vis Sci 50:4640–4645

    PubMed  Google Scholar 

  148. Mimura T, Yamagami S, Uchida S et al (2010) Isolation of adult progenitor cells with neuronal potential from rabbit corneal epithelial cells in serum- and feeder layer-free culture conditions. Mol Vis 16:1712–1719

    PubMed Central  PubMed  CAS  Google Scholar 

  149. Grueterich M, Espana EM, Tseng SCG (2003) Ex vivo expansion of limbal epithelial stem cells: amniotic membrane serving as a stem cell niche. Surv Ophthalmol 48:631–646

    PubMed  Google Scholar 

  150. Nakamura M, Okano H, Blendy JA et al (1994) Musashi, a neural RNA-binding protein required for Drosophila adult external sensory organ development. Neuron 13:67–81

    PubMed  CAS  Google Scholar 

  151. Sakakibara S, Nakamura Y, Yoshida T et al (2002) RNA-binding protein Musashi family: roles in CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation. Proc Natl Acad Sci U S A 99:15194–15199

    PubMed Central  PubMed  CAS  Google Scholar 

  152. Chen Y-T, Li W, Hayashida Y et al (2007) Human amniotic epithelial cells as novel feeder layers for promoting ex vivo expansion of limbal epithelial progenitor cells. Stem Cells 25:1995–2005

    PubMed Central  PubMed  CAS  Google Scholar 

  153. Hitoshi S, Alexson T, Tropepe V et al (2002) Notch pathway molecules are essential for the maintenance, but not the generation of mammalian neural stem cells. Gene Dev 16:846–858

    PubMed Central  PubMed  CAS  Google Scholar 

  154. Thomas PB, Liu Y-H, Zhuang FF et al (2007) Identification of notch-1 expression in the limbal basal epithelium. Mol Vis 13:337–344

    PubMed Central  PubMed  CAS  Google Scholar 

  155. Tomita K, Ishibashi M, Nakahara K et al (1996) Mammalian hairy and enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis. Neuron 16:723–734

    PubMed  CAS  Google Scholar 

  156. Nakamura T, Ohtsuka T, Sekiyama E et al (2008) Hes1 regulates corneal development and the function of corneal epithelial stem/progenitor cells. Stem Cells 26:1265–1274

    PubMed  CAS  Google Scholar 

  157. Lu R, Qu Y, Ge J, Zhang L, Su Z, Pflugfelder SC, Li D-Q (2012) Transcription factor TCF4 maintains the properties of human corneal epithelial stem cells. Stem Cells 30:753–761

    PubMed  CAS  Google Scholar 

  158. Bian F, Liu W, Yoon K-C et al (2010) Molecular signatures and biological pathway profiles of human corneal epithelial progenitor cells. Int J Biochem Cell Biol 42:1142–1153

    PubMed Central  PubMed  CAS  Google Scholar 

  159. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R (2003) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathway. Genes Dev 19:1432–1437

    Google Scholar 

  160. Barbaro V, Testa A, Di Iorio E, Mavilio F, Pellegrini G, De Luca M (2007) C/EBPδ regulates cell cycle and self-renewal of human limbal stem cells. J Cell Biol 177:1037–1049

    PubMed Central  PubMed  CAS  Google Scholar 

  161. Adachi W, Ulanovsky H, Li Y, Norman B, Davis J, Piatigorsky J (2006) Serial analysis of gene expression (SAGE) in the rat limbal and central corneal epithelium. Invest Ophthalmol Vis Sci 47:3801–3810

    PubMed  Google Scholar 

  162. Zhou M, X-m L, Lavker RM (2006) Transcriptional profiling of enriched populations of stem cells versus transient amplifying cells. J Biol Chem 281:19600–19609

    PubMed  CAS  Google Scholar 

  163. Kulkarni BB, Tighe PJ, Mohammed I et al (2010) Comparative transcriptional profiling of the limbal epithelial crypt demonstrates its putative stem cell niche characteristics. BMC Gemonics 11:526–544

    Google Scholar 

  164. Baylis O, Rooney P, Figueirdo F, Lako M, Ahmad S (2013) An investigation of donor and culture parameters which influence epithelial outgrowth from human cadaveric limbal explants cultured on amniotic membrane. J Cell Physiol 228(5):1025–1030

    PubMed  CAS  Google Scholar 

  165. Crewe JM, Armitage WJ (2001) Integrity of epithelium and endothelium in organ-cultured human corneas. Invest Ophthalmol Vis Sci 42:1757–1761

