Pluripotent Stem Cells as Models of Retina Development

  • Amy Q. Lu
  • Colin J. BarnstableEmail author


The ability of pluripotent stem cells (PSCs) to differentiate into retinal tissue has led to many attempts to direct this process to yield specific retinal cell types. The ability to do so would greatly impact both the study of normal retina development in model systems that can be precisely controlled and the generation of a homogeneous population of cells optimized for transplantation in cell replacement therapy. Thus far, many reviews have focused on the translational potential of PSC retinal studies. Here, we focus on the former by summarizing the advances and reflecting on the current limitations to using in vitro differentiation of PSCs into retinal cells and organoids to model in vivo retinal development, with a specific emphasis on photoreceptors. We discuss the versatility of PSC retinal differentiation systems in investigating specific developmental time points that are difficult to assess with classic developmental model systems as well as the potential for efficient screening of factors involved in regulating photoreceptor differentiation. PSCs can be used in conjunction with existing model systems to contribute to the understanding of retina and photoreceptor development, which in turn can enhance the success of using stem cells in translational studies.


Retina Photoreceptor Development Differentiation Pluripotent Stem cells 



  1. 1.
    Barnstable CJ (1987) Immunological studies of the diversity and development of the mammalian visual system. Immunol Rev 100:47–78. CrossRefPubMedGoogle Scholar
  2. 2.
    Zhang SS-M, Xu X, Liu M-G et al (2006) A biphasic pattern of gene expression during mouse retina development. BMC Dev Biol 6:48. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Dorrell MI, Aguilar E, Weber C, Friedlander M (2004) Global gene expression analysis of the developing postnatal mouse retina. Investig Ophthalmol Vis Sci 45:1009–1019. CrossRefGoogle Scholar
  4. 4.
    Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, Tirosh I, Bialas AR et al (2015) Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161:1202–1214. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Zuber ME (2003) Specification of the vertebrate eye by a network of eye field transcription factors. Development 130:5155–5167. CrossRefPubMedGoogle Scholar
  6. 6.
    Andreazzoli M, Gestri G, Angeloni D, Menna E, Barsacchi G (1999) Role of Xrx1 in Xenopus eye and anterior brain development. Development 126:2451–2460PubMedGoogle Scholar
  7. 7.
    Heavner W, Pevny L (2012) Eye development and retinogenesis. Cold Spring Harb Perspect Biol 4:a008391–a008391. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Centanin L, Wittbrodt J (2014) Retinal neurogenesis. Development 141:241–244. CrossRefPubMedGoogle Scholar
  9. 9.
    Jeon C-J, Strettoi E, Masland RH (1998) The major cell populations of the mouse retina. J Neurosci 18:8936–8946. CrossRefPubMedGoogle Scholar
  10. 10.
    Volland S, Esteve-Rudd J, Hoo J, Yee C, Williams DS (2015) A comparison of some organizational characteristics of the mouse central retina and the human macula. PLoS One 10:e0125631. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    May CA (2008) Comparative anatomy of the optic nerve head and inner retina in non-primate animal models used for glaucoma research. Open Ophthalmol J 2:94–101. CrossRefGoogle Scholar
  12. 12.
    Petersen-Jones SM, Occelli LM, Winkler PA, Lee W, Sparrow JR, Tsukikawa M, Boye SL, Chiodo V et al (2017) Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach. J Clin Invest 128:190–206. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Narfström K, Holland Deckman K, Menotti-Raymond M (2011) The domestic cat as a large animal model for characterization of disease and therapeutic intervention in hereditary retinal blindness. J Ophthalmol 2011:1–8. CrossRefGoogle Scholar
  14. 14.
    Occelli LM, Tran NM, Narfström K, Chen S, Petersen-Jones SM (2016) CrxRdy cat: a large animal model for CRX-associated Leber congenital amaurosis. Invest Ophthalmol Vis Sci 57:3780–3792. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Streilein JW, Ma N, Wenkel H, Fong Ng T, Zamiri P (2002) Immunobiology and privilege of neuronal retina and pigment epithelium transplants. Vis Res 42:487–495. CrossRefPubMedGoogle Scholar
  16. 16.
