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Cell-Based Therapy for Retinal Disease: The New Frontier

  • Marco Zarbin
Part of the Methods in Molecular Biology book series (MIMB, volume 1834)

Abstract

The availability of noninvasive high-resolution imaging technology, the immune-suppressive nature of the subretinal space, and the existence of surgical techniques that permit transplantation surgery to be a safe procedure all render the eye an ideal organ in which to begin cell-based therapy in the central nervous system. A number of early stage clinical trials are underway to assess the safety and feasibility of cell-based therapy for retinal blindness. Cell-based therapy using embryonic stem cell-derived differentiated cells (e.g., retinal pigment epithelium (RPE)), neural progenitor cells, photoreceptor precursors, and bone marrow-derived hematopoietic stem/progenitor cells has demonstrated successful rescue and/or replacement in preclinical models of human retinal degenerative disease. Additional research is needed to identify the mechanisms that control synapse formation/disjunction (to improve photoreceptor transplant efficacy), to identify factors that limit RPE survival in areas of geographic atrophy (to improve RPE transplant efficacy in eyes with age-related macular degeneration), and to identify factors that regulate immune surveillance of the subretinal space (to improve long-term photoreceptor and RPE transplant survival).

Key words

Retinal blindness Clinical trials Cell-based therapy Embryonic stem cell-derived differentiated cells Neural progenitor cells Photoreceptor precursors Bone marrow-derived hematopoietic stem/progenitor cells 

Notes

Acknowledgments

This is supported in part by the Joseph J. & Marguerite DiSepio Retina Research Fund, the New Jersey Lions Eye Research Foundation, the Eng Family Foundation, and the National Eye Institute (EY021542).

