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Induced Pluripotent Stem Cell-Based Cell Therapy of the Retina

  • Seiji Takagi
  • Michiko Mandai
  • Yasuhiko Hirami
  • Yasuo Kurimoto
  • Masayo TakahashiEmail author
Chapter
Part of the Current Human Cell Research and Applications book series (CHCRA)

Abstract

This review outlines the progress and current knowledge of stem cell-based treatments for the retina. Basic research, which began as a study of neural stem cells in the 1980s, is now being applied for the clinical use of embryonic stem (ES) cells and induced pluripotent stem cells (iPSCs). The author’s group had transplanted iPS cell-derived retinal pigment epithelial (RPE) cell sheets to the eye of a patient with exudative age-related macular degeneration (AMD) in 2014 as a clinical research. Since it was the first clinical study using iPS cell-derived cells, the safety and tumorigenicity of iPSCs products were especially a great concern. At 1 year after surgery, the transplanted sheet remained intact, and no serious adverse event including tumor formation had been observed.

Autologous iPSC, which have lower chance for tissue rejection, is an ideal cell source for a transplant therapy; however, production of autologous iPSC lines is too costly. To address this issue, we are currently exploring the use of allogenic RPE cells from iPSCs of HLA homozygote donors with the Center for iPSC Research and Application (CiRA) of Kyoto University.

Regarding photoreceptor implantation, we recently demonstrated a direct contact between the host bipolar cell-end and the presynaptic terminal of the graft photoreceptor by directly implanting retinal tissues derived from murine iPSC into a mouse model of end-stage retinal degeneration. We believe that our findings established a new proof of concept for transplanting ESC/iPSC retinas to restore vision in patients with end-stage retinal degeneration.