    Streilein JW (2003) Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 3:879–889. CrossRefPubMedGoogle Scholar
  17. 17.
    Barnea-Cramer AO, Wang W, Lu S-J, Singh MS, Luo C, Huo H, McClements ME, Barnard AR et al (2016) Function of human pluripotent stem cell-derived photoreceptor progenitors in blind mice. Sci Rep 6:29784. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Decembrini S, Koch U, Radtke F, Moulin A, Arsenijevic Y (2014) Derivation of traceable and transplantable photoreceptors from mouse embryonic stem cells. Stem Cell Reports 2:853–865. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gonzalez-Cordero A, West EL, Pearson RA, Duran Y, Carvalho LS, Chu CJ, Naeem A, Blackford SJI et al (2013) Photoreceptor precursors derived from three-dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina. Nat Biotechnol 31:741–747. CrossRefPubMedGoogle Scholar
  20. 20.
    Gonzalez-Cordero A, Kruczek K, Naeem A, Fernando M, Kloc M, Ribeiro J, Goh D, Duran Y et al (2017) Recapitulation of human retinal development from human pluripotent stem cells generates transplantable populations of cone photoreceptors. Stem Cell Reports 9:820–837. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    MacLaren RE, Pearson RA, MacNeil A et al (2006) Retinal repair by transplantation of photoreceptor precursors. Nature 444:203–207. CrossRefPubMedGoogle Scholar
  22. 22.
    West EL, Gonzalez-Cordero A, Hippert C, Osakada F, Martinez-Barbera JP, Pearson RA, Sowden JC, Takahashi M et al (2012) Defining the integration capacity of embryonic stem cell-derived photoreceptor precursors. Stem Cells 30:1424–1435. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Niehrs C, Glinka A, Wu W et al (1997) Head induction by simultaneous repression of Bmp and Wnt signalling in Xenopus. Nature 389:517–519. CrossRefPubMedGoogle Scholar
  24. 24.
    Kengaku M, Okamoto H (1995) bFGF as a possible morphogen for the anteroposterior axis of the central nervous system in Xenopus. Development 121:3121–3130PubMedGoogle Scholar
  25. 25.
    Durston AJ, Timmermans JPM, Hage WJ, Hendriks HFJ, de Vries NJ, Heideveld M, Nieuwkoop PD (1989) Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature 340:140–144. CrossRefPubMedGoogle Scholar
  26. 26.
    Richard-Parpaillon L, Héligon C, Chesnel F, Boujard D, Philpott A (2002) The IGF pathway regulates head formation by inhibiting Wnt signaling in Xenopus. Dev Biol 244:407–417. CrossRefPubMedGoogle Scholar
  27. 27.
    Eivers E, McCarthy K, Glynn C et al (2004) Insulin-like growth factor (IGF) signalling is required for early dorso-anterior development of the zebrafish embryo. Int J Dev Biol 48:1131–1140. CrossRefPubMedGoogle Scholar
  28. 28.
    Pera EM, Wessely O, Li S-Y, De Robertis EM (2001) Neural and head induction by insulin-like growth factor signals. Dev Cell 1:655–665. CrossRefPubMedGoogle Scholar
  29. 29.
    Onuma Y, Takahashi S, Asashima M, Kurata S, Gehring WJ (2002) Conservation of Pax 6 function and upstream activation by Notch signaling in eye development of frogs and flies. Proc Natl Acad Sci 99:2020–2025. CrossRefPubMedGoogle Scholar
  30. 30.
