Advertisement

Developing Cell-Based Therapies for RPE-Associated Degenerative Eye Diseases

  • Karim Ben M’Barek
  • Walter Habeler
  • Florian Regent
  • Christelle MonvilleEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1186)

Abstract

In developed countries, blindness and visual impairment are caused mainly by diseases affecting the retina. These retinal degenerative diseases, including age-related macular dystrophy (AMD) and inherited retinal diseases such as retinitis pigmentosa (RP), are the predominant causes of human blindness worldwide and are responsible for more than 1.5 million cases in France and more than 30 million cases worldwide. Global prevalence and disease burden projections for next 20 years are alarming (Wong et al., Lancet Glob Health 2(2):e106–e116, 2014) and strongly argue toward designing innovative eye-care strategies. At present, despite the scientific advances achieved in the last years, there is no cure for such diseases, making retinal degenerative diseases an unmet medical need.

The majority of the inherited retinal disease (IRD) genes codes for proteins acting directly in photoreceptors. Yet, a few of them are expressed in the retinal pigment epithelium (RPE), the supporting tissue necessary for proper functioning of the photoreceptors. Among retinal degenerative diseases, impairment of some RPE genes engenders a spectrum of conditions ranging from stationary visual defects to very severe forms of retinal dystrophies in which the RPE dysfunction leads to photoreceptors cell death and consecutive irreversible vision loss. The accessibility of the eye and the immune privilege of the retina, together with the availability of noninvasive imaging technologies, make such inherited retinal dystrophies a particularly attractive disease model for innovative cell therapy approaches to replace, regenerate, and/or repair the injured RPE tissue. Proof-of-concept studies in animal models have demonstrated the safety and efficacy of the engraftment of therapeutic cells either to support RPE cell functions or to provide a trophic support to photoreceptors. These different approaches are now in the pipeline of drug development with objective to provide first cell-based treatments by 2020.

This chapter will focus on the different cell-based strategies developed in the past and current approaches to prevent photoreceptor death in RPE-associated degenerative eye diseases.

Keywords

RPE Human pluripotent stem cells Cell therapy Clinical trials Inherited retinal diseases 

References

  1. 1.
    Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, Wong TY (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2(2):e106–e116CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kolb H, Nelson R, Fernandez E, Jones B (2012) WEBVISION, The Organization of the Retina and Visual System. http://webvision.med.utah.edu/
  3. 3.
    Nag TC, Wadhwa S (2012) Ultrastructure of the human retina in aging and various pathological states. Micron 43(7):759–781CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sparrow JR, Hicks D, Hamel CP (2010) The retinal pigment epithelium in health and disease. Curr Mol Med 10(9):802–823CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cuenca N, Fernandez-Sanchez L, Campello L, Maneu V, De la Villa P, Lax P, Pinilla I (2014) Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res 43:17–75CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85(3):845–881CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ben M’Barek K, Regent F, Monville C (2015) Use of human pluripotent stem cells to study and treat retinopathies. World J Stem Cells 7(3):596–604CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    da Cruz L, Chen FK, Ahmado A, Greenwood J, Coffey P (2007) RPE transplantation and its role in retinal disease. Prog Retin Eye Res 26(6):598–635CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bird AC (1995) Retinal photoreceptor dystrophies LI. Edward Jackson Memorial Lecture. Am J Ophthalmol 119(5):543–562CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sahel JA, Marazova K, Audo I (2015) Clinical characteristics and current therapies for inherited retinal degenerations. Cold Spring Harb Perspect Med 5(2):a017111CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368(9549):1795–1809CrossRefGoogle Scholar
  12. 12.
    Berger W, Kloeckener-Gruissem B, Neidhardt J (2010) The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res 29(5):335–375CrossRefGoogle Scholar
  13. 13.
    den Hollander AI, Roepman R, Koenekoop RK, Cremers FP (2008) Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 27(4):391–419CrossRefGoogle Scholar
  14. 14.
    Hamel CP (2014) Gene discovery and prevalence in inherited retinal dystrophies. C R Biol 337(3):160–166CrossRefGoogle Scholar
  15. 15.
