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Human Pluripotent Stem Cell-Derived Retinal Ganglion Cells: Applications for the Study and Treatment of Optic Neuropathies

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Abstract

Retinal ganglion cells (RGCs) are highly specialized neuronal cells located in the innermost layer of the retina and serve to relay visual information to the brain, with their axons collectively forming the optic nerve. Loss or damage to the RGCs results in visual impairment and ultimately blindness. Several diseases affect the RGCs exclusively, the most common being glaucoma. Even though the mechanisms of glaucoma are not fully understood, some common treatments can delay cell death. Pharmacological intervention or laser therapy is thought to reduce the intraocular pressure and therefore reduce cell damage, but ultimately these therapies are often transient and stop working. Additional strategies to rescue RGCs and prevent their loss are being explored. Human pluripotent stem cells (hPSCs), including both embryonic and induced pluripotent stem cells, serve as an effective in vitro model of retinal development and repair. In addition, RGCs differentiated from hPSCs can also provide an unlimited source of transplantable cells for use in cell replacement strategies. This review addresses some of the technical and clinical issues and concerns with generating bone fide RGCs in vitro. We also outline the potential applications of hPSC-derived RGCs as a useful tool in disease modeling and drug screening in order to advance knowledge of optic neuropathies.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Chang EE, Goldberg JL. Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology. 2012;119(5):979–86.

  2. 2.

    • Cho KS, Chen DF. Promoting optic nerve regeneration in adult mice with pharmaceutical approach. Neurochem Res. 2008;33(10):2126–33. Study demonstrating the importance of glial cell modulation using pharmacological compounds in order to enhance nerve regeneration in a model of glaucoma.

  3. 3.

    Levin LA. Neuroprotection and regeneration in glaucoma. Ophthalmology clinics of North America. 2005;18(4):585–596vii.

  4. 4.

    Weinreb RN. Glaucoma neuroprotection: What is it? Why is it needed? Can J Ophthalmol. 2007;42(3):396–8.

  5. 5.

    Gonzalez-Cordero A, et al. Photoreceptor precursors derived from three-dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina. Nat Biotechnol. 2013;31(8):741–7.

  6. 6.

    Lakowski J, et al. Transplantation of photoreceptor precursors isolated via a cell surface biomarker panel from embryonic stem cell-derived self-forming retina. Stem Cells. 2015;33(8):2469–82.

  7. 7.

    Lamba DA, Gust J, Reh TA. Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell. 2009;4(1):73–9.

  8. 8.

    •• 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(34):12769–74. This paper was the first to describe retinal cell differentiation from human embryonic stem cells.

  9. 9.

    •• Meyer JS, et al. Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment. Stem cells. 2011;29(8):1206–18. This study was among the first to describe the differentiation of RGCs from hPSCs, particularly from highly enriched populations of optic vesicle-like structures.  Furthermore, this study was also among the first to demonstrate the ability to model retinal degeneration in vitro with these cells

  10. 10.

    •• Meyer JS, et al. Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc Natl Acad Sci USA. 2009;106(39):16698–703. This study was the first to describe minimal and defined media components that allowed for cell intrinsic differentiation into retinal cells.

  11. 11.

    Nakano T, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012;10(6):771–85.

  12. 12.

    Osakada F, et al. Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nat Biotechnol. 2008;26(2):215–24.

  13. 13.

    Osakada F, et al. In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction. J Cell Sci. 2009;122(Pt 17):3169–79.

  14. 14.

    West EL, et al. Defining the integration capacity of embryonic stem cell-derived photoreceptor precursors. Stem cells. 2012;30(7):1424–35.

  15. 15.

    Al-Shamekh S, Goldberg JL. Retinal repair with induced pluripotent stem cells. Transl Res. 2014;163(4):377–86.

  16. 16.

    Jin ZB, Takahashi M. Generation of retinal cells from pluripotent stem cells. Prog Brain Res. 2012;201:171–81.

  17. 17.