    Kaewkhaw R, Kaya KD, Brooks M, Homma K, Zou J, Chaitankar V, Rao M, Swaroop A (2015) Transcriptome dynamics of developing photoreceptors in three-dimensional retina cultures recapitulates temporal sequence of human cone and rod differentiation revealing cell surface markers and gene networks. Stem Cells 33:3504–3518. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lu AQ, Popova EY, Barnstable CJ (2017) Activin signals through SMAD2/3 to increase photoreceptor precursor yield during embryonic stem cell differentiation. Stem Cell Reports 9:838–852. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hirano M, Yamamoto A, Yoshimura N, Tokunaga T, Motohashi T, Ishizaki K, Yoshida H, Okazaki K et al (2003) Generation of structures formed by lens and retinal cells differentiating from embryonic stem cells. Dev Dyn 228:664–671. CrossRefPubMedGoogle Scholar
  33. 33.
    Zhao X, Liu J, Ahmad I (2002) Differentiation of embryonic stem cells into retinal neurons. Biochem Biophys Res Commun 297:177–184. CrossRefPubMedGoogle Scholar
  34. 34.
    Ikeda H, Osakada F, Watanabe K, Mizuseki K, Haraguchi T, Miyoshi H, Kamiya D, Honda Y et al (2005) Generation of Rx+/Pax6+ neural retinal precursors from embryonic stem cells. Proc Natl Acad Sci U S A 102:11331–11336. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    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 103:12769–12774. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lamba DA, Reh TA, A M et al (2011) Microarray characterization of human embryonic stem cell–derived retinal cultures. Invest Ophthalmol Vis Sci 52:4897–4906. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    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 4:73–79. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lamba DA, McUsic A, Hirata RK, Wang PR, Russell D, Reh TA (2010) Generation, purification and transplantation of photoreceptors derived from human induced pluripotent stem cells. PLoS One 5:e8763. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ringuette R, Wang Y, Atkins M, Mears AJ, Yan K, Wallace VA (2014) Combinatorial hedgehog and mitogen signaling promotes the in vitro expansion but not retinal differentiation potential of retinal progenitor cells. Invest Ophthalmol Vis Sci 55:43–54. CrossRefPubMedGoogle Scholar
  40. 40.
    Wall DS, Mears AJ, McNeill B, Mazerolle C, Thurig S, Wang Y, Kageyama R, Wallace VA (2009) Progenitor cell proliferation in the retina is dependent on notch-independent Sonic hedgehog/Hes1 activity. J Cell Biol 184:101–112. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Nelson BR, Gumuscu B, Hartman BH, Reh TA (2006) Notch activity is downregulated just prior to retinal ganglion cell differentiation. Dev Neurosci 28:128–141. CrossRefPubMedGoogle Scholar
  42. 42.
    Zhang SS-M, Wei J, Qin H, Zhang L, Xie B, Hui P, Deisseroth A, Barnstable CJ et al (2004) STAT3-mediated signaling in the determination of rod photoreceptor cell fate in mouse retina. Invest Ophthalmol Vis Sci 45:2407. CrossRefPubMedGoogle Scholar
  43. 43.
    Pinzon-Guzman C, Zhang SS-M, Barnstable CJ (2011) Specific protein kinase C isoforms are required for rod photoreceptor differentiation. J Neurosci 31:18606–18617. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Jadhav AP, Mason HA, Cepko CL (2006) Notch 1 inhibits photoreceptor production in the developing mammalian retina. Development 133:913–923. CrossRefPubMedGoogle Scholar
  45. 45.
    Do Rhee K, Goureau O, Chen S, Yang X-J (2004) Cytokine-induced activation of signal transducer and activator of transcription in photoreceptor precursors regulates rod differentiation in the developing mouse retina. J Neurosci 24:9779–9788. CrossRefPubMedGoogle Scholar
  46. 46.
    Osakada F, Ikeda H, Mandai M, Wataya T, Watanabe K, Yoshimura N, Akaike A, Sasai Y et al (2008) Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nat Biotechnol 26:215–224. CrossRefPubMedGoogle Scholar
  47. 47.
