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Stem Cell-Based Therapeutic Applications in Retinal Degenerative Diseases

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Abstract

Retinal degenerative diseases that target photoreceptors or the adjacent retinal pigment epithelium (RPE) affect millions of people worldwide. Retinal degeneration (RD) is found in many different forms of retinal diseases including retinitis pigmentosa (RP), age-related macular degeneration (AMD), diabetic retinopathy, cataracts, and glaucoma. Effective treatment for retinal degeneration has been widely investigated. Gene-replacement therapy has been shown to improve visual function in inherited retinal disease. However, this treatment was less effective with advanced disease. Stem cell-based therapy is being pursued as a potential alternative approach in the treatment of retinal degenerative diseases. In this review, we will focus on stem cell-based therapies in the pipeline and summarize progress in treatment of retinal degenerative disease.

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Abbreviations

ABCR:

ATP-binding cassette retina

AMD:

Age-related macular degeneration

BMC:

Bone marrow cells

CNV:

Choroidal neovascularization

ESC:

Embryonic stem cells

FL:

flt3 ligand

G-CSF:

Granulocyte colony stimulating factor

IPE:

Iris pigment epithelium

iPS:

Induced pluripotent stem cells

LCA:

Leber congenital amaurosis

MSC:

Mesenchymal stem cells

RD:

Retinal degeneration

RP:

Retinitis pigmentosa

RPC:

Retinal progenitor cells

RPE:

Retinal pigment epithelium

SC:

Stem cells

VSEL:

Very small embryonic-like stem cells

References

  1. MacLaren, R. E., Pearson, R. A., MacNeil, A., et al. (2006). Retinal repair by transplantation of photoreceptor precursors. Nature, 444(7116), 203–207.

    Article  PubMed  CAS  Google Scholar 

  2. Lamba, D. A., Gust, J., & Reh, T. A. (2009). Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell, 4(1), 73–79.

    Article  PubMed  CAS  Google Scholar 

  3. Lamba, D. A., Karl, M. O., Ware, C. B., et al. (2006). Efficient generation of retinal progenitor cells from human embryonic stem cells. Proceedings of the National Academy of Science USA, 103(34), 12769–12774.

    Article  CAS  Google Scholar 

  4. Meyer, J. S., Shearer, R. L., Capowski, E. E., et al. (2009). Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proceedings of the National Academy of Science USA, 106(39), 16698–16703.

    Article  CAS  Google Scholar 

  5. Yu, J., Vodyanik, M. A., Smuga-Otto, K., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917–1920.

    Article  PubMed  CAS  Google Scholar 

  6. Kicic, A., Shen, W. Y., Wilson, A. S., et al. (2003). Differentiation of marrow stromal cells into photoreceptors in the rat eye. Journal of Neuroscience, 23(21), 7742–7749.

    PubMed  CAS  Google Scholar 

  7. Liu, Y., Gao, L., Zuba-Surma, E. K., et al. (2009). Identification of small Sca-1(+), Lin(-), CD45(-) multipotential cells in the neonatal murine retina. Experimental Hematology, 37(9), 1096–107–1107.

    Article  CAS  Google Scholar 

  8. Gehrs, K. M., Anderson, D. H., Johnson, L. V., et al. (2006). Age-related macular degeneration–emerging pathogenetic and therapeutic concepts. Annals of Medicine, 38(7), 450–471.

    Article  PubMed  Google Scholar 

  9. Boughman, J. A., Conneally, P. M., & Nance, W. E. (1980). Population genetic studies of retinitis pigmentosa. American Journal of Human Genetics, 32(2), 223–235.

    PubMed  CAS  Google Scholar 

  10. Berson, E. L. (1993). Retinitis pigmentosa. The Friedenwald Lecture. Investigative Ophthalmology and Visual Science, 34(5), 1659–1676.

    PubMed  CAS  Google Scholar 

  11. Gaillard, F., & Sauve, Y. (2007). Cell-based therapy for retina degeneration: the promise of a cure. Vision Research, 47(22), 2815–2824.

    Article  PubMed  Google Scholar 

  12. Bressler, N. M., Bressler, S. B., & Fine, S. L. (1988). Age-related macular degeneration. Survey of Ophthalmology, 32(6), 375–413.

    Article  PubMed  CAS  Google Scholar 

  13. Mitchell, P., Korobelnik, J. F., Lanzetta, P., et al. (2009). Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. British Journal of Ophthalmology, 94(1), 2–13.

    Article  PubMed  Google Scholar 

  14. Shintani, K., Shechtman, D. L., & Gurwood, A. S. (2009). Review and update: current treatment trends for patients with retinitis pigmentosa. Optometry, 80(7), 384–401.