Keywords

autologous transplants clinical research iPS cells retinal cells 

References

  1. 1.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.PubMedCrossRefGoogle Scholar
  3. 3.
    Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.PubMedCrossRefGoogle Scholar
  4. 4.
    Yamanaka S. A fresh look at iPS cells. Cell. 2009;137(1):13–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Osakada F, Ikeda H, Mandai M, 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.PubMedCrossRefGoogle Scholar
  6. 6.
    Hirami Y, Osakada F, Takahashi K, et al. Generation of retinal cells from mouse and human induced pluripotent stem cells. Neurosci Lett. 2009;458(3):126–31.PubMedCrossRefGoogle Scholar
  7. 7.
    Haruta M, Sasai Y, Kawasaki H, et al. In vitro and in vivo characterization of pigment epithelial cells differentiated from primate embryonic stem cells. Invest Opthalmol Vis Sci. 2004;45(3):1020.CrossRefGoogle Scholar
  8. 8.
    Mandai M, Watanabe A, Kurimoto Y, et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med. 2017;376(11):1038–46.PubMedCrossRefGoogle Scholar
  9. 9.
    Price J, Turner D, Cepko C. Lineage analysis in the vertebrate nervous system by retrovirus-mediated gene transfer (retrovirus vectors!/-galactosidase/neural progenitors/retina). Proc Natl Acad Sci U S A. 1987;84:156–60.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Luskin MB. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron. 1993;11(1):173–89.PubMedCrossRefGoogle Scholar
  11. 11.
    Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996;16(6):2027–33.PubMedCrossRefGoogle Scholar
  12. 12.
    Vescovi A, Reynolds BA, Fraser DD, Weiss S. bFCF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronallastroglial) EGF-generated CNS progenitor cells. Neuron. 1993;11:951–66.PubMedCrossRefGoogle Scholar
  13. 13.
    Gage FH. The adult rat hippocampus contains primordial neural stem cells.pdf. Mol Cell Neurosci. 1997;8:389–404.PubMedCrossRefGoogle Scholar
  14. 14.
    Takahashi M, Palmer TD, Takahashi J, Gage FH. Widespread integration and survival of adult-derived neural progenitor cells in the developing optic retina. Mol Cell Neurosci. 1998;12:340–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Akagi T, Haruta M, Akita J, et al. Different characteristics of rat retinal progenitor cells from different culture periods. Neurosci Lett. 2003;341(3):213–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Bok D. The retinal pigment epithelium: a versatile partner in vision. J Cell Sci Suppl. 1993;17:189–95.PubMedCrossRefGoogle Scholar
  17. 17.
    Strauss O. The retinal pigment epithelium in visual function. Physiol Rev. 2005;85(3):845–81.PubMedCrossRefGoogle Scholar
  18. 18.
    Adamis AP, Shima DT, Yeo KT, et al. Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells. Biochem Biophys Res Commun. 1993;193(2):631–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Dawson DW, Volpert OV, Gillis P, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 1999;285(5425):245–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Khaliq A, Patel B, Jarvis-Evans J, et al. Oxygen modulates production of bFGF and TGF-beta by retinal cells in vitro. Exp Eye Res. 1995;60(4):415–23.PubMedCrossRefGoogle Scholar
  21. 21.
    Friedman DS, O'Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564–72.PubMedCrossRefGoogle Scholar
  22. 22.
    Gass JD. Biomicroscopic and histopathologic considerations regarding the feasibility of surgical excision of subfoveal neovascular membranes. Am J Ophthalmol. 1994;118(3):285–98.PubMedCrossRefGoogle Scholar
  23. 23.
    Yasuda M, Kiyohara Y, Hata Y, et al. Nine-year incidence and risk factors for age-related macular degeneration in a defined Japanese population the Hisayama study. Ophthalmology. 2009;116(11):2135–40.PubMedCrossRefGoogle Scholar
  24. 24.
    Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57–65.e5.PubMedCrossRefGoogle Scholar
  25. 25.
    Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388–98.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Rivera A, Fisher SA, Fritsche LG, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet. 2005;14(21):3227–36.PubMedCrossRefGoogle Scholar
  27. 27.
    Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314(5801):992–3.PubMedCrossRefGoogle Scholar
  28. 28.
    Group A-REDSR. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417–36.CrossRefGoogle Scholar
  29. 29.
    Zarbin MA, Rosenfeld PJ. Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. Retina. 2010;30(9):1350–67.PubMedCrossRefGoogle Scholar
  30. 30.
