Stemness or not stemness? Current status and perspectives of adult retinal stem cells

Current Stem Cell Research and Therapy

Volumn 4, Issue 2, 2009, Pages 118-130

  Locker, Morgane ^a   Borday, Caroline ^a   Perron, Muriel ^a  

^a UNIVERSITÉ PARIS SACLAY   (France)

Author keywords

Canonical Wnt signaling; Hedgehog signaling; M ller glial cells; Neural stem cells; Notch Delta pathway; Regeneration; Retina; Retinal pigment epithelium

Indexed keywords

CELL MARKER; GROWTH FACTOR; NOTCH RECEPTOR; SONIC HEDGEHOG PROTEIN; WNT PROTEIN; BIOLOGICAL MARKER; SIGNAL PEPTIDE;

ADULT STEM CELL; CELL PROLIFERATION; CELL REGENERATION; CELL RENEWAL; CILIARY BODY; EMBRYONIC STEM CELL; EXTRACELLULAR MATRIX; FINGER DERMATOGLYPHICS; HUMAN; IRIS; MUELLER CELL; NERVE CELL; NONHUMAN; PIGMENT EPITHELIUM; PRIORITY JOURNAL; RETINA; RETINA CELL; RETINOBLASTOMA; REVIEW; SIGNAL TRANSDUCTION; STEM CELL; VERTEBRATE; ANIMAL; CELL DIFFERENTIATION; CYTOLOGY; METABOLISM; PATHOLOGY; PHYSIOLOGY; REGENERATION; RETINA DISEASE;

ADULT STEM CELLS; ANIMALS; BIOLOGICAL MARKERS; CELL DIFFERENTIATION; CELL PROLIFERATION; EXTRACELLULAR MATRIX; HEDGEHOG PROTEINS; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; NEURONS; RECEPTORS, NOTCH; REGENERATION; RETINA; RETINAL DISEASES; RETINOBLASTOMA; SIGNAL TRANSDUCTION; STEM CELLS; WNT PROTEINS;

EID: 66949137812     PISSN: 1574888X     EISSN: None     Source Type: Journal    
DOI: 10.2174/157488809788167382     Document Type: Review

References (178)

1. Johns PR. Growth of the adult goldfish eye. III. Source of the new retinal cells. J Comp Neurol 1977; 176: 343-57.
2. Beach DH, Jacobson M. Patterns of cell proliferation in the retina of the clawed frog during development. J Comp Neurol 1979; 183: 603-13.
3. Hollyfield JG. Differential addition of cells to the retina in Rana pipiens tadpoles. Dev Biol 1968; 18: 163-79.
4. Straznicky K, Gaze RM. The growth of the retina in Xenopus laevis: an autoradiographic study. J Embryol Exp Morphol 1971; 26: 67-79.
5. Reh TA, Nagy T. Characterization of Rana germinal neuroepithelial cells in normal and regenerating retina. Neurosci Res Suppl 1989; 10: S151-61.
6. Wetts R, Serbedzija GN, Fraser SE. Cell lineage analysis reveals multipotent precursors in the ciliary margin of the frog retina. Dev Biol 1989; 136: 254-63.
7. Wetts R, Fraser SE. Multipotent precursors can give rise to all major cell types of the frog retina. Science 1988; 239: 1142-5.
8. Hitchcock PF, Raymond PA. The teleost retina as a model for developmental and regeneration biology. Zebrafish 2004; 1: 257-71.
9. Hitchcock P, Ochocinska M, Sieh A, Otteson D. Persistent and injury-induced neurogenesis in the vertebrate retina. Prog Retin Eye Res 2004; 23: 183-94.
10. Amato MA, Arnault E, Perron M. Retinal stem cells in vertebrates: parallels and divergences. Int J Dev Biol 2004; 48: 993-1001.
11. Stenkamp DL. Neurogenesis in the fish retina. Int Rev Cytol 2007; 259: 173-224.
12. Moshiri A, Close J, Reh TA. Retinal stem cells and regeneration. Int J Dev Biol 2004; 48: 1003-14.
13. Fischer AJ, Reh TA. Identification of a proliferating marginal zone of retinal progenitors in postnatal chickens. Dev Biol 2000; 220: 197-210.