    Sluch VM, Zack DJ. Stem cells, retinal ganglion cells and glaucoma. Dev Ophthalmol. 2014;53:111–21.

  18. 18.

    Kuehn MH, Fingert JH, Kwon YH. Retinal ganglion cell death in glaucoma: mechanisms and neuroprotective strategies. Ophthalmol clin North Am. 2005;18(3):383–395vi.

  19. 19.

    Moore DL, Goldberg JL. Four steps to optic nerve regeneration. J Neuroophthalmol. 2010;30(4):347–60.

  20. 20.

    Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262–7.

  21. 21.

    Tham YC, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121(11):2081–90.

  22. 22.

    Carelli V, et al. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta. 2009;1787(5):518–28.

  23. 23.

    Newman NJ. Treatment of hereditary optic neuropathies. Nature reviews. Neurology. 2012;8(10):545–56.

  24. 24.

    Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF. Treatment strategies for inherited optic neuropathies: past, present and future. Eye. 2014;28(5):521–37.

  25. 25.

    Berdahl JP, Allingham RR. Intracranial pressure and glaucoma. Curr Opin Ophthalmol. 2010;21(2):106–11.

  26. 26.

    Cohen LP, Pasquale LR. Clinical characteristics and current treatment of glaucoma. Cold Spring Harb Perspect Med. 2014;4(6):a017236.

  27. 27.

    Rasmussen CA, Kaufman PL. The trabecular meshwork in normal eyes and in exfoliation glaucoma. J Glaucoma. 2014;23(8 Suppl 1):S15–9.

  28. 28.

    Kowing D, Messer D, Slagle S, Wasik A. Programs to optimize adherence in glaucoma. Optometry. 2010;81(7):339–50.

  29. 29.

    McKinnon SJ, Goldberg LD, Peeples P, Walt JG, Bramley TJ. Current management of glaucoma and the need for complete therapy. Am J Manag Care. 2008;14(1 Suppl):S20–7.

  30. 30.

    Sambhara D, Aref AA. Glaucoma management: relative value and place in therapy of available drug treatments. Ther Adv Chronic Dis. 2014;5(1):30–43.

  31. 31.

    Zhang K, Zhang L, Weinreb RN. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev Drug Discov. 2012;11(7):541–59.

  32. 32.

    Bagga H, Liu JH, Weinreb RN. Intraocular pressure measurements throughout the 24 h. Curr Opin Ophthalmol. 2009;20(2):79–83.

  33. 33.

    Grippo TM, et al. Twenty-four-hour pattern of intraocular pressure in untreated patients with ocular hypertension. Invest Ophthalmol Vis Sci. 2013;54(1):512–7.

  34. 34.

    Wilensky JT. The role of diurnal pressure measurements in the management of open angle glaucoma. Curr Opin Ophthalmol. 2004;15(2):90–2.

  35. 35.

    Johnson TV, Bull ND, Martin KR. Neurotrophic factor delivery as a protective treatment for glaucoma. Exp Eye Res. 2011;93(2):196–203.

  36. 36.

    Martin KR, et al. Gene therapy with brain-derived neurotrophic factor as a protection: retinal ganglion cells in a rat glaucoma model. Invest Ophthalmol Vis Sci. 2003;44(10):4357–65.

  37. 37.

    Pease ME, et al. Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Invest Ophthalmol Vis Sci. 2009;50(5):2194–200.

  38. 38.

    Frank L, Wiegand SJ, Siuciak JA, Lindsay RM, Rudge JS. Effects of BDNF infusion on the regulation of TrkB protein and message in adult rat brain. Exp Neurol. 1997;145(1):62–70.

  39. 39.

    Meyer-Franke A, et al. Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron. 1998;21(4):681–93.

  40. 40.

    Chen H, Weber AJ. Brain-derived neurotrophic factor reduces TrkB protein and mRNA in the normal retina and following optic nerve crush in adult rats. Brain Res. 2004;1011(1):99–106.

  41. 41.