    PubMed  CAS  Google Scholar 

  166. Raeder S, Utheim TP, Utheim OA et al (2007) Effect of organ culture and Optisol-GS storage on structural integrity, phenotypes, and apoptosis in cultured corneal epithelium. Invest Ophthalmol Vis Sci 48:5484–5493

    PubMed  Google Scholar 

  167. Espana EM, Romano AC, Kawakita T, Di Pascuale M, Smiddy R, Tseng SCG (2003) Novel enzymatic isolation of an entire viable human limbal epithelial sheet. Invest Ophthalmol Vis Sci 44:4275–4281

    PubMed  Google Scholar 

  168. Arpitha P, Prajna NV, Srinivasan M, Muthukkaruppan V (2008) A method to isolate human limbal basal calls enriched for a subset of epithelial cells with a large nucleus/cytoplasm ration expressing high levels of p63. Microsc Res Tech 71:469–476

    PubMed  CAS  Google Scholar 

  169. Chen S-Y, Hayashida Y, Vhen M-Y, Xie HT, Tseng SCG (2011) A new isolation method of human limbal progenitor cells by maintaining close association with their niche. Tissue Eng Part C 117:537–548

    Google Scholar 

  170. Li D-Q, Chen Z, Song XJ, De Paiva CS, Kim H-S, Pflugfelder SC (2005) Partial enrichment of a population of human limbal epithelial cells with putative stem cell properties based on collagen type IV adhesiveness. Exp Eye Res 80:581–590

    PubMed Central  PubMed  CAS  Google Scholar 

  171. Krulova M, Pokorna K, Lencova A et al (2008) A rapid separation of two distinct populations of mouse corneal epithelial cells with limbal stem cell characteristics by centrifugation on percoll gradient. Invest Ophthalmol Vis Sci 49:3903–3908

    PubMed  Google Scholar 

  172. Rheinwald JG, Green H (1975) Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6:331–344

    PubMed  CAS  Google Scholar 

  173. Todaro GJ, Green H (1963) Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J Cell Biol 17:299–313

    PubMed Central  PubMed  CAS  Google Scholar 

  174. Barrandon Y, Green H (1987) Three clonal types of keratinocytes with different capacities for multiplication. Proc Natl Acad Sci U S A 84:2302–2306

    PubMed Central  PubMed  CAS  Google Scholar 

  175. Stocker FW, Eiring A, Georgiade MSR, Georgiade N (1958) A tissue culture technique for growing corneal epithelial, stromal, and endothelial tissues separately. Am J Ophthalmol 46:294–298

    PubMed  CAS  Google Scholar 

  176. Newsome DA, Takasugi M, Kenyon KR, Stark WF, Opelz G (1974) Human corneal cells in vitro: morphology and histocompatibility (HL-A) antigens of pure cell populations. Invest Ophthalmol 13:23–32

    PubMed  CAS  Google Scholar 

  177. Sun T-T, Green H (1977) Cultured epithelial cells of cornea, conjunctiva and skin: absence of marker intrinsic divergence of their differentiated states. Nature 269:489–492

    PubMed  CAS  Google Scholar 

  178. Wei ZG, Wu R-L, Lavker RM, Sun T-T (1993) 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 34:1814–1828

    PubMed  CAS  Google Scholar 

  179. Kruse FE, Tseng SCG (1993) Serum differentiation modulates the clonal growth and differentiation of cultured limbal and corneal epithelium. Invest Ophthalmol Vis Sci 34:2976–2989

    PubMed  CAS  Google Scholar 

  180. Nishida K, Yamato M, Hayashida Y et al (2004) Functional bioengineered cornea epithelial sheet grafts from corneal stem cells expanded ex vivo on temperature-responsive cell culture surface. Transplantation 77:379–385

    PubMed  Google Scholar 

  181. Cooper LJ, Kinoshita S, German M et al (2005) An investigation into the composition of amniotic membrane used for ocular surface reconstruction. Cornea 24:722–729

    PubMed  Google Scholar 

  182. Koizumi NJ, Inatomi TJ, Sotozono CJ et al (2000) Growth factor mRNA and protein in preserved human amniotic membrane. Curr Eye Res 20:173–177

    PubMed  CAS  Google Scholar 

  183. Kenyon KR (2005) Amniotic membrane: mother’s own remedy for ocular surface disease. Cornea 24:639–642

    PubMed  Google Scholar 

  184. Grueterich M, Tseng SC (2002) Human limbal progenitor cells expanded on intact amniotic membrane ex vivo. Arch Ophthalmol 120:783–790