    Völkner M, Zschätzsch M, Rostovskaya M, Overall RW, Busskamp V, Anastassiadis K, Karl MO (2016) Retinal organoids from pluripotent stem cells efficiently recapitulate retinogenesis. Stem Cell Reports 6:525–538. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Reichman S, Terray A, Slembrouck A, Nanteau C, Orieux G, Habeler W, Nandrot EF, Sahel JA et al (2014) From confluent human iPS cells to self-forming neural retina and retinal pigmented epithelium. Proc Natl Acad Sci U S A 111:8518–8523. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K, Saito K, Yonemura S et al (2012) Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10:771–785. CrossRefPubMedGoogle Scholar
  50. 50.
    Kamakura S, Oishi K, Yoshimatsu T, Nakafuku M, Masuyama N, Gotoh Y (2004) Hes binding to STAT3 mediates crosstalk between Notch and JAK–STAT signalling. Nat Cell Biol 6:547–554. CrossRefPubMedGoogle Scholar
  51. 51.
    Yoshimatsu T, Kawaguchi D, Oishi K, Takeda K, Akira S, Masuyama N, Gotoh Y (2006) Non-cell-autonomous action of STAT3 in maintenance of neural precursor cells in the mouse neocortex. Development 133:2553–2563. CrossRefPubMedGoogle Scholar
  52. 52.
    Zhang SS-M, Wei J, Li C, Barnstable CJ, Fu XY (2003) Expression and activation of STAT proteins during mouse retina development. Exp Eye Res 76:421–431. CrossRefPubMedGoogle Scholar
  53. 53.
    Hirami Y, Osakada F, Takahashi K, Okita K, Yamanaka S, Ikeda H, Yoshimura N, Takahashi M (2009) Generation of retinal cells from mouse and human induced pluripotent stem cells. Neurosci Lett 458:126–131. CrossRefPubMedGoogle Scholar
  54. 54.
    Swaroop A, Kim D, Forrest D (2010) Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat Rev Neurosci 11:563–576. CrossRefPubMedGoogle Scholar
  55. 55.
    Yang X-J (2004) Roles of cell-extrinsic growth factors in vertebrate eye pattern formation and retinogenesis. Semin Cell Dev Biol 15:91–103. CrossRefPubMedGoogle Scholar
  56. 56.
    Fuhrmann S, Levine EM, Reh TA (2000) Extraocular mesenchyme patterns the optic vesicle during early eye development in the embryonic chick. Development 127:4599–4609PubMedGoogle Scholar
  57. 57.
    Cavodeassi F, Carreira-Barbosa F, Young RM, Concha ML, Allende ML, Houart C, Tada M, Wilson SW (2005) Early stages of zebrafish eye formation require the coordinated activity of Wnt11, Fz5, and the Wnt/β-catenin pathway. Neuron 47:43–56. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Hyer J, Kuhlman J, Afif E, Mikawa T (2003) Optic cup morphogenesis requires pre-lens ectoderm but not lens differentiation. Dev Biol 259:351–363. CrossRefPubMedGoogle Scholar
  59. 59.
    Singh RK, Mallela RK, Cornuet PK, Reifler AN, Chervenak AP, West MD, Wong KY, Nasonkin IO (2015) Characterization of three-dimensional retinal tissue derived from human embryonic stem cells in adherent monolayer cultures. Stem Cells Dev 24:2778–2795. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Meyer JS, Shearer RL, Capowski EE, Wright LS, Wallace KA, McMillan EL, Zhang SC, Gamm DM (2009) Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc Natl Acad Sci 106:16698–16703. CrossRefPubMedGoogle Scholar
  61. 61.
    Boucherie C, Mukherjee S, Henckaerts E, Thrasher AJ, Sowden JC, Ali RR (2013) Brief report: Self-organizing neuroepithelium from human pluripotent stem cells facilitates derivation of photoreceptors. Stem Cells 31:408–414. CrossRefPubMedGoogle Scholar
  62. 62.
    Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, Sekiguchi K, Adachi T et al (2011) Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472:51–56. CrossRefPubMedGoogle Scholar
  63. 63.