    PubMed  Google Scholar 

  15. Hamel, C. (2006). Retinitis pigmentosa. Orphanet Journal of Rare Diseases, 1, 40.

    Article  PubMed  Google Scholar 

  16. Westerfeld, C., & Mukai, S. (2008). Stargardt’s disease and the ABCR gene. Seminars in Ophthalmology, 23(1), 59–65.

    Article  PubMed  Google Scholar 

  17. Dharmaraj, S. R., Silva, E. R., Pina, A. L., et al. (2000). Mutational analysis and clinical correlation in Leber congenital amaurosis. Ophthalmic Genetics, 21(3), 135–150.

    PubMed  CAS  Google Scholar 

  18. Brownstein, Z., Ben-Yosef, T., Dagan, O., et al. (2004). The R245X mutation of PCDH15 in Ashkenazi Jewish children diagnosed with nonsyndromic hearing loss foreshadows retinitis pigmentosa. Pediatric Research, 55(6), 995–1000.

    Article  PubMed  CAS  Google Scholar 

  19. Reh, T. A. (2006). Neurobiology: right timing for retina repair. Nature, 444(7116), 156–157.

    Article  PubMed  CAS  Google Scholar 

  20. Anchan, R. M., Reh, T. A., Angello, J., et al. (1991). EGF and TGF-alpha stimulate retinal neuroepithelial cell proliferation in vitro. Neuron, 6(6), 923–936.

    Article  PubMed  CAS  Google Scholar 

  21. Reh, T. A., & Levine, E. M. (1998). Multipotential stem cells and progenitors in the vertebrate retina. Journal of Neurobiology, 36(2), 206–220.

    Article  PubMed  CAS  Google Scholar 

  22. Tropepe, V., Coles, B. L., Chiasson, B. J., et al. (2000). Retinal stem cells in the adult mammalian eye. Science, 287(5460), 2032–2036.

    Article  PubMed  CAS  Google Scholar 

  23. Qiu, G., Seiler, M. J., Mui, C., et al. (2005). Photoreceptor differentiation and integration of retinal progenitor cells transplanted into transgenic rats. Experimental Eye Research, 80(4), 515–525.

    Article  PubMed  CAS  Google Scholar 

  24. Coles, B. L., Angenieux, B., Inoue, T., et al. (2004). Facile isolation and the characterization of human retinal stem cells. Proceedings of the National Academy of Science USA, 101(44), 15772–15777.

    Article  CAS  Google Scholar 

  25. Klassen, H. J., Ng, T. F., Kurimoto, Y., et al. (2004). Multipotent retinal progenitors express developmental markers, differentiate into retinal neurons, and preserve light-mediated behavior. Investigative Ophthalmology and Visual Science, 45(11), 4167–4173.

    Article  PubMed  Google Scholar 

  26. Chacko, D. M., Rogers, J. A., Turner, J. E., et al. (2000). Survival and differentiation of cultured retinal progenitors transplanted in the subretinal space of the rat. Biochemical and Biophysical Research Communications, 268(3), 842–846.

    Article  PubMed  CAS  Google Scholar 

  27. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.

    Article  PubMed  CAS  Google Scholar 

  28. Reubinoff, B. E., Pera, M. F., Fong, C. Y., et al. (2000). Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nature Biotechnology, 18(4), 399–404.

    Article  PubMed  CAS  Google Scholar 

  29. Cowan, C. A., Klimanskaya, I., McMahon, J., et al. (2004). Derivation of embryonic stem-cell lines from human blastocysts. New England Journal of Medicine, 350(13), 1353–1356.

    Article  PubMed  CAS  Google Scholar 

  30. Reubinoff, B. E., Itsykson, P., Turetsky, T., et al. (2001). Neural progenitors from human embryonic stem cells. Nature Biotechnology, 19(12), 1134–1140.

    Article  PubMed  CAS  Google Scholar 

  31. Schuldiner, M., Eiges, R., Eden, A., et al. (2001). Induced neuronal differentiation of human embryonic stem cells. Brain Research, 913(2), 201–205.

    Article  PubMed  CAS  Google Scholar 

  32. Zhang, S. C., Wernig, M., Duncan, I. D., et al. (2001). In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nature Biotechnology, 19(12), 1129–1133.

    Article  PubMed  CAS  Google Scholar 

  33. Martinat, C., Bacci, J. J., Leete, T., et al. (2006). Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proceedings of the National Academy of Science USA, 103(8), 2874–2879.

    Article  CAS  Google Scholar 

  34. Yan, Y., Yang, D., Zarnowska, E. D., et al. (2005). Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells, 23(6), 781–790.

