Therapeutic Strategies in Ocular Tissue Regeneration: The Role of Stem Cells

  • K. Ramaesh
  • N. Stone
  • B. Dhillon


The eye is a unique window providing direct visualization of the structure and function of epithelial, vascular, and neural tissue. It thus serves as an ideal “model” for assessing cell-therapy based regenerative strategies. Loss of ocular tissues through injury and degeneration may result in visual morbidity; therefore, a need to explore possible avenues of cellular regeneration by manipulation of host and embryonic stem cells exists. In the adult eye, stem cells have been identified in various locations including the conjunctiva, corneal limbus, ciliary body, and neural retina. Recent studies have also suggested that bone marrow derived stem cells are recruited in pathological neovascularization involving both the retina and choroid.

The aim of this chapter is to translate basic scientific understanding into useful clinical application ensuring that the potential promise of stem cell studies is not “lost in translation” in the journey from laboratory to clinic.

Stem cell...


Stem Cell Ocular Surface Amniotic Membrane Corneal Epithelial Cell Bone Marrow Derive 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. Akagi T, et al. (2004) Otx2 homeobox gene induces photoreceptor-specific phenotypes in cells derived from adult iris and ciliary tissue. Invest Ophthalmol Vis Sci. 45:4570–5CrossRefGoogle Scholar
  2. Alexiades MR, Cepko CL (1997) Subsets of retinal progenitors display temporally regulated and distinct biases in the fates of their progeny. Development 124:1119–31Google Scholar
  3. Asahara T, et al. (1999) VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. Embo J. 18:3964–72CrossRefGoogle Scholar
  4. Ashery-Padan R, Gruss P (2001) Pax6 lights-up the way for eye development. Curr. Opin. Cell Biol. 13:706–14Google Scholar
  5. Baldwin AS, Jr (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 14:649–83CrossRefGoogle Scholar
  6. Bishop AE, LD Buttery, Polak JM (2002) Embryonic stem cells. J Pathol. 197:424–9Google Scholar
  7. Bizzozero G (1894) An address on growth and regeneration of organism. Br Med J. 1:728–732CrossRefGoogle Scholar
  8. Blau HM, TR Brazelton, Weimann JM (2001) The evolving concept of a stem cell: entity or function? Cell 105:829–41Google Scholar
  9. Boudreau N, Bissell MJ (1998) Extracellular matrix signaling: integration of form and function in normal and malignant cells. Curr Opin Cell Biol. 10:640–6CrossRefGoogle Scholar
  10. Brustle O, et al. (1997) In vitro-generated neural precursors participate in mammalian brain development. Proc Natl Acad Sci USA 94:14809–14.CrossRefGoogle Scholar
  11. Brustle O, et al. (1999) Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science 285:754–6CrossRefGoogle Scholar
  12. Buschke W (1949) Morphologic changes in cells of corneal epithelium in wound healing. Arch Ophthalmol 41:306–316CrossRefGoogle Scholar
  13. Chiou SH, et al. (2005) A novel in vitro retinal differentiation model by co-culturing adult human bone marrow stem cells with retinal pigmented epithelium cells. Biochem Biophys Res Commun. 326:578–85CrossRefGoogle Scholar
  14. Colville D, et al. (2000) Absence of ocular manifestations in autosomal dominant Alport syndrome associated with haematological abnormalties. Ophthalmic Genet. 21:217–25Google Scholar
  15. 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 57:201–9CrossRefGoogle Scholar
  16. Davanger M, Evensen A (1971) Role of the pericorneal papillary structure in renewal of corneal epithelium. Nature 229:560–1CrossRefGoogle Scholar
  17. Davis J, et al. (2003) Requirement for Pax6 in corneal morphogenesis: a role in adhesion. J Cell Sci. 116:2157–67CrossRefGoogle Scholar
  18. Dayton L (2002a) Biomedical research. Australia pushes stem cell advantage. Science 296:1779–81Google Scholar
  19. Dayton L (2002b) Embryonic stem cells. Australian agreement allows new lines. Science 296:238Google Scholar
  20. Dua HS (1995) Stem cells of the ocular surface: scientific principles and clinical applications. Br J Ophthalmol 79:968–9CrossRefGoogle Scholar
  21. Dursun D, et al. (2001) Treatment of recalcitrant recurrent corneal erosions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids. Am J Ophthalmol. 132:8–13CrossRefGoogle Scholar
  22. Ebato B, Friend J, Thoft RA (1987) Comparison of central and peripheral human corneal epithelium in tissue culture. Invest Ophthalmol Vis Sci. 28:1450–6Google Scholar