    Bock C, Kiskinis E, Verstappen G, Gu H, Boulting G, Smith ZD, Ziller M, Croft GF et al (2011) Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144:439–452. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Sun C, Zhang J, Zheng D, Wang J, Yang H, Zhang X (2018) Transcriptome variations among human embryonic stem cell lines are associated with their differentiation propensity. PLoS One 13:e0192625. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Osafune K, Caron L, Borowiak M, Martinez RJ, Fitz-Gerald CS, Sato Y, Cowan CA, Chien KR et al (2008) Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol 26:313–315. CrossRefPubMedGoogle Scholar
  66. 66.
    Wang L, Hiler D, Xu B, AlDiri I, Chen X, Zhou X, Griffiths L, Valentine M et al (2018) Retinal cell type DNA methylation and histone modifications predict reprogramming efficiency and retinogenesis in 3D organoid cultures. Cell Rep 22:2601–2614. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Hiler D, Chen X, Hazen J, Kupriyanov S, Carroll PA, Qu C, Xu B, Johnson D et al (2015) Quantification of retinogenesis in 3D cultures reveals epigenetic memory and higher efficiency in iPSCs derived from rod photoreceptors. Cell Stem Cell 17:101–115. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Akagawa K, Hicks D, Barnstable CJ (1987) Histiotypic organization and cell differentiation in rat retinal reaggregate cultures. Brain Res 437:298–308. CrossRefPubMedGoogle Scholar
  69. 69.
    Layer PG, Rothermel A, Willbold E (2001) From stem cells towards neural layers: a lesson from re-aggregated embryonic retinal cells. Neuroreport 12:A39–A46. CrossRefPubMedGoogle Scholar
  70. 70.
    Sheffield JB, Moscona AA (1970) Electron microscopic analysis of aggregation of embryonic cells: the structure and differentiation of aggregates of neural retina cells. Dev Biol 23:36–61. CrossRefPubMedGoogle Scholar
  71. 71.
    Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M, Yonemura S, Matsumura M, Wataya T, Nishiyama A et al (2008) Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3:519–532. CrossRefPubMedGoogle Scholar
  72. 72.
    Eiraku M, Sasai Y (2012) Mouse embryonic stem cell culture for generation of three-dimensional retinal and cortical tissues. Nat Protoc 7:69–79. CrossRefGoogle Scholar
  73. 73.
    Lu AQ, Barnstable CJ (2018) Generation of photoreceptor precursors from mouse embryonic stem cells. Stem Cell Rev 14:247–261. CrossRefPubMedGoogle Scholar
  74. 74.
    Chen HY, Kaya KD, Dong L, Swaroop A (2016) Three-dimensional retinal organoids from mouse pluripotent stem cells mimic in vivo development with enhanced stratification and rod photoreceptor differentiation. Mol Vis 22:1077–1094PubMedPubMedCentralGoogle Scholar
  75. 75.
    Zhong X, Gutierrez C, Xue T, Hampton C, Vergara MN, Cao LH, Peters A, Park TS et al (2014) Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun 5:4047. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Wahlin KJ, Maruotti JA, Sripathi SR, Ball J, Angueyra JM, Kim C, Grebe R, Li W et al (2017) Photoreceptor outer segment-like structures in long-term 3D retinas from human pluripotent stem cells. Sci Rep 7:766. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, Yao B, Hamersky GR et al (2016) Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165:1238–1254. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    DiStefano T, Chen HY, Panebianco C, Kaya KD, Brooks MJ, Gieser L, Morgan NY, Pohida T et al (2018) Accelerated and improved differentiation of retinal organoids from pluripotent stem cells in rotating-Wall vessel bioreactors. Stem Cell Reports 10:300–313. CrossRefPubMedGoogle Scholar
  79. 79.
    Zhou S, Flamier A, Abdouh M, Tétreault N, Barabino A, Wadhwa S, Bernier G (2015) Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFβ and Wnt signaling. Development 142:3294–3306. CrossRefPubMedGoogle Scholar
  80. 80.
    Arai E, Parmar VM, Sahu B, Perusek L, Parmar T, Maeda A (2017) Docosahexaenoic acid promotes differentiation of photoreceptor cells in three-dimensional neural retinas. Neurosci Res 123:1–7. CrossRefPubMedGoogle Scholar
  81. 81.