    Article  PubMed  CAS  Google Scholar 

  35. Laflamme, M. A., Chen, K. Y., Naumova, A. V., et al. (2007). Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nature Biotechnology, 25(9), 1015–1024.

    Article  PubMed  CAS  Google Scholar 

  36. Yang, L., Soonpaa, M. H., Adler, E. D., et al. (2008). Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature, 453(7194), 524–528.

    Article  PubMed  CAS  Google Scholar 

  37. Shirahashi, H., Wu, J., Yamamoto, N., et al. (2004). Differentiation of human and mouse embryonic stem cells along a hepatocyte lineage. Cell Transplantation, 13(3), 197–211.

    Article  PubMed  Google Scholar 

  38. Samadikuchaksaraei, A., Cohen, S., Isaac, K., et al. (2006). Derivation of distal airway epithelium from human embryonic stem cells. Tissue Engineering, 12(4), 867–875.

    Article  PubMed  CAS  Google Scholar 

  39. Soria, B., Roche, E., Berna, G., et al. (2000). Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes, 49(2), 157–162.

    Article  PubMed  CAS  Google Scholar 

  40. Assady, S., Maor, G., Amit, M., et al. (2001). Insulin production by human embryonic stem cells. Diabetes, 50(8), 1691–1697.

    Article  PubMed  CAS  Google Scholar 

  41. Zhao, X., Liu, J., & Ahmad, I. (2002). Differentiation of embryonic stem cells into retinal neurons. Biochemical and Biophysical Research Comunications, 297(2), 177–184.

    Article  CAS  Google Scholar 

  42. Zhao, X., Liu, J., & Ahmad, I. (2006). Differentiation of embryonic stem cells to retinal cells in vitro. Methods in Molecular Biology, 330, 401–416.

    PubMed  CAS  Google Scholar 

  43. Ikeda, H., Osakada, F., Watanabe, K., et al. (2005). Generation of Rx+/Pax6+ neural retinal precursors from embryonic stem cells. Proceedings of the National Academy of Science USA, 102(32), 11331–11336.

    Article  CAS  Google Scholar 

  44. Vugler, A., Carr, A. J., Lawrence, J., et al. (2008). Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation. Experimental Neurology, 214(2), 347–361.

    Article  PubMed  CAS  Google Scholar 

  45. Klimanskaya, I., Hipp, J., Rezai, K. A., et al. (2004). Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics. Cloning and Stem Cells, 6(3), 217–245.

    PubMed  CAS  Google Scholar 

  46. Osakada, F., Ikeda, H., Mandai, M., et al. (2008). Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nature Biotechnology, 26(2), 215–224.

    Article  PubMed  CAS  Google Scholar 

  47. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.

    Article  PubMed  CAS  Google Scholar 

  48. Takahashi, K., Tanabe, K., Ohnuki, M., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872.

    Article  PubMed  CAS  Google Scholar 

  49. Nakagawa, M., Koyanagi, M., Tanabe, K., et al. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology, 26(1), 101–106.

    Article  PubMed  CAS  Google Scholar 

  50. Wernig, M., Meissner, A., Foreman, R., et al. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature, 448(7151), 318–324.

    Article  PubMed  CAS  Google Scholar 

  51. Kyba, M., Perlingeiro, R. C., & Daley, G. Q. (2002). HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell, 109(1), 29–37.

    Article  PubMed  CAS  Google Scholar 

  52. Hanna, J., Wernig, M., Markoulaki, S., et al. (2007). Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science, 318(5858), 1920–1923.

    Article  PubMed  CAS  Google Scholar 

  53. Dimos, J. T., Rodolfa, K. T., Niakan, K. K., et al. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 321(5893), 1218–1221.

    Article  PubMed  CAS  Google Scholar 

  54. Wernig, M., Zhao, J. P., Pruszak, J., et al. (2008). Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proceedings of the National Academy of Science USA, 105(15), 5856–5861.

    Article  CAS  Google Scholar 

  55. Puzio-Kuter, A. M., & Levine, A. J. (2009). Stem cell biology meets p53. Nature Biotechnology, 27(10), 914–915.

    Article  PubMed  CAS  Google Scholar 

  56. Friedenstein, A. J., Gorskaja, J. F., & Kulagina, N. N. (1976). Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Experimental Hematology, 4(5), 267–274.

    PubMed  CAS  Google Scholar 

  57. Campagnoli, C., Roberts, I. A., Kumar, S., et al. (2001). Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood, 98(8), 2396–2402.

    Article  PubMed  CAS  Google Scholar 

  58. In 't Anker, P. S., Scherjon, S. A., Kleijburg-van der Keur, C., et al. (2004). Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells, 22(7), 1338–1345.