    PubMed  Google Scholar 

  185. Koizumi N, Cooper LJ, Fullwood NJ et al (2002) An evaluation of cultivated corneal limbal epithelial cells, using cell-suspension culture. Invest Ophthalmol Vis Sci 43:2114–2121

    PubMed  Google Scholar 

  186. Li W, Hayashida Y, He H, Kuo C-L, Tseng SCG (2007) The fate of limbal epithelial progenitor cells during explant culture on intact amniotic membrane. Invest Ophthalmol Vis Sci 48:605–613

    PubMed Central  PubMed  Google Scholar 

  187. Meyer-Blazejewska EA, Kruse FE, Bitterer K et al (2010) Preservation of the limbal stem cell phenotype by appropriate culture techniques. Invest Ophthalmol Vis Sci 51:765–774

    PubMed  Google Scholar 

  188. Gosain AK, Lyon VB (2002) The current status of tissue glues: Part II. For adhesion of soft tissues. Plast Reconstr Surg 110:1581–1584

    PubMed  Google Scholar 

  189. Talbot M, Carrier P, Giasson CJ et al (2006) Autologous transplantation of rabbit limbal epithelia cultured on fibrin gels for ocular surface reconstruction. Mol Vis 12:65–75

    PubMed  CAS  Google Scholar 

  190. Shortt AJ, Secker GA, Lomas R et al (2009) The effect of amniotic membrane preparation method on its ability to serve as a substrate for the ex-vivo expansion of limbal epithelial cells. Biomaterials 30:1056–1065

    PubMed  CAS  Google Scholar 

  191. Krishnan S, Seka S, Katheem MF, Krishnakumar S, Sastry TP (2012) Fish scale collagen – a novel material for corneal tissue engineering. Artif Organs 36:829–835

    PubMed  CAS  Google Scholar 

  192. Dravida S, Gaddipati S, Griffith M et al (2008) A biomimetic scaffold for culturing limbal stem cells: a promising alternative for clinical transplantation. J Tissue Eng Regen Med 2:263–271

    PubMed  CAS  Google Scholar 

  193. Mi S, Chen B, Wright B, Connon CJ (2010) Ex vivo construction of an artificial ocular surface by combination of corneal limbal epithelial cells on a compressed collagen scaffold containing keratocytes. Tissue Eng Part A 16:2091–2110

    PubMed  CAS  Google Scholar 

  194. Levis HJ, Brown RA, Daniels JT (2010) Plastic compressed collagen as a biomimetic substrate for human limbal epithelial culture. Biomaterials 31:7726–7737

    PubMed  CAS  Google Scholar 

  195. Bray LJ, George KA, Ainscough SL, Hutmacher DW, Chirila TV, Harkin DG (2011) Human corneal epithelial equivalents constructed on Bombyx mori silk fibroin membranes. Biomaterials 32:5086–5091

    PubMed  CAS  Google Scholar 

  196. Albert R, Vereb Z, Csomos K et al (2012) Cultivation and characterization of corneal limbal epithelial stem cells on lens capsule in animal material-free medium. PLoS One 7:e47187

    PubMed Central  PubMed  CAS  Google Scholar 

  197. Zajicova A, Pokorna K, Lencova A et al (2010) Treatment of ocular surface injuries by limbal and mesenchymal stem cells growing on nanofiber scaffolds. Cell Transplant 19:1281–1290

    PubMed  Google Scholar 

  198. Di Girolamo N, Chui J, Wakefield D, Coroneo MT (2007) Cultured human ocular surface epithelium on therapeutic contact lenses. Br J Ophthalmol 91:459–464

    PubMed Central  PubMed  Google Scholar 

  199. Di Girolamo N, Bosch M, Zamora K, Coroneo MT, Wakefield D, Watson S (2009) A contact lens-based technique for expansion and transplantation of autologous epithelial progenitors for ocular surface reconstruction. Transplantation 87:1571–1578

    PubMed  Google Scholar 

  200. Deshpande P, Notara M, Bullett N, Daniels JT, Haddow DB, MacNeil S (2009) Development of a surface-modified contact lens for the transfer of cultured limbal epithelial cells to the cornea for ocular surface disease. Tissue Eng Part A 15:1–14