    Hicks D, Barnstable CJ (1986) Lectin and antibody labelling of developing rat photoreceptor cells: An electron microscope immunocytochemical study. J Neurocytol 15:219–230. CrossRefPubMedGoogle Scholar
  82. 82.
    Sparrow JR, Hicks D, Barnstable CJ (1990) Cell commitment and differentiation in explants of embryonic rat neural retina. Comparison with the developmental potential of dissociated retina. Dev Brain Res 51:69–84. CrossRefGoogle Scholar
  83. 83.
    Wang X, Nookala S, Narayanan C, Giorgianni F, Beranova-Giorgianni S, Mccollum G, Gerling I, Penn JS et al (2009) Proteomic analysis of the retina: Removal of RPE alters outer segment assembly and retinal protein expression. Glia 57:380–392. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Stiemke MM, Landers RA, Al-Ubaidi MR et al (1994) Photoreceptor outer segment development in Xenopus laevis: influence of the pigment epithelium. Dev Biol 162:169–180. CrossRefPubMedGoogle Scholar
  85. 85.
    Jablonski MM, Tombran-Tink J, Mrazek DA, Iannaccone A (2000) Pigment epithelium-derived factor supports normal development of photoreceptor neurons and opsin expression after retinal pigment epithelium removal. J Neurosci 20:7149–7157. CrossRefPubMedGoogle Scholar
  86. 86.
    Lupo G, Novorol C, Smith JR, Vallier L, Miranda E, Alexander M, Biagioni S, Pedersen RA et al (2013) Multiple roles of Activin/Nodal, bone morphogenetic protein, fibroblast growth factor and Wnt/-catenin signalling in the anterior neural patterning of adherent human embryonic stem cell cultures. Open Biol 3:120167–120167. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Bertacchi M, Lupo G, Pandolfini L, Casarosa S, D’Onofrio M, Pedersen RA, Harris WA, Cremisi F (2015) Activin/nodal signaling supports retinal progenitor specification in a narrow time window during pluripotent stem cell neuralization. Stem Cell Reports 5:532–545. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    La Torre A, Hoshino A, Cavanaugh C et al (2015) The GIPC1-Akt1 pathway is required for the specification of the eye field in mouse embryonic stem cells. Stem Cells 33:2674–2685. CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Chang K-C, Hertz J, Zhang X, Jin XL, Shaw P, Derosa BA, Li JY, Venugopalan P et al (2017) Novel regulatory mechanisms for the SoxC transcriptional network required for visual pathway development. J Neurosci 37:4967–4981. CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Hendrickson A, Possin D, Vajzovic L, Toth CA (2012) Histologic development of the human fovea from midgestation to maturity. Am J Ophthalmol 154:767–778.e2. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Hendrickson A (2016) Development of retinal layers in prenatal human retina. Am J Ophthalmol 161:29–35.e1. CrossRefPubMedGoogle Scholar
  92. 92.
    Mellough CB, Collin J, Khazim M et al (2015) IGF-1 signaling plays an important role in the formation of three-dimensional laminated neural retina and other ocular structures from human embryonic stem cells. Stem Cells 33:2416–2430. CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Jensen AM, Wallace VA (1997) Expression of Sonic hedgehog and its putative role as a precursor cell mitogen in the developing mouse retina. Development 124:363–371PubMedGoogle Scholar
  94. 94.
    de Almeida-Pereira L, Repossi MG, Magalhães CF, Azevedo RF, Corrêa-Velloso JC, Ulrich H, Ventura ALM, Fragel-Madeira L (2018) P2Y12 but not P2Y13 purinergic receptor controls postnatal rat Retinogenesis in vivo. Mol Neurobiol 55:8612–8624. CrossRefPubMedGoogle Scholar
  95. 95.
    Popova EY, Pinzon-Guzman C, Salzberg AC, Zhang SSM, Barnstable CJ (2016) LSD1-mediated demethylation of H3K4me2 is required for the transition from late progenitor to differentiated mouse rod photoreceptor. Mol Neurobiol 53:4563–4581. CrossRefPubMedGoogle Scholar
  96. 96.
