Corneal Stem Cells: A Source of Cell Renewal with Therapeutic Potential

  • Ana J. Chucair-ElliottEmail author
  • Michael H. Elliott
  • Alex Cohen
  • Daniel J. J. Carr
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


The eye needs a healthy, transparent cornea to perform normal visual function. Stem cells residing at the limbus of the adult eye, named limbal stem cells (LSCs), are responsible for maintenance and repair of the corneal surface, thus contributing to tissue health. In the case of deficiency of LSCs a blinding disorder named stem cell deficiency (LSCD) occurs, characterized by cornea opacity, vascularization, and inflammation. Understanding corneal stem cells is critical for the development of cell-based therapies directed to treat the diseased cornea. The focus of this chapter is to provide a summarized overview of the current knowledge on corneal stem cells, including their location, phenotypic and functional characteristics, causes and consequences of the depletion of the corneal stem cell niche, as well as therapeutic options and ongoing studies dedicated to improve the success of cell-based therapies in the treatment of cornea surface disease.


Cornea Limbal stem cells Limbal stem cell deficiency Mesenchymal stem cells 



Corneal stromal stem cells


Limbal stem cell deficiency


Limbal stem cells


Macrophage inflammatory protein-1




Mesenchymal stem cells


Steven-Johnson syndrome


Tumor necrosis factor α


Factor (TNF)-α-stimulated gene/protein 6




Umbilical MSCs


Vascular endothelial growth factor



This work was supported by a grant from the Oklahoma Center for Adult Stem Cell Research through the Oklahoma Tobacco Settlement Endowment Trust.