References

  1. 1.
    Zarbin M (2016) Cell-based therapy for degenerative retinal disease. Trends Mol Med 22(2):115–134PubMedCrossRefGoogle Scholar
  2. 2.
    Sung CH, Chuang JZ (2010) The cell biology of vision. J Cell Biol 190(6):953–963PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Mustafi D, Engel AH, Palczewski K (2009) Structure of cone photoreceptors. Prog Retin Eye Res 28(4):289–302PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Binder S, Stanzel BV, Krebs I, Glittenberg C (2007) Transplantation of the RPE in AMD. Prog Retin Eye Res 26(5):516–554PubMedCrossRefGoogle Scholar
  5. 5.
    Streilein JW (2003) Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation. J Leukoc Biol 74(2):179–185PubMedCrossRefGoogle Scholar
  6. 6.
    Zarbin MA, Casaroli-Marano RP, Rosenfeld PJ (2014) Age-related macular degeneration: clinical findings, histopathology, imaging techniques. In: Casaroli-Marano RP, Zarbin MA (eds) Cell-based therapy for retinal degenerative disease. Karger Medical and Scientific Publishers, Basel, Switzerland, pp 1–32Google Scholar
  7. 7.
    Menghini M, Duncan JL (2014) Diagnosis and complementary examinations. Dev Ophthalmol 53:53–69PubMedCrossRefGoogle Scholar
  8. 8.
    Scoles D, Flatter JA, Cooper RF et al (2016) Assessing photoreceptor structure associated with ellipsoid zone disruptions visualized with optical coherence tomography. Retina 36(1):91–103PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Pearson RA, Barber AC, Rizzi M et al (2012) Restoration of vision after transplantation of photoreceptors. Nature 485(7396):99–103PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Lund RD, Adamson P, Sauve Y 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):9942–9947PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Friedman DS, O’Colmain BJ, Munoz B et al (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122(4):564–572PubMedCrossRefGoogle Scholar
  12. 12.
    Genead MA, Fishman GA, Stone EM, Allikmets R (2009) The natural history of stargardt disease with specific sequence mutation in the ABCA4 gene. Invest Ophthalmol Vis Sci 50(12):5867–5871PubMedCrossRefGoogle Scholar
  13. 13.
    Wong TY, Loon SC, Saw SM (2006) The epidemiology of age related eye diseases in Asia. Br J Ophthalmol 90(4):506–511PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Parmeggiani F (2011) Clinics, epidemiology and genetics of retinitis pigmentosa. Curr Genomics 12(4):236–237PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Ashtari M, Zhang H, Cook PA et al (2015) Plasticity of the human visual system after retinal gene therapy in patients with Leber’s congenital amaurosis. Sci Transl Med 7(296):296ra110PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Jacobson SG, Cideciyan AV, Roman AJ et al (2015) Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med 372(20):1920–1926PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Rosenfeld PJ, Brown DM, Heier JS et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355(14):1419–1431CrossRefGoogle Scholar
  18. 18.
    Brown DM, Kaiser PK, Michels M et al (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355(14):1432–1444PubMedCrossRefGoogle Scholar
  19. 19.
    Heier JS, Brown DM, Chong V et al (2012) Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 119(12):2537–2548CrossRefGoogle Scholar
  20. 20.
    Zarbin MA, Rosenfeld PJ (2010) Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. Retina 30(9):1350–1367PubMedCrossRefGoogle Scholar
  21. 21.
    Schwartz SD, Regillo CD, Lam BL et al (2015) Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet 385(9967):509–516CrossRefGoogle Scholar
  22. 22.
    Schwartz SD, Hubschman JP, Heilwell G et al (2012) Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379(9817):713–720PubMedCrossRefGoogle Scholar
  23. 23.
    Schwartz SD, Tan G, Hosseini H, Nagiel A (2016) Subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium for the treatment of macular degeneration: an assessment at 4 years. Invest Ophthalmol Vis Sci 57(5):ORSFc1–ORSFc9PubMedCrossRefGoogle Scholar
  24. 24.
    Song WK, Park KM, Kim HJ et al (2015) Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in asian patients. Stem Cell Reports 4(5):860–872PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Tsai Y, Lu B, Bakondi B et al (2015) Human iPSC-derived neural progenitors preserve vision in an AMD-like model. Stem Cells 33(8):2537–2549PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Charbel Issa P, Bolz HJ, Ebermann I, Domeier E, Holz FG, Scholl HP (2009) Characterisation of severe rod-cone dystrophy in a consanguineous family with a splice site mutation in the MERTK gene. Br J Ophthalmol 93(7):920–925PubMedCrossRefGoogle Scholar
  27. 27.
