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Clinical Applications of Limbal Stem Cells for Regenerative Medicine

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Regenerative Medicine and Stem Cell Therapy for the Eye

Part of the book series: Fundamental Biomedical Technologies ((FBMT))

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Abstract

Damage or loss of corneal and/or limbal cells from injury or infection can lead to irreversible loss of corneal transparency and blindness. A population of active limbal stem cells has been identified in the limbal epithelial crypts that provide a continuous supply of progenitors and mature epithelial cells, and participate in wound healing. With our growing knowledge of this stem cell population, our understanding of the homeostatic mechanisms regulating corneal epithelial homeostasis has expanded dramatically. Loss of these limbal stem cells leads to the range of conditions representing limbal stem cell deficiency. Here, we review the biology and cellular characterization of the limbal stem cell in health and disease. We also review clinical approaches to ocular surface stem cell transplantation that have been developed over the last 30 years, including autograft and allograft techniques currently in clinical practice, and the challenges associated with systemic immunosuppression when required. Emerging therapies in cultivated limbal epithelial transplantation are described, which may provide an unlimited source of cells for ocular surface restoration.

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References

  1. Jonas, J. B., & Holbach, L. (2005). Central corneal thickness and thickness of the lamina cribrosa in human eyes. Investigative Ophthalmology & Visual Science, 46, 1275–1279.

    Article  Google Scholar 

  2. Sack, R. A., Nunes, I., Beaton, A., & Morris, C. (2001). Host-defense mechanism of the ocular surfaces. Bioscience Reports, 21, 463–480.

    Article  CAS  PubMed  Google Scholar 

  3. Ren, H., & Wilson, G. (1996). The cell shedding rate of the corneal epithelium—A comparison of collection methods. Current Eye Research, 15, 1054–1059.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. 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. The Journal of Cell Biology, 103, 49–62.

    Article  CAS  PubMed  Google Scholar 

  6. Whitcher, J. P., Srinivasan, M., & Upadhyay, M. P. (2001). Corneal blindness: A global perspective. Bulletin of the World Health Organization, 79, 214–221.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Claesson, M., Armitage, W. J., Fagerholm, P., & Stenevi, U. (2002). Visual outcome in corneal grafts: A preliminary analysis of the Swedish Corneal Transplant Register. The British Journal of Ophthalmology, 86, 174–180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Williams, K. A., et al. (2006). How effective is penetrating corneal transplantation? Factors influencing long-term outcome in multivariate analysis. Transplantation, 81, 896–901.

    Article  PubMed  Google Scholar 

  9. Ardjomand, N., et al. (2007). Lamellar corneal dissection for visualization of the anterior chamber before triple procedure. Eye (London, England), 21, 1151–1154.

    Article  CAS  Google Scholar 

  10. Myung, D., et al. (2008). Development of hydrogel-based keratoprostheses: A materials perspective. Biotechnology Progress, 24, 735–741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chirila, T. V. (2001). An overview of the development of artificial corneas with porous skirts and the use of PHEMA for such an application. Biomaterials, 22, 3311–3317.

    Article  CAS  PubMed  Google Scholar 

  12. Thoft, R. A., & Friend, J. (1983). The X, Y, Z hypothesis of corneal epithelial maintenance. Investigative Ophthalmology & Visual Science, 24, 1442–1443.

    CAS  Google Scholar 

  13. Yoon, J. J., Ismail, S., & Sherwin, T. (2014). Limbal stem cells: Central concepts of corneal epithelial homeostasis. World Journal of Stem Cells, 6, 391–403.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Goldberg, M. F., & Bron, A. J. (1982). Limbal palisades of Vogt. Transactions of the American Ophthalmological Society, 80, 155–171.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Townsend, W. M. (1991). The limbal palisades of Vogt. Transactions of the American Ophthalmological Society, 89, 721–756.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bizheva, K., et al. (2017). In-vivo imaging of the palisades of Vogt and the limbal crypts with sub-micrometer axial resolution optical coherence tomography. Biomedical Optics Express, 8, 4141–4151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Potten, C. S., & Loeffler, M. (1987). Epidermal cell proliferation. I. Changes with time in the proportion of isolated, paired and clustered labelled cells in sheets of murine epidermis. Virchows Archives B, Cell Pathology, 53, 279–285.