  1. 1.
    Agorogiannis GI, Alexaki VI, Castana O, Kymionis GD. Topical application of autologous adipose-derived mesenchymal stem cells (MSCs) for persistent sterile corneal epithelial defect. Graefes Arch Clin Exp Ophthalmol. 2012;250:455–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Amano S, Yamagami S, Mimura T, Uchida S, Yokoo S. Corneal stromal and endothelial cell precursors. Cornea. 2006;25:S73–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Blazejewska EA, Schlotzer-Schrehardt U, Zenkel M, Bachmann B, Chankiewitz E, Jacobi C, Kruse FE. Corneal limbal microenvironment can induce transdifferentiation of hair follicle stem cells into corneal epithelial-like cells. Stem Cells. 2009;27:642–52.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Branch MJ, Hashmani K, Dhillon P, Jones DR, Dua HS, Hopkinson A. Mesenchymal stem cells in the human corneal limbal stroma. Invest Ophthalmol Vis Sci. 2012;53:5109–16.PubMedCrossRefGoogle Scholar
  5. 5.
    Budak MT, Alpdogan OS, Zhou M, Lavker RM, Akinci MA, Wolosin JM. Ocular surface epithelia contain ABCG2-dependent side population cells exhibiting features associated with stem cells. J Cell Sci. 2005;118:1715–24.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Chee KY, Kicic A, Wiffen SJ. Limbal stem cells: the search for a marker. Clin Experiment Ophthalmol. 2006;34:64–73.PubMedCrossRefGoogle Scholar
  7. 7.
    Chen SY, Hayashida Y, Chen MY, Xie HT, Tseng SC. A new isolation method of human limbal progenitor cells by maintaining close association with their niche cells. Tissue Eng Part C Methods. 2011;17:537–48.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Chen WY, Mui MM, Kao WW, Liu CY, Tseng SC. Conjunctival epithelial cells do not transdifferentiate in organotypic cultures: expression of K12 keratin is restricted to corneal epithelium. Curr Eye Res. 1994;13:765–78.PubMedCrossRefGoogle Scholar
  9. 9.
    Chen Z, de Paiva CS, Luo L, Kretzer FL, Pflugfelder SC, Li DQ. Characterization of putative stem cell phenotype in human limbal epithelia. Stem Cells. 2004;22:355–66.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Clausen H, Vedtofte P, Moe D, Dabelsteen E, Sun TT, Dale B. Differentiation-dependent expression of keratins in human oral epithelia. J Invest Dermatol. 1986;86:249–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Collinson JM, Chanas SA, Hill RE, West JD. Corneal development, limbal stem cell function, and corneal epithelial cell migration in the Pax6(+/-) mouse. Invest Ophthalmol Vis Sci. 2004;45:1101–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker RM. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell. 1989;57:201–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990;61:1329–37.PubMedCrossRefGoogle Scholar
  14. 14.
    Coulson-Thomas VJ, Caterson B, Kao WW. Transplantation of human umbilical mesenchymal stem cells cures the corneal defects of mucopolysaccharidosis VII mice. Stem Cells. 2013;31:2116–26.PubMedCrossRefGoogle Scholar
  15. 15.
    da Silva ML, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119:2204–13.CrossRefGoogle Scholar
  16. 16.
    Daniels JT, Dart JK, Tuft SJ, Khaw PT. Corneal stem cells in review. Wound Repair Regen. 2001;9:483–94.PubMedCrossRefGoogle Scholar
  17. 17.
    Davanger M, Evensen A. Role of the pericorneal papillary structure in renewal of corneal epithelium. Nature. 1971;229:560–1.PubMedCrossRefGoogle Scholar
  18. 18.
    Davies SB, Di GN. Corneal stem cells and their origins: significance in developmental biology. Stem Cells Dev. 2010;19:1651–62.PubMedCrossRefGoogle Scholar
  19. 19.
    Di GN, Bosch M, Zamora K, Coroneo MT, Wakefield D, Watson SL. A contact lens-based technique for expansion and transplantation of autologous epithelial progenitors for ocular surface reconstruction. Transplantation. 2009;87:1571–8.CrossRefGoogle Scholar
  20. 20.
    Di GN, Sarris M, Chui J, Cheema H, Coroneo MT, Wakefield D. Localization of the low-affinity nerve growth factor receptor p75 in human limbal epithelial cells. J Cell Mol Med. 2008;12:2799–811.CrossRefGoogle Scholar
  21. 21.
    Di IE, Barbaro V, Ruzza A, Ponzin D, Pellegrini G, De LM. Isoforms of DeltaNp63 and the migration of ocular limbal cells in human corneal regeneration. Proc Natl Acad Sci U S A. 2005;102:9523–8.CrossRefGoogle Scholar
  22. 22.
    Dominici M, Le BK, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Du Y, Funderburgh ML, Mann MM, SundarRaj N, Funderburgh JL. Multipotent stem cells in human corneal stroma. Stem Cells. 2005;23:1266–75.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol. 2000;44:415–25.PubMedCrossRefGoogle Scholar
  25. 25.