    Vollrath D, Feng W, Duncan JL et al (2001) Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. Proc Natl Acad Sci U S A 98(22):12584–12589PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Mackay DS, Henderson RH, Sergouniotis PI et al (2010) Novel mutations in MERTK associated with childhood onset rod-cone dystrophy. Mol Vis 16:369–377PubMedPubMedCentralGoogle Scholar
  29. 29.
    McGill TJ, Cottam B, Lu B et al (2012) Transplantation of human central nervous system stem cells - neuroprotection in retinal degeneration. Eur J Neurosci 35(3):468–477PubMedCrossRefGoogle Scholar
  30. 30.
    Fisher SK, Lewis GP (2003) Muller cell and neuronal remodeling in retinal detachment and reattachment and their potential consequences for visual recovery: a review and reconsideration of recent data. Vis Res 43(8):887–897PubMedCrossRefGoogle Scholar
  31. 31.
    Tucker BA, Park IH, Qi SD et al (2011) Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS One 6(4):e18992PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Klassen H (2016) Stem cells in clinical trials for treatment of retinal degeneration. Expert Opin Biol Ther 16(1):7–14PubMedCrossRefGoogle Scholar
  33. 33.
    Singh MS, Charbel Issa P, Butler R 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):1101–1106PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Chang B, Hawes NL, Hurd RE, Davisson MT, Nusinowitz S, Heckenlively JR (2002) Retinal degeneration mutants in the mouse. Vis Res 42(4):517–525CrossRefGoogle Scholar
  35. 35.
    Pittler SJ, Baehr W (1991) Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. Proc Natl Acad Sci U S A 88(19):8322–8326PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    McLaughlin ME, Sandberg MA, Berson EL, Dryja TP (1993) Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nat Genet 4(2):130–134PubMedCrossRefGoogle Scholar
  37. 37.
    Akimoto M, Cheng H, Zhu D et al (2006) Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors. Proc Natl Acad Sci U S A 103(10):3890–3895PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Gonzalez-Cordero A, West EL, Pearson RA et al (2013) Photoreceptor precursors derived from three-dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina. Nat Biotechnol 31(8):741–747PubMedCrossRefGoogle Scholar
  39. 39.
    Barber AC, Hippert C, Duran Y et al (2013) Repair of the degenerate retina by photoreceptor transplantation. Proc Natl Acad Sci U S A 110(1):354–359PubMedCrossRefGoogle Scholar
  40. 40.
    Singh MS, Balmer J, Barnard AR et al (2016) Transplanted photoreceptor precursors transfer proteins to host photoreceptors by a mechanism of cytoplasmic fusion. Nat Commun 7:13537PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Pearson RA, Gonzalez-Cordero A, West EL et al (2016) Donor and host photoreceptors engage in material transfer following transplantation of post-mitotic photoreceptor precursors. Nat Commun 7:13029PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Santos-Ferreira T, Llonch S, Borsch O, Postel K, Haas J, Ader M (2016) Retinal transplantation of photoreceptors results in donor-host cytoplasmic exchange. Nat Commun 7:13028PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Sanges D, Simonte G, Di Vicino U et al (2016) Reprogramming Muller glia via in vivo cell fusion regenerates murine photoreceptors. J Clin Invest 126(8):3104–3116PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Chang B, Hawes NL, Pardue MT et al (2007) Two mouse retinal degenerations caused by missense mutations in the beta-subunit of rod cGMP phosphodiesterase gene. Vis Res 47(5):624–633PubMedCrossRefGoogle Scholar
  45. 45.
    Ogle BM, Cascalho M, Platt JL (2005) Biological implications of cell fusion. Nat Rev Mol Cell Biol 6(7):567–575PubMedCrossRefGoogle Scholar
  46. 46.
    Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149(6):1192–1205PubMedCrossRefGoogle Scholar
  47. 47.
    Gullapalli VK, Sugino IK, Van Patten Y, Shah S, Zarbin MA (2005) Impaired RPE survival on aged submacular human Bruch’s membrane. Exp Eye Res 80(2):235–248PubMedCrossRefGoogle Scholar
  48. 48.
    Gullapalli VKKM, Wang H, Sugino IK, Madreperla S, Zarbin MA (2013) Transplantation frontiers. In: Ryan SJ (ed) Retina. . Vol 3, Part 1, 5th edn. Elsevier, Amsterdam, pp 2058–2077Google Scholar
  49. 49.
    Sunness JS (2015) Stem cells in age-related macular degeneration and Stargardt’s macular dystrophy. Lancet 386(9988):29PubMedCrossRefGoogle Scholar
  50. 50.
    Lu B, Wang S, Francis PJ et al (2010) Cell transplantation to arrest early changes in an ush2a animal model. Invest Ophthalmol Vis Sci 51(4):2269–2276PubMedCrossRefGoogle Scholar
  51. 51.
    Falkner-Radler CI, Krebs I, Glittenberg C et al (2011) Human retinal pigment epithelium (RPE) transplantation: outcome after autologous RPE-choroid sheet and RPE cell-suspension in a randomised clinical study. Br J Ophthalmol 95(3):370–375PubMedCrossRefGoogle Scholar