14. Kubota R, Hokoc JN, Moshiri A, McGuire C, Reh TA. A comparative study of neurogenesis in the retinal ciliary marginal zone of homeothermic vertebrates. Brain Res Dev Brain Res 2002; 134: 31-41.
15. Ahmad I, Tang L, Pham H. Identification of neural progenitors in the adult mammalian eye. Biochem Biophys Res Commun 2000; 270: 517-21.
16. Tropepe V, Coles BL, Chiasson BJ, et al. Retinal stem cells in the adult mammalian eye. Science 2000; 287: 2032-6.
17. Chow RL, Lang RA. Early eye development in vertebrates. Annu Rev Cell Dev Biol 2001; 17: 255-96.
18. Coles BL, Angenieux B, Inoue T, et al. Facile isolation and the characterization of human retinal stem cells. Proc Natl Acad Sci USA 2004; 101: 15772-7.
19. Haruta M, Kosaka M, Kanegae Y, et al. Induction of photoreceptor-specific phenotypes in adult mammalian iris tissue. Nat Neurosci 2001; 4: 1163-4.
20. Akagi T, Mandai M, Ooto S, et al. Otx2 homeobox gene induces photoreceptor-specific phenotypes in cells derived from adult iris and ciliary tissue. Invest Ophthalmol Vis Sci 2004; 45: 4570-5.
21. Sun G, Asami M, Ohta H, Kosaka J, Kosaka M. Retinal stem/progenitor properties of iris pigment epithelial cells. Dev Biol 2006; 289: 243-52.
22. Asami M, Sun G, Yamaguchi M, Kosaka M. Multipotent cells from mammalian iris pigment epithelium. Dev Biol 2007; 304: 433-46.
23. MacNeil A, Pearson RA, MacLaren RE, Smith AJ, Sowden JC, Ali RR. Comparative analysis of progenitor cells isolated from the iris, pars plana, and ciliary body of the adult porcine eye. Stem Cells 2007; 25: 2430-8.
24. Bonfanti L, Peretto P. Radial glial origin of the adult neural stem cells in the subventricular zone. Prog Neurobiol 2007; 83: 24-36.
25. Das AV, Mallya KB, Zhao X, et al. Neural stem cell properties of Muller glia in the mammalian retina: regulation by Notch and Wnt signaling. Dev Biol 2006; 299: 283-302.
26. Fausett BV, Goldman D. A role for alpha1 tubulin-expressing Muller glia in regeneration of the injured zebrafish retina. J Neurosci 2006; 26: 6303-13.
27. Bernardos RL, Barthel LK, Meyers JR, Raymond PA. Late-stage neuronal progenitors in the retina are radial Muller glia that function as retinal stem cells. J Neurosci 2007; 27: 7028-40.
28. Monnin J, Morand-Villeneuve N, Michel G, Hicks D, Versaux-Botteri C. Production of neurospheres from mammalian Muller cells in culture. Neurosci Lett 2007; 421: 22-6.
29. Seaberg RM, van der Kooy D. Stem and progenitor cells: the premature desertion of rigorous definitions. Trends Neurosci 2003; 26: 125-31.
30. Reynolds BA, Rietze RL. Neural stem cells and neurospheres: reevaluating the relationship. Nat Methods 2005; 2: 333-6.
31. Sohur US, Emsley JG, Mitchell BD, Macklis JD. Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1477-97.
32. Dorsky RI, Rapaport DH, Harris WA. Xotch inhibits cell differentiation in the Xenopus retina. Neuron 1995; 14: 487-96.
33. Perron M, Kanekar S, Vetter ML, Harris WA. The genetic sequence of retinal development in the ciliary margin of the Xenopus eye. Dev Biol 1998; 199: 185-200.
34. Casarosa S, Leone P, Cannata S, et al. Genetic analysis of metamorphic and premetamorphic Xenopus ciliary marginal zone. Dev Dyn 2005; 233: 646-51.
35. Henningfeld KA, Locker M, Perron M. Xenopus Primary Neurogenesis and Retinogenesis. Funct Deve Embryol 2007; 1: 26-36.
36. Raymond PA, Barthel LK, Bernardos RL, Perkowski JJ. Molecular characterization of retinal stem cells and their niches in adult zebrafish. BMC Dev Biol 2006; 6: 36.
37. Zuber ME, Perron M, Philpott A, Bang A, Harris WA. Giant eyes in Xenopus laevis by overexpression of XOptx2. Cell 1999; 98: 341-52.