    Hamel CP, Griffoin JM, Lasquellec L, Bazalgette C, Arnaud B (2001) Retinal dystrophies caused by mutations in RPE65: assessment of visual functions. Br J Ophthalmol 85(4):424–427CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C, Liu SY, Harris E, Redmond TM, Arnaud B, Claustres M, Hamel CP (1997) Mutations in RPE65 cause Leber’s congenital amaurosis. Nat Genet 17(2):139–141CrossRefGoogle Scholar
  17. 17.
    Marlhens F, Griffoin JM, Bareil C, Arnaud B, Claustres M, Hamel CP (1998) Autosomal recessive retinal dystrophy associated with two novel mutations in the RPE65 gene. Eur J Hum Genet 6(5):527–531CrossRefGoogle Scholar
  18. 18.
    Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP (1998) Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci U S A 95(6):3088–3093CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Burstedt MS, Forsman-Semb K, Golovleva I, Janunger T, Wachtmeister L, Sandgren O (2001) Ocular phenotype of bothnia dystrophy, an autosomal recessive retinitis pigmentosa associated with an R234W mutation in the RLBP1 gene. Arch Ophthalmol 119(2):260–267PubMedGoogle Scholar
  20. 20.
    Maw MA, Kennedy B, Knight A, Bridges R, Roth KE, Mani EJ, Mukkadan JK, Nancarrow D, Crabb JW, Denton MJ (1997) Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa. Nat Genet 17(2):198–200CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Young RW, Bok D (1969) Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol 42(2):392–403CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bok D (1985) Retinal photoreceptor-pigment epithelium interactions. Friedenwald lecture. Invest Ophthalmol Vis Sci 26(12):1659–1694PubMedGoogle Scholar
  23. 23.
    Tarnowski BI, Shepherd VL, McLaughlin BJ (1988) Mannose 6-phosphate receptors on the plasma membrane on rat retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 29(2):291–297PubMedGoogle Scholar
  24. 24.
    Ryeom SW, Silverstein RL, Scotto A, Sparrow JR (1996) Binding of anionic phospholipids to retinal pigment epithelium may be mediated by the scavenger receptor CD36. J Biol Chem 271(34):20536–20539CrossRefGoogle Scholar
  25. 25.
    Ryeom SW, Sparrow JR, Silverstein RL (1996) CD36 participates in the phagocytosis of rod outer segments by retinal pigment epithelium. J Cell Sci 109(Pt 2):387–395PubMedGoogle Scholar
  26. 26.
    Lin H, Clegg DO (1998) Integrin alphavbeta5 participates in the binding of photoreceptor rod outer segments during phagocytosis by cultured human retinal pigment epithelium. Invest Ophthalmol Vis Sci 39(9):1703–1712PubMedGoogle Scholar
  27. 27.
    Hall MO, Burgess BL, Abrams TA, Ershov AV, Gregory CY (1996) Further studies on the identification of the phagocytosis receptor of rat retinal pigment epithelial cells. Exp Eye Res 63(3):255–264CrossRefGoogle Scholar
  28. 28.
    D’Cruz PM, Yasumura D, Weir J, Matthes MT, Abderrahim H, LaVail MM, Vollrath D (2000) Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 9(4):645–651CrossRefGoogle Scholar
  29. 29.
    Nandrot EF, Kim Y, Brodie SE, Huang X, Sheppard D, Finnemann SC (2004) Loss of synchronized retinal phagocytosis and age-related blindness in mice lacking alphavbeta5 integrin. J Exp Med 200(12):1539–1545CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Gal A, Li Y, Thompson DA, Weir J, Orth U, Jacobson SG, Apfelstedt-Sylla E, Vollrath D (2000) Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet 26(3):270–271CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Mazzoni F, Safa H, Finnemann SC (2014) Understanding photoreceptor outer segment phagocytosis: use and utility of RPE cells in culture. Exp Eye Res 126:51–60CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Zarbin MA, Rosenfeld PJ (2010) Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. Retina 30(9):1350–1367CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ambati J, Ambati BK, Yoo SH, Ianchulev S, Adamis AP (2003) Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol 48(3):257–293CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Boulton M, Dayhaw-Barker P (2001) The role of the retinal pigment epithelium: topographical variation and ageing changes. Eye (Lond) 15(Pt 3):384–389CrossRefGoogle Scholar
  35. 35.
    Nowak JZ (2006) Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol Rep 58(3):353–363PubMedPubMedCentralGoogle Scholar
  36. 36.