    Article  CAS  Google Scholar 

  18. Potten, C. S., & Loeffler, M. (1987). A comprehensive model of the crypts of the small intestine of the mouse provides insight into the mechanisms of cell migration and the proliferation hierarchy. Journal of Theoretical Biology, 127, 381–391.

    Article  CAS  PubMed  Google Scholar 

  19. Lajtha, L. G. (1979). Stem cell concepts. Differentiation, 14, 23–34.

    Article  CAS  PubMed  Google Scholar 

  20. Kinoshita, S., Friend, J., & Thoft, R. A. (1983). Biphasic cell proliferation in transdifferentiation of conjunctival to corneal epithelium in rabbits. Investigative Ophthalmology & Visual Science, 24, 1008–1014.

    CAS  Google Scholar 

  21. Dua, H. S., Shanmuganathan, V. A., Powell-Richards, A. O., Tighe, P. J., & Joseph, A. (2005). Limbal epithelial crypts: A novel anatomical structure and a putative limbal stem cell niche. The British Journal of Ophthalmology, 89, 529–532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grieve, K., et al. (2015). Three-dimensional structure of the mammalian limbal stem cell niche. Experimental Eye Research, 140, 75–84.

    Article  CAS  PubMed  Google Scholar 

  23. Pajoohesh-Ganji, A., Pal-Ghosh, S., Simmens, S. J., & Stepp, M. A. (2006). Integrins in slow-cycling corneal epithelial cells at the limbus in the mouse. Stem Cells, 24, 1075–1086.

    Article  CAS  PubMed  Google Scholar 

  24. Cotsarelis, G., Cheng, S. Z., Dong, G., Sun, T. T., & Lavker, R. M. (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.

    Article  CAS  PubMed  Google Scholar 

  25. Amitai-Lange, A., et al. (2015). Lineage tracing of stem and progenitor cells of the murine corneal epithelium. Stem Cells, 33, 230–239.

    Article  CAS  PubMed  Google Scholar 

  26. Di Girolamo, N., et al. (2015). Tracing the fate of limbal epithelial progenitor cells in the murine cornea. Stem Cells, 33, 157–169.

    Article  PubMed  CAS  Google Scholar 

  27. Dorà, N. J., Hill, R. E., Collinson, J. M., & West, J. D. (2015). Lineage tracing in the adult mouse corneal epithelium supports the limbal epithelial stem cell hypothesis with intermittent periods of stem cell quiescence. Stem Cell Research, 15, 665–677.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lobo, E. P., et al. (2016). Self-organized centripetal movement of corneal epithelium in the absence of external cues. Nature Communications, 7, 12388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gonzalez, G., Sasamoto, Y., Ksander, B. R., Frank, M. H., & Frank, N. Y. (2017). Limbal stem cells: Identity, developmental origin, and therapeutic potential. Wiley Interdisciplinary Reviews: Developmental Biology, 2, PMID:29105366.

    Google Scholar 

  30. Pellegrini, G., et al. (2001). p63 identifies keratinocyte stem cells. Proceedings of the National Academy of Sciences of the United States of America, 98, 3156–3161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rama, P., et al. (2010). Limbal stem-cell therapy and long-term corneal regeneration. The New England Journal of Medicine, 363, 147–155.

    Article  CAS  PubMed  Google Scholar 

  32. Brzeszczynska, J., Ramaesh, K., Dhillon, B., & Ross, J. A. (2012). Molecular profile of organ culture-stored corneal epithelium: LGR5 is a potential new phenotypic marker of residual human corneal limbal epithelial stem cells. International Journal of Molecular Medicine, 29, 871–876.

    CAS  PubMed  Google Scholar 

  33. Lu, R., et al. (2012). Transcription factor TCF4 maintains the properties of human corneal epithelial stem cells. Stem Cells, 30, 753–761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Horenstein, A. L., et al. (2009). CD38 and CD157 ectoenzymes mark cell subsets in the human corneal limbus. Molecular Medicine, 15, 76–84.

    Article  CAS  PubMed  Google Scholar 

  35. Hayashi, R., et al. (2008). Enrichment of corneal epithelial stem/progenitor cells using cell surface markers, integrin alpha6 and CD71. Biochemical and Biophysical Research Communications, 367, 256–263.