38. Viczian AS, Bang AG, Harris WA, Zuber ME. Expression of Xenopus laevis Lhx2 during eye development and evidence for divergent expression among vertebrates. Dev Dyn 2006; 235: 1133-41.
39. Reh TA, Fischer AJ. Retinal stem cells. Methods Enzymol 2006; 419: 52-73.
40. Amato MA, Boy S, Arnault E, et al. Comparison of the expression patterns of five neural RNA binding proteins in the Xenopus retina. J Comp Neurol 2005; 481: 331-9.
41. Wilson JM, Sato K, Chernoff EA, Belecky-Adams TL. Expression patterns of chick Musashi-1 in the developing nervous system. Gene Expr Patterns 2007; 7: 817-25.
42. Yamaguchi M, Tonou-Fujimori N, Komori A, et al. Histone deacetylase 1 regulates retinal neurogenesis in zebrafish by suppressing Wnt and Notch signaling pathways. Development 2005; 132: 3027-43.
43. Liu H, Thurig S, Mohamed O, Dufort D, Wallace VA. Mapping canonical Wnt signaling in the developing and adult retina. Invest Ophthalmol Vis Sci 2006; 47: 5088-97.
44. Denayer T, Locker M, Borday C, et al. Canonical Wnt signaling controls proliferation of retinal stem/progenitor cells in postembryonic Xenopus eyes. Stem Cells 2008; 26: 2063-74.
45. Kubo F, Takeichi M, Nakagawa S. Wnt2b controls retinal cell differentiation at the ciliary marginal zone. Development 2003; 130: 587-98.
46. Perron M, Boy S, Amato MA, et al. A novel function for Hedgehog signalling in retinal pigment epithelium differentiation. Development 2003; 130: 1565-77.
47. Moshiri A, McGuire CR, Reh TA. Sonic hedgehog regulates proliferation of the retinal ciliary marginal zone in posthatch chicks. Dev Dyn 2005; 233: 66-75.
48. Wehman AM, Staub W, Meyers JR, Raymond PA, Baier H. Genetic dissection of the zebrafish retinal stem-cell compartment. Dev Biol 2005; 281: 53-65.
49. Lord-Grignon J, Abdouh M, Bernier G. Identification of genes expressed in retinal progenitor/stem cell colonies isolated from the ocular ciliary body of adult mice. Gene Expr Patterns 2006; 6: 992-9.
50. Das AV, James J, Rahnenfuhrer J, et al. Retinal properties and potential of the adult mammalian ciliary epithelium stem cells. Vision Res 2005; 45: 1653-66.
51. Xu S, Sunderland ME, Coles BL, et al. The proliferation and expansion of retinal stem cells require functional Pax6. Dev Biol 2007; 304: 713-21.
52. Fischer AJ, Omar G. Transitin, a nestin-related intermediate filament, is expressed by neural progenitors and can be induced in Muller glia in the chicken retina. J Comp Neurol 2005; 484: 1-14.
53. Ghai K, Stanke JJ, Fischer AJ. Patterning of the circumferential marginal zone of progenitors in the chicken retina. Brain Res 2008; 1192: 76-89.
54. Xu H, Sta Iglesia DD, Kielczewski JL, et al. Characteristics of progenitor cells derived from adult ciliary body in mouse, rat, and human eyes. Invest Ophthalmol Vis Sci 2007; 48: 1674-82.
55. Yurco P, Cameron DA. Responses of Muller glia to retinal injury in adult zebrafish. Vision Res 2005; 45: 991-1002.
56. Fimbel SM, Montgomery JE, Burket CT, Hyde DR. Regeneration of inner retinal neurons after intravitreal injection of ouabain in zebrafish. J Neurosci 2007; 27: 1712-24.
57. Fischer AJ, McGuire CR, Dierks BD, Reh TA. Insulin and fibroblast growth factor 2 activate a neurogenic program in Muller glia of the chicken retina. J Neurosci 2002; 22: 9387-98.
58. Fischer AJ, Reh TA. Potential of Muller glia to become neurogenic retinal progenitor cells. Glia 2003; 43: 70-6.
59. Ooto S, Akagi T, Kageyama R, et al. Potential for neural regeneration after neurotoxic injury in the adult mammalian retina. Proc Natl Acad Sci USA 2004; 101: 13654-9.