    Xu H, Chen M, Forrester JV (2009) Para-inflammation in the aging retina. Prog Retin Eye Res 28(5):348–368CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Bhutto I, Lutty G (2012) Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex. Mol Aspects Med 33(4):295–317CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Dunaief JL, Dentchev T, Ying GS, Milam AH (2002) The role of apoptosis in age-related macular degeneration. Arch Ophthalmol 120(11):1435–1442CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Fritsche LG, Chen W, Schu M, Yaspan BL, Yu Y, Thorleifsson G, Zack DJ, Arakawa S, Cipriani V, Ripke S, Igo RP Jr, Buitendijk GH, Sim X, Weeks DE, Guymer RH, Merriam JE, Francis PJ, Hannum G, Agarwal A, Armbrecht AM, Audo I, Aung T, Barile GR, Benchaboune M, Bird AC, Bishop PN, Branham KE, Brooks M, Brucker AJ, Cade WH, Cain MS, Campochiaro PA, Chan CC, Cheng CY, Chew EY, Chin KA, Chowers I, Clayton DG, Cojocaru R, Conley YP, Cornes BK, Daly MJ, Dhillon B, Edwards AO, Evangelou E, Fagerness J, Ferreyra HA, Friedman JS, Geirsdottir A, George RJ, Gieger C, Gupta N, Hagstrom SA, Harding SP, Haritoglou C, Heckenlively JR, Holz FG, Hughes G, Ioannidis JP, Ishibashi T, Joseph P, Jun G, Kamatani Y, Katsanis N, Keilhauer N, Khan JC, Kim IK, Kiyohara Y, Klein BE, Klein R, Kovach JL, Kozak I, Lee CJ, Lee KE, Lichtner P, Lotery AJ, Meitinger T, Mitchell P, Mohand-Said S, Moore AT, Morgan DJ, Morrison MA, Myers CE, Naj AC, Nakamura Y, Okada Y, Orlin A, Ortube MC, Othman MI, Pappas C, Park KH, Pauer GJ, Peachey NS, Poch O, Priya RR, Reynolds R, Richardson AJ, Ripp R, Rudolph G, Ryu E, Sahel JA, Schaumberg DA, Scholl HP, Schwartz SG, Scott WK, Shahid H, Sigurdsson H, Silvestri G, Sivakumaran TA, Smith RT, Sobrin L, Souied EH, Stambolian DE, Stefansson H, Sturgill-Short GM, Takahashi A, Tosakulwong N, Truitt BJ, Tsironi EE, Uitterlinden AG, van Duijn CM, Vijaya L, Vingerling JR, Vithana EN, Webster AR, Wichmann HE, Winkler TW, Wong TY, Wright AF, Zelenika D, Zhang M, Zhao L, Zhang K, Klein ML, Hageman GS, Lathrop GM, Stefansson K, Allikmets R, Baird PN, Gorin MB, Wang JJ, Klaver CC, Seddon JM, Pericak-Vance MA, Iyengar SK, Yates JR, Swaroop A, Weber BH, Kubo M, Deangelis MM, Leveillard T, Thorsteinsdottir U, Haines JL, Farrer LA, Heid IM, Abecasis GR, A. M. D. G. Consortium (2013) Seven new loci associated with age-related macular degeneration. Nat Genet 45(4):433–439, 439e431–432CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Macular Photocoagulation Study Group (1991) Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 109(9):1220–1231CrossRefGoogle Scholar
  41. 41.
    Azab M, Boyer DS, Bressler NM, Bressler SB, Cihelkova I, Hao Y, Immonen I, Lim JI, Menchini U, Naor J, Potter MJ, Reaves A, Rosenfeld PJ, Slakter JS, Soucek P, Strong HA, Wenkstern A, Su XY, Yang YC, Visudyne in Minimally Classic Choroidal Neovascularization Study Group (2005) Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial. Arch Ophthalmol 123(4):448–457CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR, VEGF Inhibition Study in Ocular Neovascularization Clinical Trial (2004) Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351(27):2805–2816CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T, A. S. Group (2009) Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 116(1):57–65.e55CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Chang TS, Bressler NM, Fine JT, Dolan CM, Ward J, Klesert TR, M. S. Group (2007) Improved vision-related function after ranibizumab treatment of neovascular age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol 125(11):1460–1469CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, M. S. Group (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355(14):1419–1431CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD, Ho AC, Ogura Y, Simader C, Jaffe GJ, Slakter JS, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Sowade O, Zeitz O, Norenberg C, Sandbrink R, Heier JS (2014) Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 121(1):193–201CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ (2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 364(20):1897–1908CrossRefGoogle Scholar
  48. 48.
