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Stem Cell Strategies for Diseases of the Outer Retina

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Regenerative Biology of the Eye

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

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Abstract

The outer retina contains cells essential in the first stage of visual processing. The phototransduction cascade is initiated within photoreceptor outer segments, which are heavily supported by the adjoining retinal pigmented epithelial cells. Many diseases manifest by degeneration of these cells, which invariably lead to visual impairment. Unfortunately the majority of these conditions are currently untreatable. Pluripotent stem cells are unique in that they can differentiate into any somatic cell type, including retinal cells. As such, patient-specific pluripotent stem cells provide a powerful platform for studying disease pathogenesis and mechanisms through the generation of in vitro models. Additionally, these cells may also provide a renewable source of material for cellular transplantation to replace defective or degenerative retinal cells with the aim of restoring visual function. In this review, we discuss stem cell-based strategies for understanding and treating diseases of the outer retina.

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Abbreviations

ABCA4:

ATP-binding cassette, subfamily A, member 4

AMD:

Age-related macular degeneration

BEST1:

Bestrophin

CHM:

Choroideremia

CRD:

Cone-rod dystrophy

CRX:

Cone-rod homeobox

EFEMP1:

Epidermal growth factor-containing fibulin-like extracellular matrix protein 1

ERG:

Electroretinography

hESC:

Human embryonic stem cells

iPSC:

Induced pluripotent stem cells

LCA:

Leber congenital amaurosis

MAK:

Male germ-associated kinase

OAT:

Ornithine aminotransferase

PR:

Photoreceptor

PRPH2:

Peripherin 2

PSC:

Pluripotent stem cell

RCS:

Royal College of Surgeon

REP1:

Rab escort protein-1

RHO:

Rhodopsin

RP:

Retinitis pigmentosa

RP1:

Retinitis pigmentosa 1

RP9:

Retinitis pigmentosa 9

RPE:

Retinal pigmented epithelium

RPE65:

Retinal pigment epithelium-specific protein 65 kDa

RPGR:

Retinitis pigmentosa GTPase regulator

TIMP3:

Tissue inhibitor of metalloproteinases-3

USH2A:

Usher syndrome 2A

VEGF:

Vascular endothelial growth factor

References

  1. Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85(3):845–881

    Article  CAS  PubMed  Google Scholar 

  2. Thomson JA et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147

    Article  CAS  PubMed  Google Scholar 

  3. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A (2000) Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 18(4):399–404

    Article  CAS  PubMed  Google Scholar 

  4. Takahashi K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872

    Article  CAS  PubMed  Google Scholar 

  5. Yu J et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920

    Article  CAS  PubMed  Google Scholar 

  6. Park IH et al (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451(7175):141–146

    Article  CAS  PubMed  Google Scholar 

  7. Velez-Montoya R et al (2014) Current knowledge and trends in age-related macular degeneration: genetics, epidemiology, and prevention. Retina 34(3):423–441

    Google Scholar 

  8. Klein R et al (2011) Prevalence of age-related macular degeneration in the US population. Arch Ophthalmol 129(1):75–80

    Article  PubMed  Google Scholar 

  9. Deloitte Access Economics, Mitchell P (2011) Eyes on the future: a clear outlook on age-related macular degeneration. Macular Degeneration Foundation

    Google Scholar 

  10. Hanout M et al (2013) Therapies for neovascular age-related macular degeneration: current approaches and pharmacologic agents in development. BioMed Res Int 2013:830837

    Article  PubMed Central  PubMed  Google Scholar 

  11. Walia S, Fishman GA (2009) Natural history of phenotypic changes in Stargardt macular dystrophy. Ophthalmic Genet 30(2):63–68

    Article  PubMed  Google Scholar 

  12. MacDonald IM, Lee T (2009) Best Vitelliform macular dystrophy. GeneReviews [Internet]. http://www.ncbi.nlm.nih.gov/books/NBK1167/. Accessed 9 Dec 2013