    Article  CAS  PubMed  Google Scholar 

  36. Qi, H., et al. (2008). Nerve growth factor and its receptor TrkA serve as potential markers for human corneal epithelial progenitor cells. Experimental Eye Research, 86, 34–40.

    Article  CAS  PubMed  Google Scholar 

  37. Budak, M. T., et al. (2005). Ocular surface epithelia contain ABCG2-dependent side population cells exhibiting features associated with stem cells. Journal of Cell Science, 118, 1715–1724.

    Article  CAS  PubMed  Google Scholar 

  38. de Paiva, C. S., Chen, Z., Corrales, R. M., Pflugfelder, S. C., & Li, D. Q. (2005). ABCG2 transporter identifies a population of clonogenic human limbal epithelial cells. Stem Cells, 23, 63–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Yoshida, S., et al. (2006). Cytokeratin 15 can be used to identify the limbal phenotype in normal and diseased ocular surfaces. Investigative Ophthalmology & Visual Science, 47, 4780–4786.

    Article  Google Scholar 

  40. Ksander, B. R., et al. (2014). ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature, 511, 353–357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Puangsricharern, V., & Tseng, S. C. (1995). Cytologic evidence of corneal diseases with limbal stem cell deficiency. Ophthalmology, 102, 1476–1485.

    Article  CAS  PubMed  Google Scholar 

  42. Tseng, S. C. (1985). Staging of conjunctival squamous metaplasia by impression cytology. Ophthalmology, 92, 728–733.

    Article  CAS  PubMed  Google Scholar 

  43. Tugal-Tutkun, I., Akova, Y. A., & Foster, C. S. (1995). Penetrating keratoplasty in cicatrizing conjunctival diseases. Ophthalmology, 102, 576–585.

    Article  CAS  PubMed  Google Scholar 

  44. Alldredge, O. C., & Krachmer, J. H. (1981). Clinical types of corneal transplant rejection. Their manifestations, frequency, preoperative correlates, and treatment. Archives of Ophthalmology, 99, 599–604.

    Article  CAS  PubMed  Google Scholar 

  45. Holland, E. J., & Schwartz, G. S. (2000). Changing concepts in the management of severe ocular surface disease over twenty-five years. Cornea, 19, 688–698.

    Article  CAS  PubMed  Google Scholar 

  46. Tsai, R. J., Li, L. M., & Chen, J. K. (2000). Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells. The New England Journal of Medicine, 343, 86–93.

    Article  CAS  PubMed  Google Scholar 

  47. Kenyon, K. R., & Tseng, S. C. (1989). Limbal autograft transplantation for ocular surface disorders. Ophthalmology, 96, 709–722.; discussion 722.

    Article  CAS  PubMed  Google Scholar 

  48. Tsai, R. J., Sun, T. T., & Tseng, S. C. (1990). Comparison of limbal and conjunctival autograft transplantation in corneal surface reconstruction in rabbits. Ophthalmology, 97, 446–455.

    Article  CAS  PubMed  Google Scholar 

  49. Dua, H. S., & Azuara-Blanco, A. (1999). Allo-limbal transplantation in patients with limbal stem cell deficiency. The British Journal of Ophthalmology, 83, 414–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tsubota, K., et al. (1999). Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation. The New England Journal of Medicine, 340, 1697–1703.

    Article  CAS  PubMed  Google Scholar 

  51. Shimazaki, J., et al. (1999). Evidence of long-term survival of donor-derived cells after limbal allograft transplantation. Investigative Ophthalmology & Visual Science, 40, 1664–1668.

    CAS  Google Scholar 

  52. Reinhard, T., Sundmacher, R., Spelsberg, H., & Althaus, C. (1999). Homologous penetrating central limbo-keratoplasty (HPCLK) in bilateral limbal stem cell insufficiency. Acta Ophthalmologica Scandinavica, 77, 663–667.

    Article  CAS  PubMed  Google Scholar 

  53. Sundmacher, R., & Reinhard, T. (1996). Central corneolimbal transplantation under systemic ciclosporin A cover for severe limbal stem cell insufficiency. Graefe’s Archive for Clinical and Experimental Ophthalmology, 234(Suppl 1), S122–S125.