  52. 52.
    Sugino IK, Sun Q, Wang J 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):4979–4997PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Zarbin MA (2004) Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 122(4):598–614PubMedCrossRefGoogle Scholar
  54. 54.
    Sugino IK, Rapista A, Sun Q et al (2011) A method to enhance cell survival on Bruch’s membrane in eyes affected by age and age-related macular degeneration. Invest Ophthalmol Vis Sci 52(13):9598–9609PubMedCrossRefGoogle Scholar
  55. 55.
    Sugino IK, Sun Q, Springer C et al (2016) Two bioactive molecular weight fractions of a conditioned medium enhance RPE cell survival on age-related macular degeneration and aged Bruch’s membrane. Transl Vis Sci Technol 5(1):8PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Wenkel H, Streilein JW (1998) Analysis of immune deviation elicited by antigens injected into the subretinal space. Invest Ophthalmol Vis Sci 39(10):1823–1834PubMedGoogle Scholar
  57. 57.
    Zhang X, Bok D (1998) Transplantation of retinal pigment epithelial cells and immune response in the subretinal space. Invest Ophthalmol Vis Sci 39(6):1021–1027PubMedGoogle Scholar
  58. 58.
    Lu B, Tai YC, Humayun MS (2014) Microdevice-based cell therapy for age-related macular degeneration. Dev Ophthalmol 53:155–166PubMedCrossRefGoogle Scholar
  59. 59.
    Seiler MJ, Aramant RB, Thomas BB, Peng Q, Sadda SR, Keirstead HS (2010) Visual restoration and transplant connectivity in degenerate rats implanted with retinal progenitor sheets. Eur J Neurosci 31(3):508–520PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Assawachananont J, Mandai M, Okamoto S et al (2014) Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice. Stem Cell Reports 2(5):662–674PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Seiler MJ, Lin RE, McLelland BT et al (2017) Vision recovery and connectivity by fetal retinal sheet transplantation in an immunodeficient retinal degenerate rat model. Invest Ophthalmol Vis Sci 58(1):614–630PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Mandai M, Fujii M, Hashiguchi T et al (2017) iPSC-derived retina transplants improve vision in rd1 end-stage retinal-degeneration mice. Stem Cell Reports 8(1):69–83PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Radtke ND, Aramant RB, Petry HM, Green PT, Pidwell DJ, Seiler MJ (2008) Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. Am J Ophthalmol 146(2):172–182PubMedCrossRefGoogle Scholar
  64. 64.
    Huang JC, Ishida M, Hersh P, Sugino IK, Zarbin MA (1998) Preparation and transplantation of photoreceptor sheets. Curr Eye Res 17(6):573–585PubMedCrossRefGoogle Scholar
  65. 65.
    Xian B, Huang B (2015) The immune response of stem cells in subretinal transplantation. Stem Cell Res Ther 6:161PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    West EL, Pearson RA, Barker SE et al (2010) Long-term survival of photoreceptors transplanted into the adult murine neural retina requires immune modulation. Stem Cells 28(11):1997–2007PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Wang J, Zarbin M, Sugino I, Whitehead I, Townes-Anderson E (2016) RhoA signaling and synaptic damage occur within hours in a live pig model of CNS injury, retinal detachment. Invest Ophthalmol Vis Sci 57(8):3892–3906PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Fontainhas AM, Townes-Anderson E (2011) RhoA inactivation prevents photoreceptor axon retraction in an in vitro model of acute retinal detachment. Invest Ophthalmol Vis Sci 52(1):579–587PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Townes-Anderson E, Wang J, Halasz E et al (2017) Fasudil, a clinically used ROCK inhibitor, stabilizes rod photoreceptor synapses after retinal detachment. Transl Vis Sci Technol 6(3):22PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Townes-Anderson E, Sugino I, Zarbin M (2017) Using rho kinase inhibitors for retinal detachment. JAMA Ophthalmol 135(8):895PubMedCrossRefGoogle Scholar
  71. 71.
    Tena A, Sachs DH (2014) Stem cells: immunology and immunomodulation. Dev Ophthalmol 53:122–132PubMedCrossRefGoogle Scholar
  72. 72.
    Kaplan HJ, Leibole MA, Tezel T, Ferguson TA (1999) Fas ligand (CD95 ligand) controls angiogenesis beneath the retina. Nat Med 5(3):292–297PubMedCrossRefGoogle Scholar
  73. 73.
    Boyd AS, Wood KJ (2009) Variation in MHC expression between undifferentiated mouse ES cells and ES cell-derived insulin-producing cell clusters. Transplantation 87(9):1300–1304PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Tian L, Catt JW, O’Neill C, King NJ (1997) Expression of immunoglobulin superfamily cell adhesion molecules on murine embryonic stem cells. Biol Reprod 57(3):561–568PubMedCrossRefGoogle Scholar
  75. 75.