    Algvere PV, Berglin L, Gouras P, Sheng Y. Transplantation of fetal retinal pigment epithelium in age-related macular degeneration with subfoveal neovascularization. Graefes Arch Clin Exp Ophthalmol. 1994;232(12):707–16.PubMedCrossRefGoogle Scholar
  31. 31.
    van Zeeburg EJ, Maaijwee KJ, Missotten TO, et al. A free retinal pigment epithelium-choroid graft in patients with exudative age-related macular degeneration: results up to 7 years. Am J Ophthalmol. 2012;153(1):120–7.e2.PubMedCrossRefGoogle Scholar
  32. 32.
    Kawasaki H, Suemori H, Mizuseki K, Watanabe K, Urano F, Ichinose H, Haruta M, Takahashi M, Yoshikawa K, Nishikawa S, Nakatsuji N, Sasai Y. Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity. Proc Natl Acad Sci U S A. 2002;99(3):1580–5.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Ikeda H, Osakada F, Watanabe K, Mizuseki K, Haraguchi T, Miyoshi H, Kamiya D, Honda Y, Sasai N, Yoshimura N, Takahashi M, Sasai Y. Generation of Rx Pax6neural retinal precursors from embryonic stem cells. Proc Natl Acad Sci U S A. 2005;102(32):11331–6.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Osakada F, Jin ZB, Hirami Y, 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.PubMedCrossRefGoogle Scholar
  35. 35.
    Lund RD, Wang S, Klimanskaya I, et al. Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats. Cloning Stem Cells. 2006;8(3):189–99.PubMedCrossRefGoogle Scholar
  36. 36.
    Meyer JS, Shearer RL, Capowski EE, et al. Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2009;106(39):16698–703.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Amirpour N, Nasr-Esfahani MH, Esfandiari E, et al. Comparing three methods of co-culture of retinal pigment epithelium with progenitor cells derived human embryonic stem cells. Int J Prev Med. 2013;4(11):1243–50.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Jin ZB, Okamoto S, Osakada F, et al. Modeling retinal degeneration using patient-specific induced pluripotent stem cells. PLoS One. 2011;6(2):e17084.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Kamao H, Mandai M, Wakamiya S, Ishida J, Goto K, Ono T, Suda T, Takahashi M, Kiryu J. Objective evaluation of the degree of pigmentation in human induced pluripotent stem cell–derived RPE. Invest Ophthalmol Vis Sci. 2014;55:8309–18.PubMedCrossRefGoogle Scholar
  40. 40.
    Maeda T, Lee MJ, Palczewska G, et al. Retinal pigmented epithelial cells obtained from human induced pluripotent stem cells possess functional visual cycle enzymes in vitro and in vivo. J Biol Chem. 2013;288(48):34484–93.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Schwartz SD, Hubschman J-P, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012;379(9817):713–20.PubMedCrossRefGoogle Scholar
  42. 42.
    Schwartz SD, Regillo CD, Lam BL, et al. 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. 2015;385(9967):509–16.PubMedCrossRefGoogle Scholar
  43. 43.
    Kuroda T, Yasuda S, Kusakawa S, et al. Highly sensitive in vitro methods for detection of residual undifferentiated cells in retinal pigment epithelial cells derived from human iPS cells. PLoS One. 2012;7(5):e37342.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Kanemura H, Go MJ, Shikamura M, et al. Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration. PLoS One. 2014;9(1):e85336.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kanemura H, Go MJ, Nishishita N, et al. Pigment epithelium-derived factor secreted from retinal pigment epithelium facilitates apoptotic cell death of iPSC. Sci Rep. 2013;3:2334.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Takahashi M. Retinal cell therapy using iPS cells. Nippon Ganka Gakkai Zasshi. 2016;120(3):210–24; discussion 25PubMedGoogle Scholar
  47. 47.
    Kamao H, Mandai M, Ohashi W, et al. Evaluation of the surgical device and procedure for extracellular matrix-scaffold-supported human iPSC-derived retinal pigment epithelium cell sheet transplantation. Invest Ophthalmol Vis Sci. 2017;58(1):211–20.PubMedCrossRefGoogle Scholar
  48. 48.
    Zhao T, Zhang ZN, Rong Z, Xu Y. Immunogenicity of induced pluripotent stem cells. Nature. 2011;474(7350):212–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Sugita S, Iwasaki Y, Makabe K, et al. Lack of T cell response to iPSC-derived retinal pigment epithelial cells from HLA homozygous donors. Stem Cell Rep. 2016;7(4):619–34.CrossRefGoogle Scholar
  50. 50.
    Zamiri P, Masli S, Streilein JW, Taylor AW. Pigment epithelial growth factor suppresses inflammation by modulating macrophage activation. Invest Ophthalmol Vis Sci. 2006;47(9):3912–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110(13):4576–83.PubMedCrossRefGoogle Scholar
  52. 52.