  23. Espinosa-Heidmann DG, et al. (2003) Bone marrow-derived progenitor cells contribute to experimental choroidal neovascularization. Invest Ophthalmol Vis Sci. 44:4914–9CrossRefGoogle Scholar
  24. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–6CrossRefGoogle Scholar
  25. Ferraris C, et al. (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 127:5487–95Google Scholar
  26. Fini ME, Cook JR, Mohan R (1998) Proteolytic mechanisms in corneal ulceration and repair. Arch Dermatol Res. 290:S12–23CrossRefGoogle Scholar
  27. Fischer AJ (2005) Neural regeneration in the chick retina. Prog Retin Eye Res. 24:161–82CrossRefGoogle Scholar
  28. Garrana RM, et al. (1999) Matrix metalloproteinases in epithelia from human recurrent corneal erosion. Invest Ophthalmol Vis Sci. 40:1266–70Google Scholar
  29. Gillett NA, et al. (1993) Leukemia inhibitory factor expression in human carotid plaques: possible mechanism for inhibition of large vessel endothelial regrowth. Growth Fact. 9:301–5CrossRefGoogle Scholar
  30. Girard MT, Matsubara M, Fini ME (1991) Transforming growth factor-beta and interleukin-1 modulate metalloproteinase expression by corneal stromal cells. Invest Ophthalmol Vis Sci. 32:2441–54Google Scholar
  31. Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 86:494–501CrossRefGoogle Scholar
  32. Hall PA (1989) What are stem cells and how are they controlled? J Pathol. 158:275–7CrossRefGoogle Scholar
  33. Hanson IM, et al. (1994) Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly. Nat Genet. 6:168–73CrossRefGoogle Scholar
  34. Hitchcock PF, et al. (1996) Antibodies against Pax6 immunostain amacrine and ganglion cells and neuronal progenitors, but not rod precursors, in the normal and regenerating retina of the goldfish. J Neurobiol. 29:399–413CrossRefGoogle Scholar
  35. Hovanesian JA, Shah SS, Maloney RK (2001) Symptoms of dry eye and recurrent erosion syndrome after refractive surgery. J Cataract Refract Surg. 27:577–84CrossRefGoogle Scholar
  36. Jordan T, et al. (1992) The human PAX6 gene is mutated in two patients with aniridia. Nat Genet. 1:328–32CrossRefGoogle Scholar
  37. Kenyon KR (1989) Limbal autograft transplantation for chemical and thermal burns. Dev Ophthalmol. 18:53–8Google Scholar
  38. Kenyon KR, Tseng SC (1989) Limbal autograft transplantation for ocular surface disorders. Ophthalmology. 96:709–22; discussion 722–3Google Scholar
  39. Klug MG, et al. (1996) Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. J Clin Invest. 98:216–24CrossRefGoogle Scholar
  40. Koroma B, Tseng S, Sundin OH (1997) Expression of the PAX6 gene in the anterior segment in human aniridia and Sey mouse model. Investigative Ophthalmol Vis Sci. 38:4405 (abstract).Google Scholar
  41. Krause DS, et al. (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105:369–77CrossRefGoogle Scholar
  42. Kruse FE (1994) Stem cells and corneal epithelial regeneration. Eye 8:170–83CrossRefGoogle Scholar
  43. Kruse FE, Tseng SC (1992) Proliferative and differentiative response of corneal and limbal epithelium to extracellular calcium in serum-free clonal cultures. J Cell Physiol. 151:347–60CrossRefGoogle Scholar
  44. Kruse FE, Volcker HE (1997) Stem cells, wound healing, growth factors, and angiogenesis in the cornea. Curr Opin Ophthalmol. 8:46–54CrossRefGoogle Scholar
  45. Lajtha LG (1979) Stem cell concepts. Differentiation 14:23–34CrossRefGoogle Scholar
  46. Lugo M, Putong PB (1984) Metaplasia. An overview. Arch Pathol Lab Med. 108:185–9Google Scholar
  47. MacLaren RE, et al. (2006) Retinal repair by transplantation of photoreceptor precursors. Nature 444:203–7CrossRefGoogle Scholar
  48. Marquardt T, Gruss P (2002) Generating neuronal diversity in the retina: one for nearly all. Trends Neurosci. 25:32–8CrossRefGoogle Scholar
  49. Marquardt T, et al. (2001) Pax6 is required for the multipotent state of retinal progenitor cells. Cell 105:43–55CrossRefGoogle Scholar
  50. Marquardt T (2003) Transcriptional control of neuronal diversification in the retina. Prog Retin Eye Res. 22:567–77CrossRefGoogle Scholar
  51. Maumenee A, Scholz R (1948) Histopathology of the ocular lesions produced by the sulphur and nitrogen mustards. Johns Hopkins Hospital Bull. 82:121–147Google Scholar
  52. Mayer EJ, et al. (2005) Neural progenitor cells from postmortem adult human retina. Br J Ophthalmol. 89:102–6CrossRefGoogle Scholar
  53. McDevitt DS (1989) Transdifferentiation in animals. A model for differentiation control. Dev Biol. (NY 1985). 6:149–73Google Scholar