    Sreekanth S, Rasheed VA, Soundararajan L, Antony J, Saikia M, Sivakumar KC, Das AV (2017) miR cluster 143/145 directly targets Nrl and regulates rod photoreceptor development. Mol Neurobiol 54:8033–8049. CrossRefPubMedGoogle Scholar
  97. 97.
    Khalili S, Ballios BG, Belair-Hickey J, Donaldson L, Liu J, Coles BLK, Grisé KN, Baakdhah T et al (2018) Induction of rod versus cone photoreceptor-specific progenitors from retinal precursor cells. Stem Cell Res 33:215–227. CrossRefPubMedGoogle Scholar
  98. 98.
    Kajiwara M, Aoi T, Okita K, Takahashi R, Inoue H, Takayama N, Endo H, Eto K et al (2012) Donor-dependent variations in hepatic differentiation from human-induced pluripotent stem cells. Proc Natl Acad Sci U S A 109:12538–12543. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Abyzov A, Mariani J, Palejev D, Zhang Y, Haney MS, Tomasini L, Ferrandino AF, Rosenberg Belmaker LA et al (2012) Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492:438–442. CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Koso H, Minami C, Tabata Y, Inoue M, Sasaki E, Satoh S, Watanabe S (2009) CD73, a novel cell surface antigen that characterizes retinal photoreceptor precursor cells. Invest Ophthalmol Vis Sci 50:5411. CrossRefPubMedGoogle Scholar
  101. 101.
    Lakowski J, Gonzalez-Cordero A, West EL, Han YT, Welby E, Naeem A, Blackford SJI, Bainbridge JWB et al (2015) Transplantation of photoreceptor precursors isolated via a cell surface biomarker panel from embryonic stem cell-derived self-forming retina. Stem Cells 33:2469–2482. CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Ben-David U, Benvenisty N (2011) The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer 11:268–277. CrossRefPubMedGoogle Scholar
  103. 103.
    Chaudhry GR, Fecek C, Lai MM, Wu WC, Chang M, Vasquez A, Pasierb M, Trese MT (2009) Fate of embryonic stem cell derivatives implanted into the vitreous of a slow retinal degenerative mouse model. Stem Cells Dev 18:247–258. CrossRefPubMedGoogle Scholar
  104. 104.
    Lu B, Malcuit C, Wang S, Girman S, Francis P, Lemieux L, Lanza R, Lund R (2009) Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration. Stem Cells 27:2126–2135. CrossRefPubMedGoogle Scholar
  105. 105.
    Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ, Gregori NZ, Hubschman JP, Davis JL 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 385:509–516. CrossRefPubMedGoogle Scholar
  106. 106.
    Vugler A, Carr A-J, Lawrence J, Chen LL, Burrell K, Wright A, Lundh P, Semo M' et al (2008) Elucidating the phenomenon of HESC-derived RPE: Anatomy of cell genesis, expansion and retinal transplantation. Exp Neurol 214:347–361. CrossRefPubMedGoogle Scholar
  107. 107.
    Mandai M, Fujii M, Hashiguchi T, Sunagawa GA, Ito SI, Sun J, Kaneko J, Sho J et al (2017) iPSC-derived retina transplants improve vision in rd1 end-stage retinal-degeneration mice. Stem Cell Reports 8:69–83. CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Hambright D, Park K-Y, Brooks M, McKay R, Swaroop A, Nasonkin IO (2012) Long-term survival and differentiation of retinal neurons derived from human embryonic stem cell lines in un-immunosuppressed mouse retina. Mol Vis 18:920–936PubMedPubMedCentralGoogle Scholar
  109. 109.
    Tucker BA, Park I-H, Qi SD, Klassen HJ, Jiang C, Yao J, Redenti S, Daley GQ et al (2011) Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS One 6:e18992. CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Santos-Ferreira TF, Borsch O, Ader M (2016) Rebuilding the missing part—a review on photoreceptor transplantation. Front Syst Neurosci 10:105. CrossRefPubMedGoogle Scholar
  111. 111.