    Rosenfeld PJ (2006) Intravitreal avastin: the low cost alternative to lucentis? Am J Ophthalmol 142(1):141–143CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Steinbrook R (2006) The price of sight—ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med 355(14):1409–1412CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Tolentino MJ, Dennrick A, John E, Tolentino MS (2015) Drugs in Phase II clinical trials for the treatment of age-related macular degeneration. Expert Opin Investig Drugs 24(2):183–199CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Cideciyan AV, Jacobson SG, Beltran WA, Sumaroka A, Swider M, Iwabe S, Roman AJ, Olivares MB, Schwartz SB, Komaromy AM, Hauswirth WW, Aguirre GD (2013) Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A 110(6):E517–E525CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Ali RR (2012) Gene therapy for retinal dystrophies: twenty years in the making. Hum Gene Ther 23(4):337–339CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, Georgiadis A, Mowat FM, Beattie SG, Gardner PJ, Feathers KL, Luong VA, Yzer S, Balaggan K, Viswanathan A, de Ravel TJ, Casteels I, Holder GE, Tyler N, Fitzke FW, Weleber RG, Nardini M, Moore AT, Thompson DA, Petersen-Jones SM, Michaelides M, van den Born LI, Stockman A, Smith AJ, Rubin G, Ali RR (2015) Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med 372(20):1887–1897CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Jha BS, Bharti K (2015) Regenerating retinal pigment epithelial cells to cure blindness: a road towards personalized artificial tissue. Curr Stem Cell Rep 1(2):79–91CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Gouras P, Flood MT, Kjedbye H, Bilek MK, Eggers H (1985) Transplantation of cultured human retinal epithelium to Bruch’s membrane of the owl monkey’s eye. Curr Eye Res 4(3):253–265CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Gouras P, Flood MT, Kjeldbye H (1984) Transplantation of cultured human retinal cells to monkey retina. An Acad Bras Cienc 56(4):431–443PubMedPubMedCentralGoogle Scholar
  57. 57.
    Lopez R, Gouras P, Kjeldbye H, Sullivan B, Reppucci V, Brittis M, Wapner F, Goluboff E (1989) Transplanted retinal pigment epithelium modifies the retinal degeneration in the RCS rat. Invest Ophthalmol Vis Sci 30(3):586–588PubMedPubMedCentralGoogle Scholar
  58. 58.
    World Medical Association (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310(20):2191–2194CrossRefGoogle Scholar
  59. 59.
    Liao JL, Yu J, Huang K, Hu J, Diemer T, Ma Z, Dvash T, Yang XJ, Travis GH, Williams DS, Bok D, Fan G (2010) Molecular signature of primary retinal pigment epithelium and stem-cell-derived RPE cells. Hum Mol Genet 19(21):4229–4238CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Maminishkis A, Chen S, Jalickee S, Banzon T, Shi G, Wang FE, Ehalt T, Hammer JA, Miller SS (2006) Confluent monolayers of cultured human fetal retinal pigment epithelium exhibit morphology and physiology of native tissue. Invest Ophthalmol Vis Sci 47(8):3612–3624CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Zhu M, Provis JM, Penfold PL (1998) Isolation, culture and characteristics of human foetal and adult retinal pigment epithelium. Aust N Z J Ophthalmol 26(Suppl 1):S50–S52CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Nandrot EF, Dufour EM (2010) Mertk in daily retinal phagocytosis: a history in the making. Adv Exp Med Biol 664:133–140CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Mullen RJ, LaVail MM (1976) Inherited retinal dystrophy: primary defect in pigment epithelium determined with experimental rat chimeras. Science 192(4241):799–801CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Little CW, Castillo B, DiLoreto DA, Cox C, Wyatt J, del Cerro C, del Cerro M (1996) Transplantation of human fetal retinal pigment epithelium rescues photoreceptor cells from degeneration in the Royal College of Surgeons rat retina. Invest Ophthalmol Vis Sci 37(1):204–211PubMedPubMedCentralGoogle Scholar
  65. 65.