    Funderburgh ML, Du Y, Mann MM, SundarRaj N, Funderburgh JL. PAX6 expression identifies progenitor cells for corneal keratocytes. FASEB J. 2005;19:1371–3.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Garfias Y, Nieves-Hernandez J, Garcia-Mejia M, Estrada-Reyes C, Jimenez-Martinez MC. Stem cells isolated from the human stromal limbus possess immunosuppressant properties. Mol Vis. 2012;18:2087–95.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Geerling G, Maclennan S, Hartwig D. Autologous serum eye drops for ocular surface disorders. Br J Ophthalmol. 2004;88:1467–74.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Gipson IK. The epithelial basement membrane zone of the limbus. Eye (Lond). 1989;3(Pt 2):132–40.CrossRefGoogle Scholar
  29. 29.
    Goldberg MF, Bron AJ. Limbal palisades of Vogt. Trans Am Ophthalmol Soc. 1982;80:155–71.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Haddad A. Renewal of the rabbit corneal epithelium as investigated by autoradiography after intravitreal injection of 3H-thymidine. Cornea. 2000;19:378–83.PubMedCrossRefGoogle Scholar
  31. 31.
    Hashmani K, Branch MJ, Sidney LE, Dhillon PS, Verma M, McIntosh OD, Hopkinson A, Dua HS. Characterization of corneal stromal stem cells with the potential for epithelial transdifferentiation. Stem Cell Res Ther. 2013;4:75.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Hsueh YJ, Kuo PC, Chen JK. Transcriptional regulators of the DeltaNp63: their role in limbal epithelial cell proliferation. J Cell Physiol. 2013;228:536–46.PubMedCrossRefGoogle Scholar
  33. 33.
    Jiang TS, Cai L, Ji WY, Hui YN, Wang YS, Hu D, Zhu J. Reconstruction of the corneal epithelium with induced marrow mesenchymal stem cells in rats. Mol Vis. 2010;16:1304–16.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Jordan T, Hanson I, Zaletayev D, Hodgson S, Prosser J, Seawright A, Hastie N, van Heyningen V. The human PAX6 gene is mutated in two patients with aniridia. Nat Genet. 1992;1:328–32.PubMedCrossRefGoogle Scholar
  35. 35.
    Joseph A, Hossain P, Jham S, Jones RE, Tighe P, McIntosh RS, Dua HS. Expression of CD34 and L-selectin on human corneal keratocytes. Invest Ophthalmol Vis Sci. 2003;44:4689–92.PubMedCrossRefGoogle Scholar
  36. 36.
    Kasper M. 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. 1992;93:319–32.PubMedCrossRefGoogle Scholar
  37. 37.
    Kawasaki S, Tanioka H, Yamasaki K, Connon CJ, Kinoshita S. Expression and tissue distribution of p63 isoforms in human ocular surface epithelia. Exp Eye Res. 2006;82:293–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders. Ophthalmology. 1989;96:709–22.PubMedCrossRefGoogle Scholar
  39. 39.
    Kolli S, Ahmad S, Lako M, Figueiredo F. Successful clinical implementation of corneal epithelial stem cell therapy for treatment of unilateral limbal stem cell deficiency. Stem Cells. 2010;28:597–610.PubMedGoogle Scholar
  40. 40.
    Kulkarni BB, Tighe PJ, Mohammed I, Yeung AM, Powe DG, Hopkinson A, Shanmuganathan VA, Dua HS. Comparative transcriptional profiling of the limbal epithelial crypt demonstrates its putative stem cell niche characteristics. BMC Genomics. 2010;11:526.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Kurpakus MA, Maniaci MT, Esco M. Expression of keratins K12, K4 and K14 during development of ocular surface epithelium. Curr Eye Res. 1994;13:805–14.PubMedCrossRefGoogle Scholar
  42. 42.
    Lan Y, Kodati S, Lee HS, Omoto M, Jin Y, Chauhan SK. Kinetics and function of mesenchymal stem cells in corneal injury. Invest Ophthalmol Vis Sci. 2012;53:3638–44.PubMedCrossRefGoogle Scholar
  43. 43.
    Lavker RM, Sun TT. Epidermal stem cells: properties, markers, and location. Proc Natl Acad Sci U S A. 2000;97:13473–5.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Lawrenson JG, Ruskell GL. The structure of corpuscular nerve endings in the limbal conjunctiva of the human eye. J Anat. 1991;177:75–84.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Le BK, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579–86.CrossRefGoogle Scholar
  46. 46.
    Le BK, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439–41.CrossRefGoogle Scholar
  47. 47.
    Li W, Hayashida Y, Chen YT, Tseng SC. Niche regulation of corneal epithelial stem cells at the limbus. Cell Res. 2007;17:26–36.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Lichtinger A, Pe’er J, Frucht-Pery J, Solomon A. Limbal stem cell deficiency after topical mitomycin C therapy for primary acquired melanosis with atypia. Ophthalmology. 2010;117:431–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Liu H, Zhang J, Liu CY, Wang IJ, Sieber M, Chang J, Jester JV, Kao WW. Cell therapy of congenital corneal diseases with umbilical mesenchymal stem cells: lumican null mice. PLoS One. 2010;5:e10707.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Ma Y, Xu Y, Xiao Z, Yang W, Zhang C, Song E, Du Y, Li L. Reconstruction of chemically burned rat corneal surface by bone marrow-derived human mesenchymal stem cells. Stem Cells. 2006;24:315–21.PubMedCrossRefGoogle Scholar