    Canto-Soler V, Flores-Bellver M, Vergara MN (2016) Stem cell sources and their potential for the treatment of retinal degenerations. Invest Ophthalmol Vis Sci 57:ORSFd1–ORSFd9. CrossRefPubMedGoogle Scholar
  112. 112.
    Pearson RA (2014) Advances in repairing the degenerate retina by rod photoreceptor transplantation. Biotechnol Adv 32:485–491. CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Tang Z, Zhang Y, Wang Y, Zhang D, Shen B, Luo M, Gu P (2017) Progress of stem/progenitor cell-based therapy for retinal degeneration. J Transl Med 15(99).
  114. 114.
    Mead B, Berry M, Logan A, Scott RAH, Leadbeater W, Scheven BA (2015) Stem cell treatment of degenerative eye disease. Stem Cell Res 14:243–257. CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Wright LS, Phillips MJ, Pinilla I, Hei D, Gamm DM (2014) Induced pluripotent stem cells as custom therapeutics for retinal repair: progress and rationale. Exp Eye Res 123:161–172. CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Reynolds J, Lamba DA (2014) Human embryonic stem cell applications for retinal degenerations. Exp Eye Res 123:151–160. CrossRefPubMedGoogle Scholar
  117. 117.
    Stern JH, Tian Y, Funderburgh J, Pellegrini G, Zhang K, Goldberg JL, Ali RR, Young M et al (2018) Regenerating eye tissues to preserve and restore vision. Cell Stem Cell 22:834–849. CrossRefPubMedGoogle Scholar
  118. 118.
    Markus A, Shamul A, Chemla Y, Farah N, Shaham L, Goldstein RS, Mandel Y (2018) An optimized protocol for generating labeled and transplantable photoreceptor precursors from human embryonic stem cells. Exp Eye Res 180:29–38. CrossRefPubMedGoogle Scholar
  119. 119.
    Mehat MS, Sundaram V, Ripamonti C, Robson AG, Smith AJ, Borooah S, Robinson M, Rosenthal AN et al (2018) Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells in macular degeneration. Ophthalmology 125:1765–1775. CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Pearson RA, Barber AC, Rizzi M, Hippert C, Xue T, West EL, Duran Y, Smith AJ et al (2012) Restoration of vision after transplantation of photoreceptors. Nature 485:99–103. CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Assawachananont J, Mandai M, Okamoto S, Yamada C, Eiraku M, Yonemura S, Sasai Y, Takahashi M (2014) Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice. Stem Cell Reports 2:662–674. CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Seiler MJ, Aramant RB (2012) Cell replacement and visual restoration by retinal sheet transplants. Prog Retin Eye Res 31:661–687. CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Foik AT, Lean GA, Scholl LR, McLelland BT, Mathur A, Aramant RB, Seiler MJ, Lyon DC (2018) Detailed visual cortical responses generated by retinal sheet transplants in rats with severe retinal degeneration. J Neurosci 38:10709–10724. CrossRefPubMedGoogle Scholar
  124. 124.
    McLelland BT, Lin B, Mathur A et al (2018) Transplanted hESC-derived retina organoid sheets differentiate, integrate, and improve visual function in retinal degenerate rats. Invest Ophthalmol Vis Sci 59:2586–2603. CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Iraha S, Tu H-Y, Yamasaki S, Kagawa T, Goto M, Takahashi R, Watanabe T, Sugita S et al (2018) Establishment of Immunodeficient retinal degeneration model mice and functional maturation of human ESC-derived retinal sheets after transplantation. Stem Cell Reports 10:1059–1074. CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Gust J, Reh TA (2011) Adult donor rod photoreceptors integrate into the mature mouse retina. Invest Ophthalmol Vis Sci 52:5266–5272. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neural and Behavioral SciencesPennsylvania State University College of MedicineHersheyUSA

Personalised recommendations