  13. Boon CJ et al (2009) The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog Retin Eye Res 28(3):187–205

    Article  CAS  PubMed  Google Scholar 

  14. Marmorstein L (2004) Association of EFEMP1 with malattia leventinese and age-related macular degeneration: a mini-review. Ophthalmic Genet 25(3):219–226

    Article  CAS  PubMed  Google Scholar 

  15. Ferrari S et al (2011) Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics 12(4):238–249

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Daiger SP, Sullivan LS, Bowne SJ (2013) Genes and mutations causing retinitis pigmentosa. Clin Genet 84(2):132–141

    Article  CAS  PubMed  Google Scholar 

  17. Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368(9549):1795–1809

    Article  CAS  PubMed  Google Scholar 

  18. Qi JH, Ebrahem Q, Anand-Apte B (2003) Tissue inhibitor of metalloproteinases-3 and Sorsby fundus dystrophy. Adv Exp Med Biol 533:97–105

    Article  CAS  PubMed  Google Scholar 

  19. Berger W, Kloeckener-Gruissem B, Neidhardt J (2010) The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res 29(5):335–375

    Article  CAS  PubMed  Google Scholar 

  20. Chung DC, Traboulsi EI (2009) Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J AAPOS 13(6):587–592

    Article  PubMed  Google Scholar 

  21. Cideciyan AV et al (2013) Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A 110(6):E517–E525

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Jacobson SG et al (2012) Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol 130(1):9–24

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Ramesh V, Gusella JF, Shih VE (1991) Molecular pathology of gyrate atrophy of the choroid and retina due to ornithine aminotransferase deficiency. Mol Biol Med 8(1):81–93

    CAS  PubMed  Google Scholar 

  24. Kaiser-Kupfer MI, Caruso RC, Valle D (2002) Gyrate atrophy of the choroid and retina: further experience with long-term reduction of ornithine levels in children. Arch Ophthalmol 120(2):146–153

    Article  PubMed  Google Scholar 

  25. Coussa RG, Traboulsi EI (2012) Choroideremia: a review of general findings and pathogenesis. Ophthalmic Genet 33(2):57–65

    Article  CAS  PubMed  Google Scholar 

  26. Jin ZB et al (2011) Modeling retinal degeneration using patient-specific induced pluripotent stem cells. PLoS One 6(2):e17084

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Tucker BA et al (2013) Patient-specific iPSC-derived photoreceptor precursor cells as a means to investigate retinitis pigmentosa. Elife 2:e00824

    Article  PubMed Central  PubMed  Google Scholar 

  28. Jiang LQ, Jorquera M, Streilein JW (1993) Subretinal space and vitreous cavity as immunologically privileged sites for retinal allografts. Invest Ophthalmol Vis Sci 34(12):3347–3354

    CAS  PubMed  Google Scholar 

  29. Algvere PV, Berglin L, Gouras P, Sheng Y, Kopp ED (1997) Transplantation of RPE in age-related macular degeneration: observations in disciform lesions and dry RPE atrophy. Graefes Arch Clin Exp Ophthalmol 235(3):149–158

    Article  CAS  PubMed  Google Scholar 

  30. Algvere PV, Gouras P, Dafgard Kopp E (1999) Long-term outcome of RPE allografts in non-immunosuppressed patients with AMD. Eur J Ophthalmol 9(3):217–230

    CAS  PubMed  Google Scholar 

  31. Binder S, Stanzel BV, Krebs I, Glittenberg C (2007) Transplantation of the RPE in AMD. Prog Retin Eye Res 26(5):516–554

    Article  PubMed  Google Scholar 

  32. Radtke ND et al (2008) Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. Am J Ophthalmol 146(2):172–182

    Article  PubMed  Google Scholar 

  33. Seiler MJ, Aramant RB (2012) Cell replacement and visual restoration by retinal sheet transplants. Prog Retin Eye Res 31(6):661–687