    Article  PubMed  Google Scholar 

  59. Lee, O. K., Kuo, T. K., Chen, W. M., et al. (2004). Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood, 103(5), 1669–1675.

    Article  PubMed  CAS  Google Scholar 

  60. Bianco, P., & Robey, P. G. (2001). Stem cells in tissue engineering. Nature, 414(6859), 118–121.

    Article  PubMed  CAS  Google Scholar 

  61. Bianco, P., Riminucci, M., Gronthos, S., et al. (2001). Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells, 19(3), 180–192.

    Article  PubMed  CAS  Google Scholar 

  62. Abdallah, B. M., & Kassem, M. (2008). Human mesenchymal stem cells: from basic biology to clinical applications. Gene Therapy, 15(2), 109–116.

    Article  PubMed  CAS  Google Scholar 

  63. Makino, S., Fukuda, K., Miyoshi, S., et al. (1999). Cardiomyocytes can be generated from marrow stromal cells in vitro. Journal of Clinical Investigation, 103(5), 697–705.

    Article  PubMed  CAS  Google Scholar 

  64. Xu, W., Zhang, X., Qian, H., et al. (2004). Mesenchymal stem cells from adult human bone marrow differentiate into a cardiomyocyte phenotype in vitro. Experimental Biology and Medicine (Maywood), 229(7), 623–631.

    CAS  Google Scholar 

  65. Nagaya, N., Kangawa, K., Itoh, T., et al. (2005). Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation, 112(8), 1128–1135.

    Article  PubMed  Google Scholar 

  66. Chen, S. L., Fang, W. W., Ye, F., et al. (2004). Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. American Journal of Cardiology, 94(1), 92–95.

    Article  PubMed  Google Scholar 

  67. Jiang, Y., Jahagirdar, B. N., Reinhardt, R. L., et al. (2002). Pluripotency of mesenchymal stem cells derived from adult marrow. Nature, 418(6893), 41–49.

    Article  PubMed  CAS  Google Scholar 

  68. Chopp, M., Zhang, X. H., Li, Y., et al. (2000). Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation. NeuroReport, 11(13), 3001–3005.

    Article  PubMed  CAS  Google Scholar 

  69. Chen, J., Li, Y., Wang, L., et al. (2001). Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke, 32(4), 1005–1011.

    Article  PubMed  CAS  Google Scholar 

  70. Karnieli, O., Izhar-Prato, Y., Bulvik, S., et al. (2007). Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation. Stem Cells, 25(11), 2837–2844.

    Article  PubMed  CAS  Google Scholar 

  71. Inoue, Y., Iriyama, A., Ueno, S., et al. (2007). Subretinal transplantation of bone marrow mesenchymal stem cells delays retinal degeneration in the RCS rat model of retinal degeneration. Experimental Eye Research, 85(2), 234–241.

    Article  PubMed  CAS  Google Scholar 

  72. Kucia, M., Reca, R., Campbell, F. R., et al. (2006). A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4(+) stem cells identified in adult bone marrow. Leukemia, 20, 857–869.

    Article  PubMed  CAS  Google Scholar 

  73. Zuba-Surma, E. K., Kucia, M., Dawn, B., et al. (2008). Bone marrow-derived pluripotent very small embryonic-like stem cells (VSELs) are mobilized after acute myocardial infarction. Journal of Molecular and Cellular Cardiology, 44(5), 865–873.

    Article  PubMed  CAS  Google Scholar 

  74. Wojakowski, W., Tendera, M., Kucia, M., et al. (2009). Mobilization of bone marrow-derived Oct-4+ SSEA-4+ very small embryonic-like stem cells in patients with actue myocardial infarction. Journal of the American College of Cardiology, 53, 1–9.

    Article  PubMed  CAS  Google Scholar 

  75. Paczkowska, E., Kucia, M., Koziarska, D., et al. (2009). Clinical evidence that very small embryonic-like stem cells are mobilized into peripheral blood in patients after stroke. Stroke, 40(4), 1237–1244.

    Article  PubMed  CAS  Google Scholar 

  76. Kucia, M. J., Wysoczynski, M., Wu, W., et al. (2008). Evidence that very small embryonic-like stem cells are mobilized into peripheral blood. Stem Cells, 26(8), 2083–2092.

    Article  PubMed  CAS  Google Scholar 

  77. Huang, Y., Kucia, M., Hussain, L. R., et al. (2010). Bone marrow transplantation temporarily improves pancreatic function in streptozotocin-induced diabetes: Potential involvement of very small embryonic-like cells. Transplantation, 89, 677–685.

    Google Scholar 

  78. Li, Y., Atmaca-Sonmez, P., Schanie, C. L., et al. (2007). Endogenous Bone marrow derived cells express retinal pigment epithelium cell markers and migrate to focal areas of RPE damage. Investigative Ophthalmology and Visual Science, 48(9), 4321–4327.