    Capowski EE, et al. Loss of MITF expression during human embryonic stem cell differentiation disrupts retinal pigment epithelium development and optic vesicle cell proliferation. Hum Mol Genet. 2014;23(23):6332–44.

  42. 42.

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

  43. 43.

    Mellough CB, Sernagor E, Moreno-Gimeno I, Steel DH, Lako M. Efficient stage-specific differentiation of human pluripotent stem cells toward retinal photoreceptor cells. Stem cells. 2012;30(4):673–86.

  44. 44.

    Ohlemacher SK, Iglesias CL, Sridhar A, Gamm DM, Meyer JS. Generation of highly enriched populations of optic vesicle-like retinal cells from human pluripotent stem cells. Current protocols in stem cell biology. 2015;32:1h.8.1–8.20.

  45. 45.

    Phillips MJ, et al. Blood-derived human iPS cells generate optic vesicle-like structures with the capacity to form retinal laminae and develop synapses. Invest Ophthalmol Vis Sci. 2012;53(4):2007–19.

  46. 46.

    Reichman S, et al. From confluent human iPS cells to self-forming neural retina and retinal pigmented epithelium. Proc Natl Acad Sci USA. 2014;111(23):8518–23.

  47. 47.

    Sridhar A, Steward MM, Meyer JS. Nonxenogeneic growth and retinal differentiation of human induced pluripotent stem cells. Stem Cells Transl Med. 2013;2(4):255–64.

  48. 48.

    • Tucker BA, et al. Duplication of TBK1 stimulates autophagy in iPSC-derived retinal cells from a patient with normal tension glaucoma. J Stem Cell Res Ther. 2014;3(5):161. One of the few papers that attempts to address disease modeling from hPSC-derived RGC-like cells.

  49. 49.

    • Zhong X, et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun. 2014;5:4047. Through the three-dimensional differentiation and organization of retinal cells from hPSCs, the authors are able to demonstrate a yield of Brn3-positive RGCs with the correct localization within retinal neuropsheres.

  50. 50.

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

  51. 51.

    Schwarz N, et al. Translational read-through of the RP2 Arg120stop mutation in patient iPSC-derived retinal pigment epithelium cells. Hum Mol Genet. 2015;24(4):972–86.

  52. 52.

    Carr AJ, et al. Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat. PLoS One. 2009;4(12):e8152.

  53. 53.

    Hu Y, et al. A novel approach for subretinal implantation of ultrathin substrates containing stem cell-derived retinal pigment epithelium monolayer. Ophthalmic Res. 2012;48(4):186–91.

  54. 54.

    Nakagawa M, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2008;26(1):101–6.

  55. 55.

    • Takahashi K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72. One of the first two papers to describe the induction of pluripotency from human somatic cells. This method really revolutionized the ability to study early human development and to now model diseases using patient-specific cells.

  56. 56.

    Yu J, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science. 2009;324(5928):797–801.

  57. 57.

    • Yu J, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20. This paper was also the first to describe the induction of pluripotency in human somatic cells. The two seminal studies were announced on the same day.

  58. 58.

    Hirami Y, et al. Generation of retinal cells from mouse and human induced pluripotent stem cells. Neurosci Lett. 2009;458(3):126–31.

  59. 59.

    Buchholz DE, et al. Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells. Stem cells. 2009;27(10):2427–34.

  60. 60.

    Vugler A, et al. Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation. Exp Neurol. 2008;214(2):347–61.

  61. 61.

    Dingwell KS, Holt CE, Harris WA. The multiple decisions made by growth cones of RGCs as they navigate from the retina to the tectum in Xenopus embryos. J Neurobiol. 2000;44(2):246–59.

  62. 62.

    Erskine L, Herrera E. The retinal ganglion cell axon’s journey: insights into molecular mechanisms of axon guidance. Dev Biol. 2007;308(1):1–14.

  63. 63.

    Erskine L, Herrera E. Connecting the retina to the brain. ASN Neuro. 2014;6(6):1759091414562107.

  64. 64.