    Article  PubMed Central  PubMed  Google Scholar 

  34. Idelson M et al (2009) Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells. Cell Stem Cell 5(4):396–408

    Article  CAS  PubMed  Google Scholar 

  35. Zahabi A et al (2012) A new efficient protocol for directed differentiation of retinal pigmented epithelial cells from normal and retinal disease induced pluripotent stem cells. Stem Cells Dev 21(12):2262–2272

    Article  CAS  PubMed  Google Scholar 

  36. Klimanskaya I et al (2004) Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics. Cloning Stem Cells 6(3):217–245

    Article  CAS  PubMed  Google Scholar 

  37. Buchholz DE et al (2013) Rapid and efficient directed differentiation of human pluripotent stem cells into retinal pigmented epithelium. Stem Cells Transl Med 2(5):384–393

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. La Torre A, Lamba DA, Jayabalu A, Reh TA (2012) Production and transplantation of retinal cells from human and mouse embryonic stem cells. Methods Mol Biol 884:229–246

    Article  PubMed  Google Scholar 

  39. Meyer JS et al (2009) Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc Natl Acad Sci U S A 106(39):16698–16703

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Banin E et al (2006) Retinal incorporation and differentiation of neural precursors derived from human embryonic stem cells. Stem Cells 24(2):246–257

    Article  PubMed  Google Scholar 

  41. Hirami Y et al (2009) Generation of retinal cells from mouse and human induced pluripotent stem cells. Neurosci Lett 458(3):126–131

    Article  CAS  PubMed  Google Scholar 

  42. Lamba DA, Karl MO, Ware CB, Reh TA (2006) Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A 103(34):12769–12774

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Lamba DA et al (2010) Generation, purification and transplantation of photoreceptors derived from human induced pluripotent stem cells. PLoS One 5(1):e8763

    Article  PubMed Central  PubMed  Google Scholar 

  44. Mellough CB, Sernagor E, Moreno-Gimeno I, Steel DH, Lako M (2012) Efficient stage-specific differentiation of human pluripotent stem cells toward retinal photoreceptor cells. Stem Cells 30(4):673–686

    Article  CAS  PubMed  Google Scholar 

  45. Meyer JS et al (2011) Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment. Stem Cells 29(8):1206–1218

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Osakada F et al (2009) In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction. J Cell Sci 122(pt 17):3169–3179

    Article  CAS  PubMed  Google Scholar 

  47. Lund RD et al (2001) Subretinal transplantation of genetically modified human cell lines attenuates loss of visual function in dystrophic rats. Proc Natl Acad Sci U S A 98(17):9942–9947

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Pinilla I, Cuenca N, Sauve Y, Wang S, Lund RD (2007) Preservation of outer retina and its synaptic connectivity following subretinal injections of human RPE cells in the Royal College of Surgeons rat. Exp Eye Res 85(3):381–392

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Sauve Y, Girman SV, Wang S, Keegan DJ, Lund RD (2002) Preservation of visual responsiveness in the superior colliculus of RCS rats after retinal pigment epithelium cell transplantation. Neuroscience 114(2):389–401

    Article  CAS  PubMed  Google Scholar 

  50. Whiteley SJ, Litchfield TM, Coffey PJ, Lund RD (1996) Improvement of the pupillary light reflex of Royal College of Surgeons rats following RPE cell grafts. Exp Neurol 140(1):100–104

    Article  CAS  PubMed  Google Scholar 

  51. Carr AJ 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 Central  PubMed  Google Scholar 

  52. Li Y et al (2012) Long-term safety and efficacy of human-induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa. Mol Med 18:1312–1319

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Lund RD et al (2006) Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats. Cloning Stem Cells 8(3):189–199