    Article  PubMed  Google Scholar 

  79. Lavail, M. M., Li, L., Turner, J. E., et al. (1992). Retinal pigment epithelial cell transplantation in RCS rats: normal metabolism in rescued photoreceptors. Experimental Eye Research, 55(4), 555–562.

    Article  PubMed  CAS  Google Scholar 

  80. Chaum, E. (2003). Retinal neuroprotection by growth factors: a mechanistic perspective. Journal of Cellular Biochemistry, 88(1), 57–75.

    Article  PubMed  CAS  Google Scholar 

  81. Wahlin, K. J., Campochiaro, P. A., Zack, D. J., et al. (2000). Neurotrophic factors cause activation of intracellular signaling pathways in Muller cells and other cells of the inner retina, but not photoreceptors. Investigative Ophthalmology and Visual Science, 41(3), 927–936.

    PubMed  CAS  Google Scholar 

  82. Parysek, L. M., del Cerro, M., & Olmsted, J. B. (1985). Microtubule-associated protein 4 antibody: a new marker for astroglia and oligodendroglia. Neuroscience, 15(3), 869–875.

    Article  PubMed  CAS  Google Scholar 

  83. Gouras, P., Flood, M. T., Kjedbye, H., et al. (1985). Transplantation of cultured human retinal epithelium to Bruch's membrane of the owl monkey's eye. Current Eye Research, 4(3), 253–265.

    Article  PubMed  CAS  Google Scholar 

  84. Binder, S., Krebs, I., Hilgers, R. D., et al. (2004). Outcome of transplantation of autologous retinal pigment epithelium in age-related macular degeneration: a prospective trial. Investigative Ophthalmology and Visual Science, 45(11), 4151–4160.

    Article  PubMed  Google Scholar 

  85. Weisz, J. M., Humayun, M. S., de Juan, E. J., et al. (1999). Allogenic fetal retinal pigment epithelial cell transplant in a patient with geographic atrophy. Retina, 19(6), 540–545.

    Article  PubMed  CAS  Google Scholar 

  86. MacLaren, R. E., Uppal, G. S., Balaggan, K. S., et al. (2007). Autologous transplantation of the retinal pigment epithelium and choroid in the treatment of neovascular age-related macular degeneration. Ophthalmology, 114(3), 561–570.

    Article  PubMed  Google Scholar 

  87. van Meurs, J. C., ter Averst, E., Hofland, L. J., et al. (2004). Autologous peripheral retinal pigment epithelium translocation in patients with subfoveal neovascular membranes. British Journal of Ophthalmology, 88(1), 110–113.

    Article  PubMed  Google Scholar 

  88. Rezai, K. A., Lappas, A., Farrokh-Siar, L., et al. (1997). Iris pigment epithelial cells of long evans rats demonstrate phagocytic activity. Experimental Eye Research, 65(1), 23–29.

    Article  PubMed  CAS  Google Scholar 

  89. Perrault, I., Rozet, J. M., Gerber, S., et al. (1999). Leber congenital amaurosis. Molecular Genetics and Metabolism, 68(2), 200–208.

    Article  PubMed  CAS  Google Scholar 

  90. Aramant, R. B., & Seiler, M. J. (1994). Human embryonic retinal cell transplants in athymic immunodeficient rat hosts. Cell Transplantation, 3(6), 461–474.

    PubMed  CAS  Google Scholar 

  91. Radtke, N. D., Aramant, R. B., Petry, H. M., et al. (2008). Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. American Journal of Ophthalmology, 146(2), 172–182.

    Article  PubMed  Google Scholar 

  92. Marc, R. E., Jones, B. W., Watt, C. B., et al. (2003). Neural remodeling in retinal degeneration. Progress in Retinal and Eye Research, 22(5), 607–655.

    Article  PubMed  Google Scholar 

  93. Lund, R. D., Kwan, A. S., Keegan, D. J., et al. (2001). Cell transplantation as a treatment for retinal disease. Progress in Retinal and Eye Research, 20(4), 415–449.

    Article  PubMed  CAS  Google Scholar 

  94. Hoffman, L. M., & Carpenter, M. K. (2005). Characterization and culture of human embryonic stem cells. Nature Biotechnology, 23(6), 699–708.

    Article  PubMed  CAS  Google Scholar 

  95. Idelson, M., Alper, R., Obolensky, A., et al. (2009). Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells. Cell Stem Cell, 5(4), 396–408.

    Article  PubMed  CAS  Google Scholar 

  96. Arnhold, S., Klein, H., Semkova, I., et al. (2004). Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Investigative Ophthalmology and Visual Science, 45(12), 4251–4255.