    Sheng Y, Gouras P, Cao H, Berglin L, Kjeldbye H, Lopez R, Rosskothen H (1995) Patch transplants of human fetal retinal pigment epithelium in rabbit and monkey retina. Invest Ophthalmol Vis Sci 36(2):381–390PubMedPubMedCentralGoogle Scholar
  66. 66.
    Berglin L, Gouras P, Sheng Y, Lavid J, Lin PK, Cao H, Kjeldbye H (1997) Tolerance of human fetal retinal pigment epithelium xenografts in monkey retina. Graefes Arch Clin Exp Ophthalmol 235(2):103–110CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Lai CC, Gouras P, Doi K, Tsang SH, Goff SP, Ashton P (2000) Local immunosuppression prolongs survival of RPE xenografts labeled by retroviral gene transfer. Invest Ophthalmol Vis Sci 41(10):3134–3141PubMedPubMedCentralGoogle Scholar
  68. 68.
    Aramant RB, Seiler MJ (2002) Transplanted sheets of human retina and retinal pigment epithelium develop normally in nude rats. Exp Eye Res 75(2):115–125CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Algvere PV, Berglin L, Gouras P, Sheng Y (1994) Transplantation of fetal retinal pigment epithelium in age-related macular degeneration with subfoveal neovascularization. Graefes Arch Clin Exp Ophthalmol 232(12):707–716CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Algvere PV, Gouras P, Dafgard Kopp E (1999) Long-term outcome of RPE allografts in non-immunosuppressed patients with AMD. Eur J Ophthalmol 9(3):217–230CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Weisz JM, Humayun MS, De Juan E Jr, Del Cerro M, Sunness JS, Dagnelie G, Soylu M, Rizzo L, Nussenblatt RB (1999) Allogenic fetal retinal pigment epithelial cell transplant in a patient with geographic atrophy. Retina 19(6):540–545PubMedPubMedCentralGoogle Scholar
  72. 72.
    Radtke ND, Seiler MJ, Aramant RB, Petry HM, Pidwell DJ (2002) Transplantation of intact sheets of fetal neural retina with its retinal pigment epithelium in retinitis pigmentosa patients. Am J Ophthalmol 133(4):544–550CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    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):172–182CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Binder S, Stanzel BV, Krebs I, Glittenberg C (2007) Transplantation of the RPE in AMD. Prog Retin Eye Res 26(5):516–554CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Castillo BV Jr, del Cerro M, White RM, Cox C, Wyatt J, Nadiga G, del Cerro C (1997) Efficacy of nonfetal human RPE for photoreceptor rescue: a study in dystrophic RCS rats. Exp Neurol 146(1):1–9CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Phillips SJ, Sadda SR, Tso MO, Humayan MS, de Juan E Jr, Binder S (2003) Autologous transplantation of retinal pigment epithelium after mechanical debridement of Bruch’s membrane. Curr Eye Res 26(2):81–88CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Binder S, Stolba U, Krebs I, Kellner L, Jahn C, Feichtinger H, Povelka M, Frohner U, Kruger A, Hilgers RD, Krugluger W (2002) Transplantation of autologous retinal pigment epithelium in eyes with foveal neovascularization resulting from age-related macular degeneration: a pilot study. Am J Ophthalmol 133(2):215–225CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Dunn KC, Aotaki-Keen AE, Putkey FR, Hjelmeland LM (1996) ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. Exp Eye Res 62(2):155–169CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Pinilla I, Cuenca N, Sauve Y, Wang S, Lund RD (2007) Preservation of outer retina and its synaptic connectivity following subretinal injections of human RPE cells in the Royal College of Surgeons rat. Exp Eye Res 85(3):381–392CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Coffey PJ, Girman S, Wang SM, Hetherington L, Keegan DJ, Adamson P, Greenwood J, Lund RD (2002) Long-term preservation of cortically dependent visual function in RCS rats by transplantation. Nat Neurosci 5(1):53–56CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Salero E, Blenkinsop TA, Corneo B, Harris A, Rabin D, Stern JH, Temple S (2012) Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives. Cell Stem Cell 10(1):88–95CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Chiba C (2014) The retinal pigment epithelium: an important player of retinal disorders and regeneration. Exp Eye Res 123:107–114CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Stanzel BV, Liu Z, Somboonthanakij S, Wongsawad W, Brinken R, Eter N, Corneo B, Holz FG, Temple S, Stern JH, Blenkinsop TA (2014) Human RPE stem cells grown into polarized RPE monolayers on a polyester matrix are maintained after grafting into rabbit subretinal space. Stem Cell Rep 2(1):64–77CrossRefGoogle Scholar
  84. 84.