    Google Scholar 

  201. Tan XW, Tan D, Beuerman RW, Mehta JS (2012) Study of novel Chitosan-coated contact lens as an equivalent substrate for the therapeutic delivery of rabbit limbal epithelium. ARVO Abstr 6124/D94

    Google Scholar 

  202. Vascotto SG, Griffith M (2006) Localization of candidate stem and progenitor cell markers within the human cornea, limbus, and bulbar conjunctiva in vivo and in cell culture. Anat Rec A Discov Mol Cell Evol Biol 288:921–931

    PubMed  Google Scholar 

  203. Duffy P, Wolf J, Collins G et al (1974) Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med 290:692–693

    PubMed  CAS  Google Scholar 

  204. Schwab IR, Johnson NT, Harkin DG (2006) Inherent risks associated with manufacture of bioengineered ocular surface tissue. Arch Ophthalmol 124:1734–1740

    PubMed  Google Scholar 

  205. Johnen S, Wickert L, Meier M, Salz AK, Walter P, Thumann G (2011) Presence of xenogenic mouse RNA in RPE and IPE cells cultures on mitotically inhibited 3T3 fibroblasts. Invest Ophthalmol Vis Sci 52:2817–2829

    PubMed  CAS  Google Scholar 

  206. Holland EJ, Schwartz GS (1996) The evolution of epithelial transplantation for severe ocular surface disease and a proposed classification system. Cornea 15:549–556

    PubMed  CAS  Google Scholar 

  207. Nishida K, Kinoshita S, Ohashi Y, Kuwayama Y, Yamamoto S (1995) Ocular surface abnormalities in Aniridia. Am J Ophthalmol 120:368–375

    PubMed  CAS  Google Scholar 

  208. Ramaesh K, Ramaesh T, Dutton GN, Dhillon B (2005) Evolving concepts on the pathogenic mechanisms of aniridia related keratopathy. Int J Biochem Cell Biol 37:547–557

    PubMed  CAS  Google Scholar 

  209. Shortt AJ, Tuft SJ, Daniels JT (2011) Corneal stem cells in the eye clinic. Br Med Bull 100:209–225

    PubMed  Google Scholar 

  210. Shimazaki J, Higa K, Morito F et al (2007) Factor influencing outcomes in cultivated limbal epithelial transplantation for chronic cicatricial ocular surface disease. Am J Ophthalmol 143:945–953

    PubMed  Google Scholar 

  211. Daya SM, Chan CC, Holland EJ (2011) Cornea Society nomenclature for ocular surface rehabilitative procedures. Cornea 30:1115–1119

    PubMed  Google Scholar 

  212. Williams KA, Brereton HM, Aggarwal R et al (1995) Use of DNA polymorphisms and the polymerase chain reaction to examine the survival of a human limbal stem cell allograft. Am J Ophthalmol 120:342–350

    PubMed  CAS  Google Scholar 

  213. Daya SM, Watson A, Sharpe JR et al (2005) Outcomes and DNA analysis of ex vivo expanded stem cell allograft for ocular surface reconstruction. Ophthalmology 112:470–477

    PubMed  Google Scholar 

  214. Shimazaki J, Kaido M, Shinozaki N, Shimmura S et al (1999) Evidence of long-term survival of donor-derived cells after limbal allograft transplantation. Invest Ophthalmol Vis Sci 40:1664–1668

    PubMed  CAS  Google Scholar 

  215. Stenevi U, Hanson C, Claesson M, Corneliusson E, Ek S (2002) Survival of transplanted human corneal stem cells: case report. Acta Ophthalmol Scand 80:105–108

    PubMed  Google Scholar 

  216. Bradshaw JJ, Obritsch WF, Cho BJ, Gregerson DS, Holland EJ (1999) Ex vivo transduction of corneal epithelial progenitor cells using a retroviral vector. Invest Ophthalmol Vis Sci 40:230–235

    PubMed  CAS  Google Scholar 

  217. Holan V, Pokorna K, Prochazkova J, Krulova M, Zajicova A (2010) Immunoregulatory properties of mouse limbal stem cells. J Immunol 184:2124–2129

    PubMed  CAS  Google Scholar 

  218. Abumaree M, Al Jumah M, Pace RA, Kalionis B (2012) Immunosuppressive properties of mesenchymal stem cells. Stem Cell Rev 8:375–392

    PubMed  CAS  Google Scholar 

  219. Ang LPK, Tanioka H, Kawasaki S, Ang LPS, Yamasaki K, Do TP et al (2010) Cultivated human conjunctival epithelial transplantation for total limbal stem cell deficiency. Invest Ophthalmol Vis Sci 51:758–764