  51. 51.
    Majo F, Rochat A, Nicolas M, Jaoude GA, Barrandon Y. Oligopotent stem cells are distributed throughout the mammalian ocular surface. Nature. 2008;456:250–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001;119:1050–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Matic M, Petrov IN, Chen S, Wang C, Dimitrijevich SD, Wolosin JM. Stem cells of the corneal epithelium lack connexins and metabolite transfer capacity. Differentiation. 1997;61:251–60.PubMedCrossRefGoogle Scholar
  54. 54.
    Nakamura T, Inatomi T, Sotozono C, Amemiya T, Kanamura N, Kinoshita S. Transplantation of cultivated autologous oral mucosal epithelial cells in patients with severe ocular surface disorders. Br J Ophthalmol. 2004;88:1280–4.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Nishida K, Yamato M, Hayashida Y, Watanabe K, Yamamoto K, Adachi E, Nagai S, Kikuchi A, Maeda N, Watanabe H, Okano T, Tano Y. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med. 2004;351:1187–96.PubMedCrossRefGoogle Scholar
  56. 56.
    Notara M, Shortt AJ, Galatowicz G, Calder V, Daniels JT. IL6 and the human limbal stem cell niche: a mediator of epithelial-stromal interaction. Stem Cell Res. 2010;5:188–200.PubMedCrossRefGoogle Scholar
  57. 57.
    Oh JY, Kim MK, Shin MS, Lee HJ, Ko JH, Wee WR, Lee JH. The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. Stem Cells. 2008;26:1047–55.PubMedCrossRefGoogle Scholar
  58. 58.
    Oh JY, Roddy GW, Choi H, Lee RH, Ylostalo JH, Rosa Jr RH, Prockop DJ. Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury. Proc Natl Acad Sci U S A. 2010;107:16875–80.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Oh W, Kim DS, Yang YS, Lee JK. Immunological properties of umbilical cord blood-derived mesenchymal stromal cells. Cell Immunol. 2008;251:116–23.PubMedCrossRefGoogle Scholar
  60. 60.
    Ordonez P, Chow S, Wakefield D, Di GN. Human limbal epithelial progenitor cells express alphavbeta5-integrin and the interferon-inducible chemokine CXCL10/IP-10. Stem Cell Res. 2013;11:888–901.PubMedCrossRefGoogle Scholar
  61. 61.
    Osei-Bempong C, Figueiredo FC, Lako M. The limbal epithelium of the eye—a review of limbal stem cell biology, disease and treatment. Bioessays. 2013;35:211–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Pellegrini G, De LM, Arsenijevic Y. Towards therapeutic application of ocular stem cells. Semin Cell Dev Biol. 2007;18:805–18.PubMedCrossRefGoogle Scholar
  63. 63.
    Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, Bondanza S, Ponzin D, McKeon F, De LM. p63 identifies keratinocyte stem cells. Proc Natl Acad Sci U S A. 2001;98:3156–61.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Pellegrini G, Rama P, Di RA, Panaras A, De LM. Hurdles in a successful example of limbal stem cell-based regenerative medicine. Stem Cells. 2013;32:26–34.CrossRefGoogle Scholar
  65. 65.
    Pinnamaneni N, Funderburgh JL. Concise review: stem cells in the corneal stroma. Stem Cells. 2012;30:1059–63.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Polisetty N, Fatima A, Madhira SL, Sangwan VS, Vemuganti GK. Mesenchymal cells from limbal stroma of human eye. Mol Vis. 2008;14:431–42.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Poon AC, Geerling G, Dart JK, Fraenkel GE, Daniels JT. Autologous serum eyedrops for dry eyes and epithelial defects: clinical and in vitro toxicity studies. Br J Ophthalmol. 2001;85:1188–97.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Roddy GW, Oh JY, Lee RH, Bartosh TJ, Ylostalo J, Coble K, Rosa Jr RH, Prockop DJ. Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-alpha stimulated gene/protein 6. Stem Cells. 2011;29:1572–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Santos MS, Gomes JA, Hofling-Lima AL, Rizzo LV, Romano AC, Belfort Jr R. Survival analysis of conjunctival limbal grafts and amniotic membrane transplantation in eyes with total limbal stem cell deficiency. Am J Ophthalmol. 2005;140:223–30.PubMedGoogle Scholar
  71. 71.
    Schermer A, Galvin S, Sun TT. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells. J Cell Biol. 1986;103:49–62.PubMedCrossRefGoogle Scholar
  72. 72.
    Schlotzer-Schrehardt U, Kruse FE. Identification and characterization of limbal stem cells. Exp Eye Res. 2005;81:247–64.PubMedCrossRefGoogle Scholar
  73. 73.
    Schofield R. The stem cell system. Biomed Pharmacother. 1983;37:375–80.PubMedGoogle Scholar
  74. 74.
    Shortt AJ, Secker GA, Notara MD, Limb GA, Khaw PT, Tuft SJ, Daniels JT. Transplantation of ex vivo cultured limbal epithelial stem cells: a review of techniques and clinical results. Surv Ophthalmol. 2007;52:483–502.PubMedCrossRefGoogle Scholar