    Article  PubMed  Google Scholar 

  54. Holland, E. J., & Schwartz, G. S. (1996). The evolution of epithelial transplantation for severe ocular surface disease and a proposed classification system. Cornea, 15, 549–556.

    Article  CAS  PubMed  Google Scholar 

  55. Daya, S. M., Chan, C. C., Holland, E. J., & Members, OTCSOSPNC. (2011). Cornea Society nomenclature for ocular surface rehabilitative procedures. Cornea, 30, 1115–1119.

    Article  PubMed  Google Scholar 

  56. Thoft, R. A. (1977). Conjunctival transplantation. Archives of Ophthalmology, 95, 1425–1427.

    Article  CAS  PubMed  Google Scholar 

  57. Shapiro, M. S., Friend, J., & Thoft, R. A. (1981). Corneal re-epithelialization from the conjunctiva. Investigative Ophthalmology & Visual Science, 21, 135–142.

    CAS  Google Scholar 

  58. Tseng, S. C., Hirst, L. W., Farazdaghi, M., & Green, W. R. (1984). Goblet cell density and vascularization during conjunctival transdifferentiation. Investigative Ophthalmology & Visual Science, 25, 1168–1176.

    CAS  Google Scholar 

  59. Dua, H. S., & Forrester, J. V. (1990). The corneoscleral limbus in human corneal epithelial wound healing. American Journal of Ophthalmology, 110, 646–656.

    Article  CAS  PubMed  Google Scholar 

  60. Jenkins, C., Tuft, S., Liu, C., & Buckley, R. (1993). Limbal transplantation in the management of chronic contact-lens-associated epitheliopathy. Eye (London, England), 7, 629–633.

    Article  Google Scholar 

  61. Thoft, R. A. (1984). Keratoepithelioplasty. American Journal of Ophthalmology, 97, 1–6.

    Article  CAS  PubMed  Google Scholar 

  62. Turgeon, P. W., Nauheim, R. C., Roat, M. I., Stopak, S. S., & Thoft, R. A. (1990). Indications for keratoepithelioplasty. Archives of Ophthalmology, 108, 233–236.

    Article  CAS  PubMed  Google Scholar 

  63. Tsai, R. J., & Tseng, S. C. (1994). Human allograft limbal transplantation for corneal surface reconstruction. Cornea, 13, 389–400.

    Article  CAS  PubMed  Google Scholar 

  64. Tsubota, K., Toda, I., Saito, H., Shinozaki, N., & Shimazaki, J. (1995). Reconstruction of the corneal epithelium by limbal allograft transplantation for severe ocular surface disorders. Ophthalmology, 102, 1486–1496.

    Article  CAS  PubMed  Google Scholar 

  65. Kwitko, S., et al. (1995). Allograft conjunctival transplantation for bilateral ocular surface disorders. Ophthalmology, 102, 1020–1025.

    Article  CAS  PubMed  Google Scholar 

  66. Kenyon, K. R., & Rapoza, P. A. (1995). Limbal allograft transplantation for ocular surface disorders. Ophthalmology, 102, 101–102.

    Article  Google Scholar 

  67. Biber, J. M., Skeens, H. M., Neff, K. D., & Holland, E. J. (2011). The cincinnati procedure: Technique and outcomes of combined living-related conjunctival limbal allografts and keratolimbal allografts in severe ocular surface failure. Cornea, 30, 765–771.

    Article  PubMed  Google Scholar 

  68. Chan, C. C., Biber, J. M., & Holland, E. J. (2012). The modified Cincinnati procedure: Combined conjunctival limbal autografts and keratolimbal allografts for severe unilateral ocular surface failure. Cornea, 31, 1264–1272.

    Article  PubMed  Google Scholar 

  69. Holland, E. J., et al. (2012). Systemic immunosuppression in ocular surface stem cell transplantation: Results of a 10-year experience. Cornea, 31, 655–661.

    Article  PubMed  Google Scholar 

  70. Niederkorn, J. Y. (1995). Effect of cytokine-induced migration of Langerhans cells on corneal allograft survival. Eye (London, England), 9, 215–218.

    Article  Google Scholar 

  71. Daya, S. M., Bell, R. W., Habib, N. E., Powell-Richards, A., & Dua, H. S. (2000). Clinical and pathologic findings in human keratolimbal allograft rejection. Cornea, 19, 443–450.