    PubMed  Google Scholar 

  220. Ricardo JR, Cristovam PC, Filho PA et al (2013) Transplantation of conjunctival epithelial cells cultivated ex vivo in patients with total limbal stem cell deficiency. Cornea 32(3):221–228

    PubMed  Google Scholar 

  221. Nishida K, Yamato M, Hayashida Y et al (2004) Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med 351:1187–1196

    PubMed  CAS  Google Scholar 

  222. Chen H-CJ, Chen H-L, Lai J-Y et al (2009) Persistence of transplanted oral mucosal epithelial cells in human corneas. Invest Ophthalmol Vis Sci 50:4660–4668

    PubMed  Google Scholar 

  223. Eslani M, Baradaran-Rafii A, Ahmad S (2012) Cultivated limbal and oral mucosal epithelial transplantation. Semin Ophthalmol 27:80–93

    PubMed  Google Scholar 

  224. Burillon C, Huot L, Justin V et al (2012) Cultured autologous oral mucosal epithelial sheet (CAOMECS) transplantation for the treatment of corneal limbal epithelial stem cell deficiency. Invest Ophthalmol Vis Sci 53:1325–1332

    PubMed  Google Scholar 

  225. Chen H-CJ, Yeh L-K, Tsai YJ et al (2012) Expression of angiogenesis-related factors in human corneas after cultivated oral mucosal epithelial transplantation. Invest Ophthalmol Vis Sci 53(9):5615–5623

    PubMed  CAS  Google Scholar 

  226. Kim JH, Chun YS, Lee SH et al (2010) Ocular surface reconstruction with autologous nasal mucosa in cicatricial ocular surface disease. Am J Ophthalmol 149:45–53

    PubMed  Google Scholar 

  227. Reza HM, Ng BY, Gimeno FL, Phan TT, Ang LP (2011) Umbilical cord lining stem cells as a novel and promising source for ocular surface regeneration. Stem Cell Rev 7:935–947

    PubMed  Google Scholar 

  228. Jiang T-S, Cai L, Ji W-Y et al (2010) Reconstruction of the corneal epithelium with induced marrow mesenchymal stem cells in rats. Mol Vis 16:1304–1316

    PubMed Central  PubMed  Google Scholar 

  229. Reinshagen H, Auw-Haedrich C, Sorg RV et al (2011) Corneal surface reconstruction using mesenchymal stem cells in experimental limbal stem cells deficiency in rabbits. Acta Ophthalmol 89:741–748

    PubMed  Google Scholar 

  230. Homma R, Yoshikawa H, Takeno M et al (2004) Induction of epithelial progenitors in vitro from mouse embryonic stem cells and application for reconstruction of damaged cornea in mice. Invest Ophthalmol Vis Sci 45:4320–4326

    PubMed  Google Scholar 

  231. Notara M, Hernandez D, Mason C, Daniels JT (2012) Characterization of the phenotype and functionality of corneal epithelial cells derived from mouse embryonic stem cells. Regen Med 7:167–178

    PubMed  CAS  Google Scholar 

  232. Hanson C, Hardarson T, Ellerstrom C et al (2013) Transplantation of human embryonic stem cells into a partially wounded human cornea in vitro. Acta Ophthalmol 91(2):127–130

    PubMed Central  PubMed  CAS  Google Scholar 

  233. Hayashi R, Ishikawa Y, Ito M et al (2012) Generation of corneal epithelial cells from induced pluripotent stem cells derived from human dermal fibroblasts and corneal epithelium. PLoS One 7:e45435

    PubMed Central  PubMed  CAS  Google Scholar 

  234. Daniels JT, Secker GA, Shortt AJ et al (2006) Stem cell therapy delivery: treading the regulatory tightrope. Regen Med 1:715–719

    PubMed  Google Scholar 

Download references

Acknowledgments

The author thanks Associate Professor Damien Harkin (Queensland University of Technology, Brisbane, Australia) for providing an image of human limbal epithelial cells in coculture with murine 3T3 fibroblasts and Associate Professor Trevor Sherwin (Department of Ophthalmology, University of Auckland, New Zealand) for providing an image of human limbal epithelial cells forming spheres in culture.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nick Di Girolamo .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Di Girolamo, N. (2014). Adult Human Corneal Epithelial Stem Cells. In: Turksen, K. (eds) Adult Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-9569-7_7

Download citation

Publish with us

Policies and ethics