60. Lawrence JM, Singhal S, Bhatia B, et al. MIO-M1 cells and similar muller glial cell lines derived from adult human retina exhibit neural stem cell characteristics. Stem Cells 2007; 25: 2033-43.
61. Blackshaw S, Harpavat S, Trimarchi J, et al. Genomic analysis of mouse retinal development. PLoS Biol 2004; 2: E247.
62. Rizzolo LJ, Chen X, Weitzman M, Sun R, Zhang H. Analysis of the RPE transcriptome reveals dynamic changes during the development of the outer blood-retinal barrier. Mol Vis 2007; 13: 1259-73.
63. Yu J, Farjo R, MacNee SP, Baehr W, Stambolian DE, Swaroop A. Annotation and analysis of 10,000 expressed sequence tags from developing mouse eye and adult retina. Genome Biol 2003; 4: R65.
64. Chowers I, Gunatilaka TL, Farkas RH, et al. Identification of novel genes preferentially expressed in the retina using a custom human retina cDNA microarray. Invest Ophthalmol Vis Sci 2003; 44: 3732-41.
65. Livesey FJ, Young TL, Cepko CL. An analysis of the gene expression program of mammalian neural progenitor cells. Proc Natl Acad Sci USA 2004; 101: 1374-9.
66. Trimarchi JM, Stadler MB, Roska B, et al. Molecular heterogeneity of developing retinal ganglion and amacrine cells revealed through single cell gene expression profiling. J Comp Neurol 2007; 502: 1047-65.
67. Dyer MA, Bremner R. The search for the retinoblastoma cell of origin. Nat Rev Cancer 2005; 5: 91-101.
68. Vermeulen L, Sprick MR, Kemper K, Stassi G, Medema JP. Cancer stem cells - old concepts, new insights. Cell Death Differ 2008; 15(6): 947-58.
69. Seigel GM, Hackam AS, Ganguly A, Mandell LM, Gonzalez-Fernandez F. Human embryonic and neuronal stem cell markers in retinoblastoma. Mol Vis 2007; 13: 823-32.
70. Ajioka I, Martins RA, Bayazitov IT, et al. Differentiated horizontal interneurons clonally expand to form metastatic retinoblastoma in mice. Cell 2007; 131: 378-90.
71. Capela A, Temple S. LeX is expressed by principle progenitor cells in the embryonic nervous system, is secreted into their environment and binds Wnt-1. Dev Biol 2006; 291: 300-13.
72. Koso H, Ouchi Y, Tabata Y, et al. SSEA-1 marks regionally restricted immature subpopulations of embryonic retinal progenitor cells that are regulated by the Wnt signaling pathway. Dev Biol 2006; 292: 265-76.
73. Morris SA, Almeida AD, Tanaka H, Ohta K, Ohnuma S. Tsukushi Modulates Xnr2, FGF and BMP Signaling: Regulation of Xenopus Germ Layer Formation. PLoS ONE 2007; 2: e1004.
74. Ohta K, Ito A, Tanaka H. Neuronal stem/progenitor cells in the vertebrate eye. Dev Growth Differ 2008; 50: 253-9.
75. Burmeister M, Novak J, Liang MY, et al. Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nat Genet 1996; 12: 376-84.
76. Levine EM, Green ES. Cell-intrinsic regulators of proliferation in vertebrate retinal progenitors. Semin Cell Dev Biol 2004; 15: 63-74.
77. Coles BL, Horsford DJ, McInnes RR, van der Kooy D. Loss of retinal progenitor cells leads to an increase in the retinal stem cell population in vivo. Eur J Neurosci 2006; 23: 75-82.
78. Dhomen NS, Balaggan KS, Pearson RA, et al. Absence of chx10 causes neural progenitors to persist in the adult retina. Invest Ophthalmol Vis Sci 2006; 47: 386-96.
79. Martins RA, Pearson RA. Control of cell proliferation by neurotransmitters in the developing vertebrate retina. Brain Res 2008; 1192: 37-60.
80. Fischer AJ, Omar G, Walton NA, Verrill TA, Unson CG. Glucagon-expressing neurons within the retina regulate the proliferation of neural progenitors in the circumferential marginal zone of the avian eye. J Neurosci 2005; 25: 10157-66.