    Schraermeyer U, Enzmann V, Kohen L, Addicks K, Wiedemann P, Heimann K (1997) Porcine iris pigment epithelial cells can take up retinal outer segments. Exp Eye Res 65(2):277–287CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Schraermeyer U, Kociok N, Heimann K (1999) Rescue effects of IPE transplants in RCS rats: short-term results. Invest Ophthalmol Vis Sci 40(7):1545–1556PubMedPubMedCentralGoogle Scholar
  86. 86.
    Thumann G, Salz AK, Walter P, Johnen S (2009) Preservation of photoreceptors in dystrophic RCS rats following allo- and xenotransplantation of IPE cells. Graefes Arch Clin Exp Ophthalmol 247(3):363–369CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Abe T, Yoshida M, Tomita H, Kano T, Sato M, Wada Y, Fuse N, Yamada T, Tamai M (2000) Auto iris pigment epithelial cell transplantation in patients with age-related macular degeneration: short-term results. Tohoku J Exp Med 191(1):7–20CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Abe T, Yoshida M, Yoshioka Y, Wakusawa R, Tokita-Ishikawa Y, Seto H, Tamai M, Nishida K (2007) Iris pigment epithelial cell transplantation for degenerative retinal diseases. Prog Retin Eye Res 26(3):302–321CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Semkova I, Kreppel F, Welsandt G, Luther T, Kozlowski J, Janicki H, Kochanek S, Schraermeyer U (2002) Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye. Proc Natl Acad Sci U S A 99(20):13090–13095CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Hojo M, Abe T, Sugano E, Yoshioka Y, Saigo Y, Tomita H, Wakusawa R, Tamai M (2004) Photoreceptor protection by iris pigment epithelial transplantation transduced with AAV-mediated brain-derived neurotrophic factor gene. Invest Ophthalmol Vis Sci 45(10):3721–3726CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Lawrence JM, Sauve Y, Keegan DJ, Coffey PJ, Hetherington L, Girman S, Whiteley SJ, Kwan AS, Pheby T, Lund RD (2000) Schwann cell grafting into the retina of the dystrophic RCS rat limits functional deterioration. Royal College of Surgeons. Invest Ophthalmol Vis Sci 41(2):518–528PubMedPubMedCentralGoogle Scholar
  92. 92.
    Keegan DJ, Kenna P, Humphries MM, Humphries P, Flitcroft DI, Coffey PJ, Lund RD, Lawrence JM (2003) Transplantation of syngeneic Schwann cells to the retina of the rhodopsin knockout (rho(−/−)) mouse. Invest Ophthalmol Vis Sci 44(8):3526–3532CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Lawrence JM, Keegan DJ, Muir EM, Coffey PJ, Rogers JH, Wilby MJ, Fawcett JW, Lund RD (2004) Transplantation of Schwann cell line clones secreting GDNF or BDNF into the retinas of dystrophic Royal College of Surgeons rats. Invest Ophthalmol Vis Sci 45(1):267–274CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Gamm DM, Wang S, Lu B, Girman S, Holmes T, Bischoff N, Shearer RL, Sauve Y, Capowski E, Svendsen CN, Lund RD (2007) Protection of visual functions by human neural progenitors in a rat model of retinal disease. PLoS One 2(3):e338CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Wang S, Girman S, Lu B, Bischoff N, Holmes T, Shearer R, Wright LS, Svendsen CN, Gamm DM, Lund RD (2008) Long-term vision rescue by human neural progenitors in a rat model of photoreceptor degeneration. Invest Ophthalmol Vis Sci 49(7):3201–3206CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Francis PJ, Wang S, Zhang Y, Brown A, Hwang T, McFarland TJ, Jeffrey BG, Lu B, Wright L, Appukuttan B, Wilson DJ, Stout JT, Neuringer M, Gamm DM, Lund RD (2009) Subretinal transplantation of forebrain progenitor cells in nonhuman primates: survival and intact retinal function. Invest Ophthalmol Vis Sci 50(7):3425–3431CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Tsukamoto A, Uchida N, Capela A, Gorba T, Huhn S (2013) Clinical translation of human neural stem cells. Stem Cell Res Ther 4(4):102CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    McGill TJ, Cottam B, Lu B, Wang S, Girman S, Tian C, Huhn SL, Lund RD, Capela A (2012) Transplantation of human