    Article  PubMed  Google Scholar 

  97. Haruta, M., Sasai, Y., Kawasaki, H., et al. (2004). In vitro and in vivo characterization of pigment epithelial cells differentiated from primate embryonic stem cells. I Investigative Ophthalmology and Visual Science, 45(3), 1020–1025.

    Article  Google Scholar 

  98. Lund, R. D., Wang, S., Klimanskaya, I., et al. (2006). Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats. Cloning and Stem Cells, 8(3), 189–199.

    Article  PubMed  CAS  Google Scholar 

  99. Kucia, M., Halasa, M., Wysoczynski, M., et al. (2007). Morphological and molecular characterization of novel population of CXCR4+ SSEA-4+ Oct-4+ very small embryonic-like cells purified from human cord blood: preliminary report. Leukemia, 21(2), 297–303.

    Article  PubMed  CAS  Google Scholar 

  100. Virchow, R. (1855). Leukemia. Archiv für pathologische Anatomie und Physiologie, und für klinische Medizin, 8, 23–54.

    Google Scholar 

  101. Carr, A. J., Vugler, A. A., Hikita, S. T., et al. (2009). Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat. PLoS One, 4(12), e8152.

    Article  PubMed  CAS  Google Scholar 

  102. Lagasse, E., Connors, H., Al Dhalimy, M., et al. (2000). Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature Medicine, 6(11), 1229–1234.

    Article  PubMed  CAS  Google Scholar 

  103. Anderson, D. J., Gage, F. H., & Weissman, I. L. (2001). Can stem cells cross lineage boundaries? Nature Medicine, 7(4), 393–395.

    Article  PubMed  CAS  Google Scholar 

  104. Svendsen, C. N., & Smith, A. G. (1999). New prospects for human stem-cell therapy in the nervous system. Trends in Neurosciences, 22(8), 357–364.

    Article  PubMed  CAS  Google Scholar 

  105. Shimazaki, T. (2003). Biology and clinical application of neural stem cells. Hormone Research, 60(Suppl 3), 1–9.

    Article  PubMed  CAS  Google Scholar 

  106. Bez, A., Corsini, E., Curti, D., et al. (2003). Neurosphere and neurosphere-forming cells: morphological and ultrastructural characterization. Brain Research, 993(1–2), 18–29.

    Article  PubMed  CAS  Google Scholar 

  107. Clarke, D. L., Johansson, C. B., Wilbertz, J., et al. (2000). Generalized potential of adult neural stem cells. Science, 288(5471), 1660–1663.

    Article  PubMed  CAS  Google Scholar 

  108. Bjornson, C. R., Rietze, R. L., Reynolds, B. A., et al. (1999). Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science, 283(5401), 534–537.

    Article  PubMed  CAS  Google Scholar 

  109. Dong, X., Pulido, J. S., Qu, T., et al. (2003). Differentiation of human neural stem cells into retinal cells. NeuroReport, 14(1), 143–146.

    Article  PubMed  CAS  Google Scholar 

  110. Enzmann, V., Howard, R. M., Yamauchi, Y., et al. (2003). Enhanced induction of RPE lineage markers in pluripotent neural stem cells engrafted into the adult rat subretinal space. Investigative Ophthalmology and Visual Science, 44(12), 5417–5422.

    Article  PubMed  Google Scholar 

  111. Ahmad, I., Tang, L., & Pham, H. (2000). Identification of neural progenitors in the adult mammalian eye. Biochemical and Biophysical Research Comunications, 270(2), 517–521.

    Article  CAS  Google Scholar 

  112. Merhi-Soussi, F., Angenieux, B., Canola, K., et al. (2006). High yield of cells committed to the photoreceptor fate from expanded mouse retinal stem cells. Stem Cells, 24(9), 2060–2070.

    Article  PubMed  CAS  Google Scholar 

  113. Ahmad, I. (2001). Stem cells: new opportunities to treat eye diseases. Investigative Ophthalmology and Visual Science, 42(12), 2743–2748.

    PubMed  CAS  Google Scholar 

  114. Ratajczak, M. Z., Kucia, M., Reca, R., et al. (2004). Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells 'hide out' in the bone marrow. Leukemia, 18(1), 29–40.

    Article  PubMed  CAS  Google Scholar 

  115. Friedlander, M., Dorrell, M. I., Ritter, M. R., et al. (2007). Progenitor cells and retinal angiogenesis. Angiogenesis, 10(2), 89–101.

    Article  PubMed  Google Scholar 

  116. Gandy, K. L., Domen, J., Aguila, H. L., et al. (1999). CD8+TCR+ and CD8+TCR- cells in whole bone marrow facilitate the engraftment of hematopoietic stem cells across allogeneic barriers. Immunity, 11(5), 579–590.