81. De Lucchini S, Ori M, Cremisi F, Nardini M, Nardi I. 5-HT2Bmediated serotonin signaling is required for eye morphogenesis in Xenopus. Mol Cell Neurosci 2005; 29: 299-312.
82. De Lucchini S, Ori M, Nardini M, Marracci S, Nardi I. Expression of 5-HT2B and 5-HT2C receptor genes is associated with proliferative regions of Xenopus developing brain and eye. Brain Res Mol Brain Res 2003; 115: 196-201.
83. Alvaro AR, Martins J, Araujo IM, Rosmaninho-Salgado J, Ambrosio AF, Cavadas C. Neuropeptide Y stimulates retinal neural cell proliferation - involvement of nitric oxide. J Neurochem 2008; [Epub ahead of print].
84. Takeda M, Takamiya A, Jiao JW, et al. alpha-Aminoadipate induces progenitor cell properties of Muller glia in adult mice. Invest Ophthalmol Vis Sci 2008; 49: 1142-50.
85. Boucher SE, Hitchcock PF. Insulin-related growth factors stimulate proliferation of retinal progenitors in the goldfish. J Comp Neurol 1998; 394: 386-94.
86. Fischer AJ, Dierks BD, Reh TA. Exogenous growth factors induce the production of ganglion cells at the retinal margin. Development 2002; 129: 2283-91.
87. Fischer AJ, Reh TA. Growth factors induce neurogenesis in the ciliary body. Dev Biol 2003; 259: 225-40.
88. Abdouh M, Bernier G. In vivo reactivation of a quiescent cell population located in the ocular ciliary body of adult mammals. Exp Eye Res 2006; 83: 153-64.
89. Close JL, Liu J, Gumuscu B, Reh TA. Epidermal growth factor receptor expression regulates proliferation in the postnatal rat retina. Glia 2006; 54: 94-104.
90. Close JL, Gumuscu B, Reh TA. Retinal neurons regulate proliferation of postnatal progenitors and Muller glia in the rat retina via TGF beta signaling. Development 2005; 132: 3015-26.
91. Locker M, Agathocleous M, Amato MA, Parain K, Harris WA, Perron M. Hedgehog signaling and the retina: insights into the mechanisms controlling the proliferative properties of neural precursors. Genes Dev 2006; 20: 3036-48.
92. Agathocleous M, Locker M, Harris WA, Perron M. A general role of hedgehog in the regulation of proliferation. Cell Cycle 2007; 6: 156-9.
93. Moshiri A, Reh TA. Persistent progenitors at the retinal margin of ptc+/- mice. J Neurosci 2004; 24: 229-37.
94. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004; 20: 781-810.
95. Kubo F, Nakagawa S. Wnt signaling in retinal stem cells and regeneration. Dev Growth Differ 2008; 50: 245-51.
96. Inoue T, Kagawa T, Fukushima M, et al. Activation of canonical Wnt pathway promotes proliferation of retinal stem cells derived from adult mouse ciliary margin. Stem Cells 2006; 24: 95-104.
97. Van Raay TJ, Moore KB, Iordanova I, et al. Frizzled 5 signaling governs the neural potential of progenitors in the developing Xenopus retina. Neuron 2005; 46: 23-36.
98. Perron M, Harris WA. Determination of vertebrate retinal progenitor cell fate by the Notch pathway and basic helix-loop-helix transcription factors. Cell Mol Life Sci 2000; 57: 215-23.
99. Cepko CL. The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates. Curr Opin Neurobiol 1999; 9: 37-46.
100. Livesey FJ, Cepko CL. Vertebrate neural cell-fate determination: lessons from the retina. Nat Rev Neurosci 2001; 2: 109-18.
101. Jadhav AP, Cho SH, Cepko CL. Notch activity permits retinal cells to progress through multiple progenitor states and acquire a stem cell property. Proc Natl Acad Sci USA 2006; 103: 18998-9003.
102. Alexson TO, Hitoshi S, Coles BL, Bernstein A, van der Kooy D. Notch signaling is required to maintain all neural stem cell populations irrespective of spatial or temporal niche. Dev Neurosci 2006; 28: 34-48.
103. Bunting KD. ABC transporters as phenotypic markers and functional regulators of stem cells. Stem Cells 2002; 20: 11-20.
104. Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996; 183: 1797-806.