  54. Mitchell KE, et al. (2003) Matrix cells from Wharton's jelly form neurons and glia. Stem Cells. 21:50–60CrossRefGoogle Scholar
  55. Mohan RR, et al. (1997) Apoptosis in the cornea: further characterization of Fas/Fas ligand system. Exp Eye Res 65:575–89CrossRefGoogle Scholar
  56. Mohan R, et al. (2002) Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration. J Biol Chem. 277:2065–72CrossRefGoogle Scholar
  57. O'Guin WM, et al. (1987) Patterns of keratin expression define distinct pathways of epithelial development and differentiation. Curr Top Dev Biol. 22:97–125CrossRefGoogle Scholar
  58. Pearton DJ, Yang Y, Dhouailly D (2005) Trans differentiation of corneal epithelium into epidermis occurs by means of a multistep process triggered by dermal developmental signals. Proc Natl Acad Sci USA 102:3714–9CrossRefGoogle Scholar
  59. Pellegrini G, et al. (1999) Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface. J Cell Biol. 145:769–82CrossRefGoogle Scholar
  60. Potten CS, Loeffler M (1990) Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110:1001–20Google Scholar
  61. Ramaesh K, Dhillon B (2003) Ex vivo expansion of corneal limbal epithelial/stem cells for corneal surface reconstruction. Eur J Ophthalmol. 13:515–24Google Scholar
  62. Reubinoff BE, et al. (2001) Neural progenitors from human embryonic stem cells. Nat Biotechnol. 19:1134–40CrossRefGoogle Scholar
  63. Schnieke AE, et al. (1997) Human factor IX transgenic sheep produced by transfer of nuclei from transfected fetal fibroblasts. Science 278:2130–3CrossRefGoogle Scholar
  64. Simpson TI, Price DJ (2002) Pax6; a pleiotropic player in development. Bioessays 24:1041–51CrossRefGoogle Scholar
  65. Sivak JM, Fini M (2002a) MMPs in the eye: emerging roles for matrix metalloproteinases in ocular physiology. Prog Retin Eye Res. 21:1–14Google Scholar
  66. Sivak J Fini M (2002b) Pax-6 Deficient Mice Show Altered Phenotype and Gene Expression During Corneal Re-Epithelialization. ARVO poster. Presentation Number:4197.Google Scholar
  67. Sivak JM, et al. (2000) Pax-6 expression and activity are induced in the reepithelializing cornea and control activity of the transcriptional promoter for matrix metalloproteinase gelatinase B. Dev Biol. 222:41–54CrossRefGoogle Scholar
  68. Sobrin L, et al. (2000) Regulation of MMP-9 activity in human tear fluid and corneal epithelial culture supernatant. Invest Ophthalmol Vis Sci. 41:1703–9Google Scholar
  69. Soria B, et al. (2000) Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49:157–62CrossRefGoogle Scholar
  70. Spence JR, et al. (2004) The hedgehog pathway is a modulator of retina regeneration. Development 131:4607–21CrossRefGoogle Scholar
  71. Stoykova A, et al. (1997) Pax6-dependent regulation of adhesive patterning, R-cadherin expression and boundary formation in developing forebrain. Development 124:3765–77Google Scholar
  72. Thomson JA, et al. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–7CrossRefGoogle Scholar
  73. Tropepe V, et al. (2000) Retinal stem cells in the adult mammalian eye. Science 287:2032–6CrossRefGoogle Scholar
  74. Tsai RJ, Tseng SC (1995) Effect of stromal inflammation on the outcome of limbal transplantation for corneal surface reconstruction. Cornea 14:439–49CrossRefGoogle Scholar
  75. Tsai R, Lin-Min, Chen J-K (2000) Reconstruction of damaged corneas by transplanation of autologous limbal epithelial cells. New Engl J Med. 343:86–94Google Scholar
  76. Watt FM, Hogan BL (2000) Out of Eden: stem cells and their niches. Science 287:1427–30CrossRefGoogle Scholar
  77. Whikehart DR, et al. (2005) Evidence suggesting the existence of stem cells for the human corneal endothelium. Mol Vis. 11:816–24Google Scholar
  78. Wiles MV, Keller G (1991) Multiple hematopoietic lineages develop from embryonic stem (ES) cells in culture. Development 111:259–67Google Scholar
  79. Wilson SE, et al. (2001) The corneal wound healing response: cytokine-mediated interaction of the epithelium, stroma, and inflammatory cells. Prog Retin Eye Res. 20:625–37CrossRefGoogle Scholar
  80. Wong TT, et al. (2002) Matrix metalloproteinases in disease and repair processes in the anterior segment. Surv Ophthalmol. 47:239–56CrossRefGoogle Scholar
  81. Zhang SC, et al. (2001) In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol. 19:1129–33CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • K. Ramaesh
    • 1
  • N. Stone
  • B. Dhillon
  1. 1.Tennent Institute of Ophthalmology Gartnavel General HospitalGlasgowScotland, UK

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