    Wakayama T, Tabar V, Rodriguez I, Perry AC, Studer L, Mombaerts P (2001) Differentiation of embryonic stem cell lines generated from adult somatic cells by nuclear transfer. Science 292(5517):740–743PubMedCrossRefGoogle Scholar
  76. 76.
    Fairchild PJ, Nolan KF, Cartland S, Waldmann H (2005) Embryonic stem cells: a novel source of dendritic cells for clinical applications. Int Immunopharmacol 5(1):13–21PubMedCrossRefGoogle Scholar
  77. 77.
    Robertson NJ, Brook FA, Gardner RL, Cobbold SP, Waldmann H, Fairchild PJ (2007) Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance. Proc Natl Acad Sci U S A 104(52):20920–20925PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Fairchild PJ (2010) The challenge of immunogenicity in the quest for induced pluripotency. Nat Rev Immunol 10(12):868–875PubMedCrossRefGoogle Scholar
  79. 79.
    Tezel TH, Del Priore LV, Berger AS, Kaplan HJ (2007) Adult retinal pigment epithelial transplantation in exudative age-related macular degeneration. Am J Ophthalmol 143(4):584–595PubMedCrossRefGoogle Scholar
  80. 80.
    Boyd AS, Fairchild PJ (2010) Approaches for immunological tolerance induction to stem cell-derived cell replacement therapies. Expert Rev Clin Immunol 6(3):435–448PubMedCrossRefGoogle Scholar
  81. 81.
    Nakatsuji N, Nakajima F, Tokunaga K (2008) HLA-haplotype banking and iPS cells. Nat Biotechnol 26(7):739–740PubMedCrossRefGoogle Scholar
  82. 82.
    Zimmermann A, Preynat-Seauve O, Tiercy JM, Krause KH, Villard J (2012) Haplotype-based banking of human pluripotent stem cells for transplantation: potential and limitations. Stem Cells Dev 21(13):2364–2373PubMedCrossRefGoogle Scholar
  83. 83.
    Taylor CJ, Peacock S, Chaudhry AN, Bradley JA, Bolton EM (2012) Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. Cell Stem Cell 11(2):147–152PubMedCrossRefGoogle Scholar
  84. 84.
    Turner M, Leslie S, Martin NG et al (2013) Toward the development of a global induced pluripotent stem cell library. Cell Stem Cell 13(4):382–384PubMedCrossRefGoogle Scholar
  85. 85.
    Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U (2004) Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci 45(12):4251–4255PubMedCrossRefGoogle Scholar
  86. 86.
    Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448(7151):313–317PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Yamanaka S (2007) Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1(1):39–49PubMedCrossRefGoogle Scholar
  88. 88.
    Nakagawa M, Koyanagi M, Tanabe K et al (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26(1):101–106PubMedCrossRefGoogle Scholar
  89. 89.
    Li W, Zhou H, Abujarour R et al (2009) Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells 27(12):2992–3000PubMedPubMedCentralGoogle Scholar
  90. 90.
    Zhu S, Li W, Zhou H et al (2010) Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 7(6):651–655PubMedCrossRefGoogle Scholar
  91. 91.
    Kolomeyer AM, Zarbin MA (2014) Trophic factors in the pathogenesis and therapy for retinal degenerative diseases. Surv Ophthalmol 59(2):134–165CrossRefGoogle Scholar
  92. 92.
    Huangfu D, Osafune K, Maehr R et al (2008) Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 26(11):1269–1275PubMedCrossRefGoogle Scholar
  93. 93.
    Shi Y, Desponts C, Do JT, Hahm HS, Scholer HR, Ding S (2008) Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3(5):568–574PubMedCrossRefGoogle Scholar
  94. 94.
    Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S (2008) Generation of mouse induced pluripotent stem cells without viral vectors. Science 322(5903):949–953PubMedCrossRefGoogle Scholar
  95. 95.
    Yu J, Hu K, Smuga-Otto K et al (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324(5928):797–801PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458(7239):771–775PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Warren L, Manos PD, Ahfeldt T et al (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7(5):618–630PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Zhou H, Wu S, Joo JY et al (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4(5):381–384PubMedCrossRefGoogle Scholar
  99. 99.
    Kim D, Kim CH, Moon JI et al (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4(6):472–476PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Balasubramanian S, Babai N, Chaudhuri A et al (2009) Non cell-autonomous reprogramming of adult ocular progenitors: generation of pluripotent stem cells without exogenous transcription factors. Stem Cells 27(12):3053–3062PubMedGoogle Scholar

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Authors and Affiliations

  • Marco Zarbin
    • 1
  1. 1.Institute of Ophthalmology and Visual Science, Rutgers-New Jersey Medical SchoolRutgers UniversityNewarkUSA

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