105. Kim M, Turnquist H, Jackson J, et al. The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res 2002; 8: 22-8.
106. Scharenberg CW, Harkey MA, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood 2002; 99: 507-12.
107. Zhou S, Morris JJ, Barnes Y, Lan L, Schuetz JD, Sorrentino BP. Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo. Proc Natl Acad Sci USA 2002; 99: 12339-44.
108. Bhattacharya S, Das A, Mallya K, Ahmad I. Maintenance of retinal stem cells by Abcg2 is regulated by notch signaling. J Cell Sci 2007; 120: 2652-62.
109. Limb GA, Daniels JT. Ocular regeneration by stem cells: present status and future prospects. Br Med Bull 2008; 85: 47-61.
110. Wallace VA. Stem cells: a source for neuron repair in retinal disease. Can J Ophthalmol 2007; 42: 442-6.
111. Pellegrini G, De Luca M, Arsenijevic Y. Towards therapeutic application of ocular stem cells. Semin Cell Dev Biol 2007; 18: 805-18.
112. MaClaren RE, Pearson RA. Stem cell therapy and the retina. Eye 2007; 21: 1352-9.
113. Vugler A, Lawrence J, Walsh J, et al. Embryonic stem cells and retinal repair. Mech Dev 2007; 124: 807-29.
114. Tsonis PA, Del Rio-Tsonis K. Lens and retina regeneration: transdifferentiation, stem cells and clinical applications. Exp Eye Res 2004; 78: 161-72.
115. Araki M. Regeneration of the amphibian retina: role of tissue interaction and related signaling molecules on RPE transdifferentiation. Dev Growth Differ 2007; 49: 109-20.
116. Chiba C, Mitashov VI. Cellular and molecular events in the adult newt retinal regeneration. In: Chiba C, Ed, Strategies for Retinal Tissue Repair and Regeneration in Vertebrates: From Fish to Human. Research Signpost publisher 2007; 15-34.
117. Yoshii C, Ueda Y, Okamoto M, Araki M. Neural retinal regeneration in the anuran amphibian Xenopus laevis post-metamorphosis: transdifferentiation of retinal pigmented epithelium regenerates the neural retina. Dev Biol 2007; 303: 45-56.
118. Otteson DC, Hitchcock PF. Stem cells in the teleost retina: persistent neurogenesis and injury-induced regeneration. Vision Res 2003; 43: 927-36.
119. Fischer AJ. Neural regeneration in the chick retina. Prog Retin Eye Res 2005; 24: 161-82.
120. Coulombre JL, Coulombre AJ. Regeneration of neural retina from the pigmented epithelium in the chick embryo. Dev Biol 1965; 12: 79-92.
121. Park CM, Hollenberg MJ. Growth factor-induced retinal regeneration in vivo. Int Rev Cytol 1993; 146: 49-74.
122. Sakaguchi DS, Janick LM, Reh TA. Basic fibroblast growth factor (FGF-2) induced transdifferentiation of retinal pigment epithelium: generation of retinal neurons and glia. Dev Dyn 1997; 209: 387-98.
123. Pittack C, Jones M, Reh TA. Basic fibroblast growth factor induces retinal pigment epithelium to generate neural retina in vitro. Development 1991; 113: 577-88.
124. Guillemot F, Cepko CL. Retinal fate and ganglion cell differentiation are potentiated by acidic FGF in an in vitro assay of early retinal development. Development 1992; 114: 743-54.
125. Pittack C, Grunwald GB, Reh TA. Fibroblast growth factors are necessary for neural retina but not pigmented epithelium differentiation in chick embryos. Development 1997; 124: 805-16.
126. Zhao S, Thornquist SC, Barnstable CJ. In vitro transdifferentiation of embryonic rat retinal pigment epithelium to neural retina. Brain Res 1995; 677: 300-10.
127. Galy A, Neron B, Planque N, Saule S, Eychene A. Activated MAPK/ERK kinase (MEK-1) induces transdifferentiation of pigmented epithelium into neural retina. Dev Biol 2002; 248: 251-64.
128. Spence JR, Madhavan M, Aycinena JC, Del Rio-Tsonis K. Retina regeneration in the chick embryo is not induced by spontaneous Mitf downregulation but requires FGF/FGFR/MEK/Erk dependent upregulation of Pax6. Mol Vis 2007; 13: 57-65.