    Williams SE, Mason CA, Herrera E. The optic chiasm as a midline choice point. Curr Opin Neurobiol. 2004;14(1):51–60.

  65. 65.

    Chambers SM, et al. Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors. Nat Biotechnol. 2012;30(7):715–20.

  66. 66.

    Koehler KR, Mikosz AM, Molosh AI, Patel D, Hashino E. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature. 2013;500(7461):217–21.

  67. 67.

    Shlens J, Rieke F, Chichilnisky E. Synchronized firing in the retina. Curr Opin Neurobiol. 2008;18(4):396–402.

  68. 68.

    Velte TJ, Masland RH. Action potentials in the dendrites of retinal ganglion cells. J Neurophysiol. 1999;81(3):1412–7.

  69. 69.

    •• Maekawa Y, et al. Optimized culture system to induce neurite outgrowth from retinal ganglion cells in three-dimensional retinal aggregates differentiated from mouse and human embryonic stem cells. Curr Eye Res. 2015;16:1–11. The authors attempt considerable characterization of neurite outgrowth from the hPSC-derived RGCs in this study. Alongside classic RGC markers the authors also identified RGCs using additional protein markers further delineating cell fate.

  70. 70.

    •• Riazifar H, Jia Y, Chen J, Lynch G, Huang T. Chemically induced specification of retinal ganglion cells from human embryonic and induced pluripotent stem cells. Stem Cells Transl Med. 2014;3(4):424–32. Cells differentiated in this study were characterized with more extensive RGC markers and the authors make first attempts at analyzing the cells functionality by whole-cell recording.

  71. 71.

    •• Tanaka T, et al. Generation of retinal ganglion cells with functional axons from human induced pluripotent stem cells. Sci Rep. 2015;5:8344. This study shows more extensive characterization of RGC differentiated from hPSCs and touches upon functionality of the cells generated.

  72. 72.

    Marchetto MC, Brennand KJ, Boyer LF, Gage FH. Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises. Hum Mol Genet. 2011;20(R2):R109–15.

  73. 73.

    Merkle FT, Eggan K. Modeling human disease with pluripotent stem cells: from genome association to function. Cell Stem Cell. 2013;12(6):656–68.

  74. 74.

    Minegishi Y, et al. Enhanced optineurin E50 K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma. Hum Mol Genet. 2013;22(17):3559–67.

  75. 75.

    Heilker R, Traub S, Reinhardt P, Scholer HR, Sterneckert J. iPS cell derived neuronal cells for drug discovery. Trends Pharmacol Sci. 2014;35(10):510–9.

  76. 76.

    Ko HC, Gelb BD. Concise review: drug discovery in the age of the induced pluripotent stem cell. Stem Cells Transl Med. 2014;3(4):500–9.

  77. 77.

    Schadt EE, Buchanan S, Brennand KJ, Merchant KM. Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders. Front Pharmacol. 2014;5:252.

  78. 78.

    Jeffery G, Levitt JB, Cooper HM. Segregated hemispheric pathways through the optic chiasm distinguish primates from rodents. Neuroscience. 2008;157(3):637–43.

  79. 79.

    Neveu MM, Jeffery G. Chiasm formation in man is fundamentally different from that in the mouse. Eye. 2007;21(10):1264–70.

  80. 80.

    Schmidt KG, Bergert H, Funk RH. Neurodegenerative diseases of the retina and potential for protection and recovery. Curr Neuropharmacol. 2008;6(2):164–78.

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Correspondence to Jason S. Meyer.

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Cooke, J.A., Meyer, J.S. Human Pluripotent Stem Cell-Derived Retinal Ganglion Cells: Applications for the Study and Treatment of Optic Neuropathies. Curr Ophthalmol Rep 3, 200–206 (2015). https://doi.org/10.1007/s40135-015-0081-9

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Keywords

  • Retinal Pigment Epithelium
  • Neurotrophic Factor
  • Pluripotent Stem Cell
  • Retinal Ganglion Cell
  • Optic Neuropathy