    Sugita S, Iwasaki Y, Makabe K, et al. Successful transplantation of retinal pigment epithelial cells from MHC homozygote iPSCs in MHC-matched models. Stem Cell Rep. 2016;7(4):635–48.CrossRefGoogle Scholar
  53. 53.
    Saito S, Ota S, Yamada E, Inoko H, Ota M. Allele frequencies and haplotypic associations defined by allelic DNA typing at HLA class I and class II loci in the Japanese population. Tissue Antigens. 2000;56:522–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Stronks HC, Dagnelie G. The functional performance of the Argus II retinal prosthesis. Expert Rev Med Devices. 2014;11(1):23–30.PubMedCrossRefGoogle Scholar
  55. 55.
    da Cruz L, Dorn JD, Humayun MS, et al. Five-year safety and performance results from the Argus II retinal prosthesis system clinical trial. Ophthalmology. 2016;123(10):2248–54.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Cideciyan AV, Jacobson SG, Beltran WA, et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A. 2013;110(6):E517–25.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Jacobson SG, Matsui R, Sumaroka A, Cideciyan AV. Retinal structure measurements as inclusion criteria for stem cell-based therapies of retinal degenerations. Invest Ophthalmol Vis Sci. 2016;57(5):ORSFn1–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Young MJ, Ray J, Whiteley SJ, et al. Neuronal differentiation and morphological integration of hippocampal progenitor cells transplanted to the retina of immature and mature dystrophic rats. Mol Cell Neurosci. 2000;16(3):197–205.PubMedCrossRefGoogle Scholar
  59. 59.
    Nishida A, Takahashi M, Tanihara H, et al. Incorporation and differentiation of hippocampus-derived neural stem cells transplanted in injured adult rat retina. Invest Ophthalmol Vis Sci. 2000;41(13):4268–74.PubMedGoogle Scholar
  60. 60.
    Ooto S, Akagi T, Kageyama R, Akita J, Mandai M, Honda Y, Takahashi M. Potential for neural regeneration after neurotoxic injury in the adult mammalian retina. Proc Natl Acad Sci U S A. 2004;101(37):13654–9.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Radtke ND, Aramant RB, Petry HM, et al. Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. Am J Ophthalmol. 2008;146(2):172–82.PubMedCrossRefGoogle Scholar
  62. 62.
    Pearson RA, Barber AC, Rizzi M, et al. Restoration of vision after transplantation of photoreceptors. Nature. 2012;485(7396):99–103.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Pearson RA, Gonzalez-Cordero A, West EL, et al. Donor and host photoreceptors engage in material transfer following transplantation of post-mitotic photoreceptor precursors. Nat Commun. 2016;7:13029.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Santos-Ferreira T, Llonch S, Borsch O, et al. Retinal transplantation of photoreceptors results in donor-host cytoplasmic exchange. Nat Commun. 2016;7:13028.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Eiraku M, Takata N, Ishibashi H, et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature. 2011;472(7341):51–6.Google Scholar
  66. 66.
    Nakano T, Ando S, Takata N, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012;10(6):771–85.PubMedCrossRefGoogle Scholar
  67. 67.
    Gonzalez-Cordero A, West EL, Pearson RA, 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.PubMedCrossRefGoogle Scholar
  68. 68.
    Mandai M, Homma K, Okamoto S, et al. Adequate time window and environmental factors supporting retinal graft cell survival in rd mice. Cell Med. 2012;4(1):45–54.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Assawachananont J, Mandai M, Okamoto S, et al. Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice. Stem Cell Rep. 2014;2(5):662–74.CrossRefGoogle Scholar
  70. 70.
    Shirai H, Mandai M, Matsushita K, et al. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration. Proc Natl Acad Sci U S A. 2016;113(1):E81–90.PubMedCrossRefGoogle Scholar
  71. 71.
    Mandai M, Fujii M, Hashiguchi T, et al. iPSC-derived retina transplants improve vision in rd1 end-stage retinal-degeneration mice. Stem Cell Rep. 2017;8(1):69–83.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Seiji Takagi
    • 1
    • 2
    • 3
  • Michiko Mandai
    • 1
    • 4
  • Yasuhiko Hirami
    • 1
    • 2
  • Yasuo Kurimoto
    • 1
    • 2
  • Masayo Takahashi
    • 1
    • 4
    Email author
  1. 1.Department of OphthalmologyKobe City Medical Center General HospitalKobeJapan
  2. 2.Department of Translational Research Division of OphthalmologyInstitute of Biomedical Research and InnovationKobeJapan
  3. 3.Department of OphthalmologyToho University Ohashi Medical CenterTokyoJapan
  4. 4.RIKEN Center for Developmental BiologyKobeJapan

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