129. Azuma N, Tadokoro K, Asaka A, et al. Transdifferentiation of the retinal pigment epithelia to the neural retina by transfer of the Pax6 transcriptional factor. Hum Mol Genet 2005; 14: 1059-68.
130. Fuhrmann S, Levine EM, Reh TA. Extraocular mesenchyme patterns the optic vesicle during early eye development in the embryonic chick. Development 2000; 127: 4599-609.
131. Sakami S, Etter P, Reh TA. Activin signaling limits the competence for retinal regeneration from the pigmented epithelium. Mech Dev 2008; 125: 106-16.
132. Zhang XM, Yang XJ. Temporal and spatial effects of Sonic hedgehog signaling in chick eye morphogenesis. Dev Biol 2001; 233: 271-90.
133. Spence JR, Madhavan M, Ewing JD, Jones DK, Lehman BM, Del Rio-Tsonis K. The hedgehog pathway is a modulator of retina regeneration. Development 2004; 131: 4607-21.
134. Spence JR, Aycinena JC, Del Rio-Tsonis K. Fibroblast growth factor-hedgehog interdependence during retina regeneration. Dev Dyn 2007; 236: 1161-74.
135. Haynes T, Gutierrez C, Aycinena JC, Tsonis PA, Del Rio-Tsonis K. BMP signaling mediates stem/progenitor cell-induced retina regeneration. Proc Natl Acad Sci USA 2007; 104: 20380-5.
136. Nickerson PE, Emsley JG, Myers T, Clarke DB. Proliferation and expression of progenitor and mature retinal phenotypes in the adult mammalian ciliary body after retinal ganglion cell injury. Invest Ophthalmol Vis Sci 2007; 48: 5266-75.
137. Fischer AJ, Reh TA. Muller glia are a potential source of neural regeneration in the postnatal chicken retina. Nat Neurosci 2001; 4: 247-52.
138. Wan J, Zheng H, Chen ZL, Xiao HL, Shen ZJ, Zhou GM. Preferential regeneration of photoreceptor from Muller glia after retinal degeneration in adult rat. Vision Res 2008; 48: 223-34.
139. Osakada F, Ooto S, Akagi T, Mandai M, Akaike A, Takahashi M. Wnt signaling promotes regeneration in the retina of adult mammals. J Neurosci 2007; 27: 4210-9.
140. Karl MO, Hayes S, Nelson BR, Tan K, Buckingham B, Reh TA. Stimulation of neural regeneration in the mouse retina. Proc Natl Acad Sci USA 2008; 105(49): 19508-13.
141. Yi H, Nakamura RE, Mohamed O, Dufort D, Hackam AS. Characterization of Wnt signaling during photoreceptor degeneration. Invest Ophthalmol Vis Sci 2007; 48: 5733-41.
142. Cameron DA, Gentile KL, Middleton FA, Yurco P. Gene expression profiles of intact and regenerating zebrafish retina. Mol Vis 2005; 11: 775-91.
143. Yurco P, Cameron DA. Cellular correlates of proneural and Notchdelta gene expression in the regenerating zebrafish retina. Vis Neurosci 2007; 24: 437-43.
144. Hayes S, Nelson BR, Buckingham B, Reh TA. Notch signaling regulates regeneration in the avian retina. Dev Biol 2007; 312: 300-11.
145. Wan J, Zheng H, Xiao HL, She ZJ, Zhou GM. Sonic hedgehog promotes stem-cell potential of Muller glia in the mammalian retina. Biochem Biophys Res Commun 2007; 363: 347-54.
146. Guo Y, Saloupis P, Shaw SJ, Rickman DW. Engraftment of adult neural progenitor cells transplanted to rat retina injured by transient ischemia. Invest Ophthalmol Vis Sci 2003; 44: 3194-201.
147. Nishida A, Takahashi M, Tanihara H, et al. Incorporation and differentiation of hippocampus-derived neural stem cells transplanted in injured adult rat retina. Invest Ophthalmol Vis Sci 2000; 41: 4268-74.
148. Young MJ, Ray J, Whiteley SJ, Klassen H, Gage FH. Neuronal differentiation and morphological integration of hippocampal progenitor cells transplanted to the retina of immature and mature dystrophic rats. Mol Cell Neurosci 2000; 16: 197-205.