    Article  CAS  PubMed  Google Scholar 

  72. Holland, E. J. (1996). Epithelial transplantation for the management of severe ocular surface disease. Transactions of the American Ophthalmological Society, 94, 677–743.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Thoft, R. A., & Sugar, J. (1993). Graft failure in keratoepithelioplasty. Cornea, 12, 362–365.

    Article  CAS  PubMed  Google Scholar 

  74. Maruyama-Hosoi, F., Shimazaki, J., Shimmura, S., & Tsubota, K. (2006). Changes observed in keratolimbal allograft. Cornea, 25, 377–382.

    Article  PubMed  Google Scholar 

  75. Reinhard, T., et al. (2004). Long-term results of allogeneic penetrating limbo-keratoplasty in total limbal stem cell deficiency. Ophthalmology, 111, 775–782.

    Article  PubMed  Google Scholar 

  76. Ilari, L., & Daya, S. M. (2002). Long-term outcomes of keratolimbal allograft for the treatment of severe ocular surface disorders. Ophthalmology, 109, 1278–1284.

    Article  PubMed  Google Scholar 

  77. Shimazaki, J., Maruyama, F., Shimmura, S., Fujishima, H., & Tsubota, K. (2001). Immunologic rejection of the central graft after limbal allograft transplantation combined with penetrating keratoplasty. Cornea, 20, 149–152.

    Article  CAS  PubMed  Google Scholar 

  78. Meller, D., & Tseng, S. C. (2000). Amniotic membrane transplantation with or without limbal allografts in corneal surface reconstruction in limbal deficiency. Der Ophthalmologe: Zeitschrift der Deutschen Ophthalmologischen Gesellschaft Ophthalmologe, 97, 100–107 Transplantation von Amnionmembran mit oder ohne allogener Limbustransplantation zur Rekonstruktion der kornealen Oberflache bei Limbusinsuffizienz.

    Article  CAS  Google Scholar 

  79. Tan, D. T., Ficker, L. A., & Buckley, R. J. (1996). Limbal transplantation. Ophthalmology, 103, 29–36.

    Article  CAS  PubMed  Google Scholar 

  80. Holland, E. J., Djalilian, A. R., & Schwartz, G. S. (2003). Management of aniridic keratopathy with keratolimbal allograft: A limbal stem cell transplantation technique. Ophthalmology, 110, 125–130.

    Article  PubMed  Google Scholar 

  81. Burdmann, E. A., Andoh, T. F., Yu, L., & Bennett, W. M. (2003). Cyclosporine nephrotoxicity. Seminars in Nephrology, 23, 465–476.

    Article  CAS  PubMed  Google Scholar 

  82. Curtis, J. J. (2002). Hypertensinogenic mechanism of the calcineurin inhibitors. Current Hypertension Reports, 4, 377–380.

    Article  PubMed  Google Scholar 

  83. Luke, R. G. (1991). Mechanism of cyclosporine-induced hypertension. American Journal of Hypertension, 4, 468–471.

    Article  CAS  PubMed  Google Scholar 

  84. Kobashigawa, J. A., & Kasiske, B. L. (1997). Hyperlipidemia in solid organ transplantation. Transplantation, 63, 331–338.

    Article  CAS  PubMed  Google Scholar 

  85. Woodle, E. S. (2002). Corticosteroid elimination in renal transplantation: Pro. Transplantation Proceedings, 34, 1693.

    Article  CAS  PubMed  Google Scholar 

  86. Alloway, R. R., et al. (2005). A prospective, pilot study of early corticosteroid cessation in high-immunologic-risk patients: The Cincinnati experience. Transplantation Proceedings, 37, 802–803.

    Article  CAS  PubMed  Google Scholar 

  87. European Mycophenolate Mofetil Cooperative Study Group. (1999). Mycophenolate mofetil in renal transplantation: 3-Year results from the placebo-controlled trial. Transplantation, 68, 391–396.

    Article  Google Scholar 

  88. Ekberg, H., et al. (2007). Reduced exposure to calcineurin inhibitors in renal transplantation. The New England Journal of Medicine, 357, 2562–2575.