    Article  PubMed  CAS  Google Scholar 

  117. Schuchert, M. J., Wright, R. D., & Colson, Y. L. (2000). Characterization of a newly discovered T-cell receptor beta-chain heterodimer expressed on a CD8+ bone marrow subpopulation that promotes allogeneic stem cell engraftment. Nature Medicine, 6(8), 904–909.

    Article  PubMed  CAS  Google Scholar 

  118. Huang, Y., Rezzoug, F., Chilton, P. M., et al. (2004). Matching at the MHC Class I K locus is essential for long-term engraftment of purified hematopoietic stem cells: a role for host NK cells in regulating HSC engraftment. Blood, 104, 873–880.

    Article  PubMed  CAS  Google Scholar 

  119. Fugier-Vivier, I., Rezzoug, F., Huang, Y., et al. (2005). Plasmacytoid precursor dendritic cells facilitate allogeneic hematopoietic stem cell engraftment. Journal of Experimental Medicine, 201(3), 373–383. PMCID: PMC2213023.

    Article  PubMed  CAS  Google Scholar 

  120. Rezzoug, F., Huang, Y., Tanner, M. K., et al. (2008). TNFa is critical to facilitation of hematopoietic stem cell engraftment and function. Journal of Immunology, 180(1), 49–57.

    CAS  Google Scholar 

  121. Grimes, H. L., Schanie, C. L., Huang, Y., et al. (2004). Graft facilitating cells are derived from hematopoietic stem cells and functionally require CD3, but are distinct from T lymphocytes. Experimental Hematology, 32(10), 946–954.

    Article  PubMed  CAS  Google Scholar 

  122. Huang, Y., Fugier-Vivier, I., Miller, T., et al. (2008). Plasmacytoid precursor dendritic cells from NOD mice exhibit impaired function: are they a component of diabetes pathogenesis? Diabetes, 57, 2360–2370. PMCID: PMC2518487.

    Article  PubMed  CAS  Google Scholar 

  123. Colson, Y. L., Christopher, K., Glickman, J., et al. (2004). Absence of Clinical GVHD and the In Vivo Induction of Regulatory T cells following Facilitating Cell Transplantation. Blood, 104, 3829–3835.

    Article  PubMed  CAS  Google Scholar 

  124. Taylor, K. N., Shinde-Patil, V. R., Cohick, E., et al. (2007). Induction of FoxP3+CD4+25+ regulatory T cells following hemopoietic stem cell transplantation: role of bone marrow-derived facilitating cells. Journal of Immunology, 179(4), 2153–2162.

    CAS  Google Scholar 

  125. Neipp, M., Zorina, T., Domenick, M. A., et al. (1998). Effect of FLT3 ligand and granulocyte colony-stimulating factor on expansion and mobilization of facilitating cells and hematopoietic stem cells in mice: kinetics and repopulating potential. Blood, 92(9), 3177–3188.

    PubMed  CAS  Google Scholar 

  126. Dawn, B., Guo, Y., Rezazadeh, A., et al. (2006). Postinfarct cytokine therapy regenerates cardiac tissue and improves left ventricular function. Circulation Research, 98(8), 1098–1105.

    Article  PubMed  CAS  Google Scholar 

  127. Sanganalmath, S. K., Stein, A. B., Guo, Y., et al. (2009). The beneficial effects of postinfarct cytokine combination therapy are sustained during long-term follow-up. Journal of Molecular and Cellular Cardiology, 47(4), 528–535. PMCID: PMC2760590.

    Article  PubMed  CAS  Google Scholar 

  128. Li, Y., Reca, R., Sonmez, P., et al. (2006). Retinal pigment epithelium damage enhances expression of chemoattracts and migration of bone marrow-derived stem cells. Investigative Ophthalmology and Visual Science, 47(4), 1646–1652.

    Article  PubMed  Google Scholar 

  129. Atmaca-Sonmez, P., Li, Y., Yamauchi, Y., et al. (2006). Systemically transferred hematopoietic stem cells home to the subretinal space and express RPE-65 in a mouse model of retinal pigment epithelium damage. Experimental Eye Research, 83, 1295–1302.

    Article  PubMed  CAS  Google Scholar 

  130. Humphries, M. M., Rancourt, D., Farrar, G. J., et al. (1997). Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nature Genetics, 15(2), 216–219.

    Article  PubMed  CAS  Google Scholar 

  131. Sanyal, S., De Ruiter, A., & Hawkins, R. K. (1980). Development and degeneration of retina in rds mutant mice: light microscopy. Journal of Comparative Neurology, 194(1), 193–207.