    Article  CAS  PubMed  Google Scholar 

  54. Schwartz SD et al (2012) Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379(9817):713–720

    Article  CAS  PubMed  Google Scholar 

  55. Pearson RA et al (2012) Restoration of vision after transplantation of photoreceptors. Nature 485(7396):99–103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Singh MS et al (2013) Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation. Proc Natl Acad Sci U S A 110(3):1101–1106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. MacLaren RE et al (2006) Retinal repair by transplantation of photoreceptor precursors. Nature 444(7116):203–207

    Article  CAS  PubMed  Google Scholar 

  58. Lamba DA, Gust J, Reh TA (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  CAS  PubMed Central  PubMed  Google Scholar 

  59. Hu Y et al (2012) A novel approach for subretinal implantation of ultrathin substrates containing stem cell-derived retinal pigment epithelium monolayer. Ophthalmic Res 48(4):186–191

    Article  PubMed  Google Scholar 

  60. Rose S (2013) Several new stem cell clinical trials poised to begin in two to three years. In Foundation fighting blindness—eye on the cure: a blog covering the world of retinal diseases. http://www.blindness.org/blog/index.php/several-new-stem-cell-clinical-trials-poised-to-begin-in-two-to-three-years/. Accessed 16 Dec 2013

  61. Nakano T et al (2012) Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10(6):771–785

    Article  CAS  PubMed  Google Scholar 

  62. Phillips MJ et al (2012) Blood-derived human iPS cells generate optic vesicle-like structures with the capacity to form retinal laminae and develop synapses. Invest Ophthalmol Vis Sci 53(4):2007–2019

    Article  PubMed Central  PubMed  Google Scholar 

  63. Nistor G, Seiler MJ, Yan F, Ferguson D, Keirstead HS (2010) Three-dimensional early retinal progenitor 3D tissue constructs derived from human embryonic stem cells. J Neurosci Methods 190(1):63–70

    Article  PubMed  Google Scholar 

  64. Diniz B et al (2013) Subretinal implantation of retinal pigment epithelial cells derived from human embryonic stem cells: improved survival when implanted as a monolayer. Invest Ophthalmol Vis Sci 54(7):5087–5096

    Article  PubMed Central  PubMed  Google Scholar 

  65. Del Priore LV, Tezel TH (1998) Reattachment rate of human retinal pigment epithelium to layers of human Bruch’s membrane. Arch Ophthalmol 116(3):335–341

    Article  PubMed  Google Scholar 

  66. Sugino IK et al (2011) Comparison of FRPE and human embryonic stem cell-derived RPE behavior on aged human Bruch’s membrane. Invest Ophthalmol Vis Sci 52(8):4979–4997

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Stanzel BV et al (2012) Subretinal delivery of ultrathin rigid-elastic cell carriers using a metallic shooter instrument and biodegradable hydrogel encapsulation. Invest Ophthalmol Vis Sci 53(1):490–500

    Article  CAS  PubMed  Google Scholar 

  68. Kearns V et al (2012) Plasma polymer coatings to aid retinal pigment epithelial growth for transplantation in the treatment of age related macular degeneration. J Mater Sci Mater Med 23(8):2013–2021

    Article  CAS  PubMed  Google Scholar 

  69. Subrizi A et al (2012) Generation of hESC-derived retinal pigment epithelium on biopolymer coated polyimide membranes. Biomaterials 33(32):8047–8054

    Article  CAS  PubMed  Google Scholar 

  70. Carr AJ et al (2013) Development of human embryonic stem cell therapies for age-related macular degeneration. Trends Neurosci 36(7):385–395

    Article  CAS  PubMed  Google Scholar 

  71. Aramant RB, Seiler MJ (1994) Human embryonic retinal cell transplants in athymic immunodeficient rat hosts. Cell Transplant 3(6):461–474

    CAS  PubMed  Google Scholar 

  72. Lamba DA, Reh TA (2011) Microarray characterization of human embryonic stem cell-derived retinal cultures. Invest Ophthalmol Vis Sci 52(7):4897–4906