  75. 75.
    Shortt AJ, Tuft SJ, Daniels JT. Corneal stem cells in the eye clinic. Br Med Bull. 2011;100:209–25.PubMedCrossRefGoogle Scholar
  76. 76.
    Sosnova M, Bradl M, Forrester JV. CD34+ corneal stromal cells are bone marrow-derived and express hemopoietic stem cell markers. Stem Cells. 2005;23:507–15.PubMedCrossRefGoogle Scholar
  77. 77.
    Stepp MA, Zhu L, Sheppard D, Cranfill RL. Localized distribution of alpha 9 integrin in the cornea and changes in expression during corneal epithelial cell differentiation. J Histochem Cytochem. 1995;43:353–62.PubMedCrossRefGoogle Scholar
  78. 78.
    Su WR, Zhang QZ, Shi SH, Nguyen AL, Le AD. Human gingiva-derived mesenchymal stromal cells attenuate contact hypersensitivity via prostaglandin E2-dependent mechanisms. Stem Cells. 2011;29:1849–60.PubMedCrossRefGoogle Scholar
  79. 79.
    Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S, Xu T, Le A, Shi S. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells. 2009;27:1421–32.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Toti P, Tosi GM, Traversi C, Schurfeld K, Cardone C, Caporossi A. CD-34 stromal expression pattern in normal and altered human corneas. Ophthalmology. 2002;109:1167–71.PubMedCrossRefGoogle Scholar
  81. 81.
    Tsai RJ, Li LM, Chen JK. Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells. N Engl J Med. 2000;343:86–93.PubMedCrossRefGoogle Scholar
  82. 82.
    Uchida S, Yokoo S, Yanagi Y, Usui T, Yokota C, Mimura T, Araie M, Yamagami S, Amano S. Sphere formation and expression of neural proteins by human corneal stromal cells in vitro. Invest Ophthalmol Vis Sci. 2005;46:1620–5.PubMedCrossRefGoogle Scholar
  83. 83.
    Van Buskirk EM. The anatomy of the limbus. Eye (Lond). 1989;3(Pt 2):101–8.CrossRefGoogle Scholar
  84. 84.
    Watanabe K, Nishida K, Yamato M, Umemoto T, Sumide T, Yamamoto K, Maeda N, Watanabe H, Okano T, Tano Y. Human limbal epithelium contains side population cells expressing the ATP-binding cassette transporter ABCG2. FEBS Lett. 2004;565:6–10.PubMedCrossRefGoogle Scholar
  85. 85.
    Watt FM, Hogan BL. Out of Eden: stem cells and their niches. Science. 2000;287:1427–30.PubMedCrossRefGoogle Scholar
  86. 86.
    Wolosin JM. Cell markers and the side population phenotype in ocular surface epithelial stem cell characterization and isolation. Ocul Surf. 2006;4:10–23.PubMedCrossRefGoogle Scholar
  87. 87.
    Xie HT, Chen SY, Li GG, Tseng SC. Limbal epithelial stem/progenitor cells attract stromal niche cells by SDF-1/CXCR4 signaling to prevent differentiation. Stem Cells. 2011;29:1874–85.PubMedCrossRefGoogle Scholar
  88. 88.
    Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V, Andrews NC, Caput D, McKeon F. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998;2:305–16.PubMedCrossRefGoogle Scholar
  89. 89.
    Yao L, Li ZR, Su WR, Li YP, Lin ML, Zhang WX, Liu Y, Wan Q, Liang D. Role of mesenchymal stem cells on cornea wound healing induced by acute alkali burn. PLoS One. 2012;7:e30842.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Ye J, Yao K, Kim JC. Mesenchymal stem cell transplantation in a rabbit corneal alkali burn model: engraftment and involvement in wound healing. Eye (Lond). 2006;20:482–90.CrossRefGoogle Scholar
  91. 91.
    Yoshida S, Shimmura S, Nagoshi N, Fukuda K, Matsuzaki Y, Okano H, Tsubota K. Isolation of multipotent neural crest-derived stem cells from the adult mouse cornea. Stem Cells. 2006;24:2714–22.PubMedCrossRefGoogle Scholar
  92. 92.
    Yoshida S, Shimmura S, Shimazaki J, Shinozaki N, Tsubota K. Serum-free spheroid culture of mouse corneal keratocytes. Invest Ophthalmol Vis Sci. 2005;46:1653–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Young AL, Cheng AC, Ng HK, Cheng LL, Leung GY, Lam DS. The use of autologous serum tears in persistent corneal epithelial defects. Eye (Lond). 2004;18:609–14.CrossRefGoogle Scholar
  94. 94.
    Zannettino AC, Paton S, Arthur A, Khor F, Itescu S, Gimble JM, Gronthos S. Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. J Cell Physiol. 2008;214:413–21.PubMedCrossRefGoogle Scholar
  95. 95.
    Zhang Q, Shi S, Liu Y, Uyanne J, Shi Y, Shi S, Le AD. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J Immunol. 2009;183:7787–98.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP. 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. 2001;7:1028–34.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ana J. Chucair-Elliott
    • 1
    Email author
  • Michael H. Elliott
    • 1
  • Alex Cohen
    • 1
  • Daniel J. J. Carr
    • 2
  1. 1.Department of OphthalmologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Departments of Ophthalmology and Microbiology and ImmunologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

Personalised recommendations