    Article  CAS  PubMed  Google Scholar 

  89. Boratynska, M., Banasik, M., Patrzalek, D., & Klinger, M. (2006). Conversion from cyclosporine-based immunosuppression to tacrolimus/mycophenolate mofetil in patients with refractory and ongoing acute renal allograft rejection. Annals of Transplantation, 11, 51–56.

    PubMed  Google Scholar 

  90. Tabbara, K. F. (2008). Pharmacologic strategies in the prevention and treatment of corneal transplant rejection. International Ophthalmology, 28, 223–232.

    Article  PubMed  Google Scholar 

  91. Vanrenterghem, Y. F. (1999). Which calcineurin inhibitor is preferred in renal transplantation: Tacrolimus or cyclosporine? Current Opinion in Nephrology and Hypertension, 8, 669–674.

    Article  CAS  PubMed  Google Scholar 

  92. Mogilishetty, G., Haird, D., Alloway, R. R., et al. (2008). Comparison of immunosuppression related toxicities and complications in ocular surface transplant and renal transplant recipients: Implications for composite tissue transplantation [abstract]. Transplantation, 86, 11.

    Article  Google Scholar 

  93. Salisbury, J. D., & Gebhardt, B. M. (1981). Blood group antigens on human corneal cells demonstrated by immunoperoxidase staining. American Journal of Ophthalmology, 91, 46–50.

    Article  CAS  PubMed  Google Scholar 

  94. Treseler, P. A., Foulks, G. N., & Sanfilippo, F. (1984). The expression of HLA antigens by cells in the human cornea. American Journal of Ophthalmology, 98, 763–772.

    Article  CAS  PubMed  Google Scholar 

  95. Clinch, T. E., Goins, K. M., & Cobo, L. M. (1992). Treatment of contact lens-related ocular surface disorders with autologous conjunctival transplantation. Ophthalmology, 99, 634–638.

    Article  CAS  PubMed  Google Scholar 

  96. Pellegrini, G., et al. (1997). Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet, 349, 990–993.

    Article  CAS  PubMed  Google Scholar 

  97. Ouyang, H., et al. (2014). WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis. Nature, 511, 358–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Pellegrini, G., et al. (1999). Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface. The Journal of Cell Biology, 145, 769–782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Miri, A., Al-Deiri, B., & Dua, H. S. (2010). Long-term outcomes of autolimbal and allolimbal transplants. Ophthalmology, 117, 1207–1213.

    Article  PubMed  Google Scholar 

  100. Okita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448, 313–317.

    Article  CAS  PubMed  Google Scholar 

  101. Takahashi, K., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–872.

    Article  CAS  PubMed  Google Scholar 

  102. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663–676.

    Article  CAS  PubMed  Google Scholar 

  103. Hayashi, R., et al. (2012). Generation of corneal epithelial cells from induced pluripotent stem cells derived from human dermal fibroblast and corneal limbal epithelium. PLoS One, 7, e45435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kheirkhah, A., Raju, V. K., & Tseng, S. C. (2008). Minimal conjunctival limbal autograft for total limbal stem cell deficiency. Cornea, 27, 730–733.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Sangwan, V. S., Basu, S., MacNeil, S., & Balasubramanian, D. (2012). Simple limbal epithelial transplantation (SLET): A novel surgical technique for the treatment of unilateral limbal stem cell deficiency. The British Journal of Ophthalmology, 96, 931–934.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada

    Brian G. Ballios & Allan R. Slomovic

  2. Toronto General Hospital, University Health Network, Toronto, ON, Canada

    Allan R. Slomovic

  3. Department of Ophthalmology, Toronto Western Hospital, Toronto, ON, Canada

    Allan R. Slomovic

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  1. Brian G. Ballios
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Correspondence to Allan R. Slomovic .

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Editors and Affiliations

  1. Department Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada

    Brian G. Ballios

  2. Schepens Eye Research Institute, Harvard Medical School, Boston, MA, USA

    Michael J. Young

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Ballios, B.G., Slomovic, A.R. (2018). Clinical Applications of Limbal Stem Cells for Regenerative Medicine. In: Ballios, B., Young, M. (eds) Regenerative Medicine and Stem Cell Therapy for the Eye. Fundamental Biomedical Technologies. Springer, Cham. https://doi.org/10.1007/978-3-319-98080-5_7

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