    Article  PubMed  CAS  Google Scholar 

  132. Carter-Dawson, L. D., Lavail, M. M., & Sidman, R. L. (1978). Differential effect of the rd mutation on rods and cones in the mouse retina. Investigative Ophthalmology and Visual Science, 17(6), 489–498.

    PubMed  CAS  Google Scholar 

  133. Bowes, C., Li, T., Danciger, M., et al. (1990). Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature, 347(6294), 677–680.

    Article  PubMed  CAS  Google Scholar 

  134. Redmond, T. M., Yu, S., Lee, E., et al. (1998). Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nature Genetics, 20(4), 344–351.

    Article  PubMed  CAS  Google Scholar 

  135. Liu, S. Y., & Redmond, T. M. (1998). Role of the 3'-untranslated region of RPE65 mRNA in the translational regulation of the RPE65 gene: identification of a specific translation inhibitory element. Archives of Biochemistry and Biophysics, 357(1), 37–44.

    Article  PubMed  CAS  Google Scholar 

  136. Lavail, M. M., Unoki, K., Yasumura, D., et al. (1992). Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proceedings of the National Academy of Science USA, 89(23), 11249–11253.

    Article  CAS  Google Scholar 

  137. D'Cruz, P. M., Yasumura, D., Weir, J., et al. (2009). Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Human Molecular Genetics, 9(4), 645–651.

    Article  Google Scholar 

  138. Jobst, K. (1967). Teratogenous changes and tumors in rats following treatment with methylnitroso-urea (MNU). Neoplasma, 14(4), 435–436.

    PubMed  CAS  Google Scholar 

  139. Nagar, S., Krishnamoorthy, V., Cherukuri, P., et al. (2009). Early remodeling in an inducible animal model of retinal degeneration. Neuroscience, 160(2), 517–529.

    Article  PubMed  CAS  Google Scholar 

  140. Marano, R. J., & Rakoczy, P. E. (2006). An improved method using densitometry for evaluating severity of laser photocoagulation induced CNV. Biotechnic & Histochemistry, 81(2–3), 59–62.

    Article  CAS  Google Scholar 

  141. Ambati, J., Anand, A., Fernandez, S., et al. (2003). An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nature Medicine, 9(11), 1390–1397.

    Article  PubMed  CAS  Google Scholar 

  142. Frank, R. N., Das, A., & Weber, M. L. (1989). A model of subretinal neovascularization in the pigmented rat. Current Eye Research, 8(3), 239–247.

    Article  PubMed  CAS  Google Scholar 

  143. elDirini, A. A., Ogden, T. E., & Ryan, S. J. (1991). Subretinal endophotocoagulation. A new model of subretinal neovascularization in the rabbit. Retina, 11(2), 244–249.

    Article  PubMed  CAS  Google Scholar 

  144. Ohkuma, H., & Ryan, S. J. (1982). Vascular casts of experimental subretinal neovascularization in monkeys: a preliminary report. Japan’s Journal of Ophthalmology, 26(2), 150–158.

    CAS  Google Scholar 

  145. Noell, W. K. (1953). Experimentally induced toxic effects on structure and function of visual cells and pigment epithelium. American Journal of Ophthalmology, 36(6:2), 103–116.

    PubMed  CAS  Google Scholar 

  146. Enzmann, V., Row, B. W., Yamauchi, Y., et al. (2006). Behavioral and anatomical abnormalities in a sodium iodate-induced model of retinal pigment epithelium degeneration. Experimental Eye Research, 82(3), 441–448.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Haval Shirwan, Larry Bozulic, and Deborah Ramsey for review of the manuscript and helpful comments; Carolyn DeLautre for manuscript preparation. This work was supported in part by the following: NIH R01 DK069766. This publication was also made possible by the Commonwealth of Kentucky Research Challenge Trust Fund; the W. M. Keck Foundation; The Jewish Hospital Foundation; and the Swiss National Science Foundation.

Disclosures

S. Ildstad has significant equity interest in Regenerex, LLC, a start-up biotech company based on the facilitating cell technology.

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  1. Institute for Cellular Therapeutics, University of Louisville, 570 S. Preston Street, Suite 404, Louisville, KY, 40202-1760, USA

    Yiming Huang & Suzanne T. Ildstad

  2. Department of Ophthalmology, Inselspital, University of Bern, Bern, Switzerland

    Volker Enzmann

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  1. Yiming Huang
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Correspondence to Suzanne T. Ildstad.

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Huang, Y., Enzmann, V. & Ildstad, S.T. Stem Cell-Based Therapeutic Applications in Retinal Degenerative Diseases. Stem Cell Rev and Rep 7, 434–445 (2011). https://doi.org/10.1007/s12015-010-9192-8

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