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Vugler A et al (2008) Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation. Exp Neurol 214(2):347–361

    Article  CAS  PubMed  Google Scholar 

  74. Liao JL et al (2010) Molecular signature of primary retinal pigment epithelium and stem-cell-derived RPE cells. Hum Mol Genet 19(21):4229–4238

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Lu B et al (2009) Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration. Stem Cells 27(9):2126–2135

    Article  CAS  PubMed  Google Scholar 

  76. Meyer JS, Katz ML, Maruniak JA, Kirk MD (2006) Embryonic stem cell-derived neural progenitors incorporate into degenerating retina and enhance survival of host photoreceptors. Stem Cells 24(2):274–283

    Article  PubMed Central  PubMed  Google Scholar 

  77. Lu B et al (2010) Human adult bone marrow-derived somatic cells rescue vision in a rodent model of retinal degeneration. Exp Eye Res 91(3):449–455

    Article  CAS  PubMed  Google Scholar 

  78. Lund RD et al (2007) Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells 25(3):602–611

    Article  CAS  PubMed  Google Scholar 

  79. Xu W, Xu GX (2011) Mesenchymal stem cells for retinal diseases. Int J Ophthalmol 4(4):413–421

    PubMed Central  PubMed  Google Scholar 

  80. Terada N et al (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416(6880):542–545

    Article  CAS  PubMed  Google Scholar 

  81. Tomita M et al (2006) A comparison of neural differentiation and retinal transplantation with bone marrow-derived cells and retinal progenitor cells. Stem Cells 24(10):2270–2278

    Article  CAS  PubMed  Google Scholar 

  82. Singh R et al (2013) iPS cell modeling of Best disease: insights into the pathophysiology of an inherited macular degeneration. Hum Mol Genet 22(3):593–607

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Vasireddy V et al (2013) AAV-mediated gene therapy for choroideremia: preclinical studies in personalized models. PLoS One 8(5):e61396

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Howden SE et al (2011) Genetic correction and analysis of induced pluripotent stem cells from a patient with gyrate atrophy. Proc Natl Acad Sci U S A 108(16):6537–6542

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Lustremant C et al (2013) Human induced pluripotent stem cells as a tool to model a form of leber congenital amaurosis. Cell Reprogram 15(3):233–246

    CAS  PubMed  Google Scholar 

  86. Tucker BA et al (2011) Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase (MAK) as a cause of retinitis pigmentosa. Proc Natl Acad Sci U S A 108(34):E569–E576

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Jin ZB, Okamoto S, Xiang P, Takahashi M (2012) Integration-free induced pluripotent stem cells derived from retinitis pigmentosa patient for disease modeling. Stem Cells Transl Med 1(6):503–509

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by funding from the National Stem Cell Foundation of Australia, the Ophthalmic Research Institute of Australia, and the Australian National Health and Medical Research Council (Project Grant 1059369 and a Centres of Research Excellence Grant 1023911). AWH is supported by an Australian National Health and Medical Research Council Peter Doherty Fellowship. CERA receives Operational Infrastructure Support from the Victorian Government.

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Authors and Affiliations

  1. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, East Melbourne, VIC, Australia

    Alex W. Hewitt & Kathryn C. Davidson

  2. Centre for Ophthalmology and Vision Science, University of Western Australia and the Lions Eye Institute, Perth, WA, Australia

    Alex W. Hewitt

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  1. Alex W. Hewitt
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  2. Kathryn C. Davidson
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Correspondence to Kathryn C. Davidson .

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  1. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Department of Ophthalmology, The University of Melbourne, East Melbourne, Victoria, Australia

    Alice Pébay

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Hewitt, A.W., Davidson, K.C. (2014). Stem Cell Strategies for Diseases of the Outer Retina. In: Pébay, A. (eds) Regenerative Biology of the Eye. Stem Cell Biology and Regenerative Medicine. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0787-8_7

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