149. Klassen H, Sakaguchi DS, Young MJ. Stem cells and retinal repair. Prog Retin Eye Res 2004; 23: 149-81.
150. Chacko DM, Das AV, Zhao X, James J, Bhattacharya S, Ahmad I. Transplantation of ocular stem cells: the role of injury in incorporation and differentiation of grafted cells in the retina. Vision Res 2003; 43: 937-46.
151. MacLaren RE, Pearson RA, MacNeil A, et al. Retinal repair by transplantation of photoreceptor precursors. Nature 2006; 444: 203-7.
152. Furukawa T, Morrow EM, Cepko CL. Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell 1997; 91: 531-41.
153. Nishida A, Furukawa A, Koike C, et al. Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development. Nat Neurosci 2003; 6: 1255-63.
154. Akagi T, Akita J, Haruta M, et al. Iris-derived cells from adult rodents and primates adopt photoreceptor-specific phenotypes. Invest Ophthalmol Vis Sci 2005; 46: 3411-9.
155. Akagi T. Photoreceptors derived from adult iris tissue: prospects for retinal transplantation. Semin Ophthalmol 2005; 20: 11-5.
156. Jomary C, Jones SE. Induction of functional photoreceptor phenotype by exogenous Crx expression in mouse retinal stem cells. Invest Ophthalmol Vis Sci 2008; 49: 429-37.
157. Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 2008; 132: 661-80.
158. Deb KD, Sarda K. Human embryonic stem cells: preclinical perspectives. J Transl Med 2008; 6: 7.
159. Takahashi K, Okita K, Nakagawa M, Yamanaka S. Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc 2007; 2: 3081-9.
160. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318: 1917-20.
161. Zhao X, Liu J, Ahmad I. Differentiation of embryonic stem cells into retinal neurons. Biochem Biophys Res Commun 2002; 297: 177-84.
162. Ikeda H, Osakada F, Watanabe K, et al. Generation of Rx+/Pax6+ neural retinal precursors from embryonic stem cells. Proc Natl Acad Sci USA 2005; 102: 11331-6.
163. Sugie Y, Yoshikawa M, Ouji Y, et al. Photoreceptor cells from mouse ES cells by co-culture with chick embryonic retina. Biochem Biophys Res Commun 2005; 332: 241-7.
164. Lamba DA, Karl MO, Ware CB, Reh TA. Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci USA 2006; 103: 12769-74.
165. Osakada F, Ikeda H, Mandai M, et al. Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nat Biotechnol 2008; 26: 215-24.
166. Klassen H, Reubinoff B. Stem cells in a new light. Nat Biotechnol 2008; 26: 187-8.
167. Banin E, Obolensky A, Idelson M, et al. Retinal incorporation and differentiation of neural precursors derived from human embryonic stem cells. Stem Cells 2006; 24: 246-57.
168. Meyer JS, Katz ML, Maruniak JA, Kirk MD. Embryonic stem cellderived neural progenitors incorporate into degenerating retina and enhance survival of host photoreceptors. Stem Cells 2006; 24: 274-83.
169. Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U. Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci 2004; 45: 4251-5.
170. Otani A, Dorrell MI, Kinder K, et al. Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineagenegative hematopoietic stem cells. J Clin Invest 2004; 114: 765-74.
171. Kicic A, Shen WY, Wilson AS, Constable IJ, Robertson T, Rakoczy PE. Differentiation of marrow stromal cells into photoreceptors in the rat eye. J Neurosci 2003; 23: 7742-9.
172. Zhang J, Shan Q, Ma P, et al. Differentiation potential of bone marrow mesenchymal stem cells into retina in normal and laserinjured rat eye. Sci China C Life Sci 2004; 47: 241-50.
173. Tomita M, Adachi Y, Yamada H, et al. Bone marrow-derived stem cells can differentiate into retinal cells in injured rat retina. Stem Cells 2002; 20: 279-83.
174. Weiss ML, Troyer DL. Stem cells in the umbilical cord. Stem Cell Rev 2006; 2: 155-62.
175. Weiss ML, Medicetty S, Bledsoe AR, et al. Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease. Stem Cells 2006; 24: 781-92.
176. Lund RD, Wang S, Lu B, et al. Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells 2007; 25: 602-11.
177. Tang HL, Zhu JH. Epigenetics and neural stem cell commitment. Neurosci Bull 2007; 23: 241-8.
178. Li X, Zhao X. Epigenetic regulation of mammalian stem cells. Stem Cells Dev 2008; (In press).