central nervous system stem cells - neuroprotection in retinal degeneration. Eur J Neurosci 35(3):468–477CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Casarosa S, Bozzi Y, Conti L (2014) Neural stem cells: ready for therapeutic applications? Mol Cell Ther 2:31CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Chen Y, Shao JZ, Xiang LX, Dong XJ, Zhang GR (2008) Mesenchymal stem cells: a promising candidate in regenerative medicine. Int J Biochem Cell Biol 40(5):815–820CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Chen Q, Long Y, Yuan X, Zou L, Sun J, Chen S, Perez-Polo JR, Yang K (2005) Protective effects of bone marrow stromal cell transplantation in injured rodent brain: synthesis of neurotrophic factors. J Neurosci Res 80(5):611–619CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Arnhold S, Heiduschka P, Klein H, Absenger Y, Basnaoglu S, Kreppel F, Henke-Fahle S, Kochanek S, Bartz-Schmidt KU, Addicks K, Schraermeyer U (2006) Adenovirally transduced bone marrow stromal cells differentiate into pigment epithelial cells and induce rescue effects in RCS rats. Invest Ophthalmol Vis Sci 47(9):4121–4129CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Inoue Y, Iriyama A, Ueno S, Takahashi H, Kondo M, Tamaki Y, Araie M, Yanagi Y (2007) Subretinal transplantation of bone marrow mesenchymal stem cells delays retinal degeneration in the RCS rat model of retinal degeneration. Exp Eye Res 85(2):234–241CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Lu B, Wang S, Girman S, McGill T, Ragaglia V, Lund R (2010) Human adult bone marrow-derived somatic cells rescue vision in a rodent model of retinal degeneration. Exp Eye Res 91(3):449–455CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Tzameret A, Sher I, Belkin M, Treves AJ, Meir A, Nagler A, Levkovitch-Verbin H, Barshack I, Rosner M, Rotenstreich Y (2014) Transplantation of human bone marrow mesenchymal stem cells as a thin subretinal layer ameliorates retinal degeneration in a rat model of retinal dystrophy. Exp Eye Res 118:135–144CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Ahmad I, Tang L, Pham H (2000) Identification of neural progenitors in the adult mammalian eye. Biochem Biophys Res Commun 270(2):517–521CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Ballios BG, Clarke L, Coles BL, Shoichet MS, Van Der Kooy D (2012) The adult retinal stem cell is a rare cell in the ciliary epithelium whose progeny can differentiate into photoreceptors. Biol Open 1(3):237–246CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Tropepe V, Coles BL, Chiasson BJ, Horsford DJ, Elia AJ, McInnes RR, van der Kooy D (2000) Retinal stem cells in the adult mammalian eye. Science 287(5460):2032–2036CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Coles BL, Angenieux B, Inoue T, Del Rio-Tsonis K, Spence JR, McInnes RR, Arsenijevic Y, van der Kooy D (2004) Facile isolation and the characterization of human retinal stem cells. Proc Natl Acad Sci U S A 101(44):15772–15777CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Cicero SA, Johnson D, Reyntjens S, Frase S, Connell S, Chow LM, Baker SJ, Sorrentino BP, Dyer MA (2009) Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells. Proc Natl Acad Sci U S A 106(16):6685–6690CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Froen R, Johnsen EO, Nicolaissen B, Facsko A, Petrovski G, Moe MC (2013) Does the adult human ciliary body epithelium contain “true” retinal stem cells? Biomed Res Int 2013:531579CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Lund RD, Wang S, Lu B, Girman S, Holmes T, Sauve Y, Messina DJ, Harris IR, Kihm AJ, Harmon AM, Chin FY, Gosiewska A, Mistry SK (2007) Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells 25(3):602–611CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Kamao H, Mandai M, Okamoto S, Sakai N, Suga A, Sugita S, Kiryu J, Takahashi M (2014) Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application. Stem Cell Rep 2(2):205–218CrossRefGoogle Scholar
  117. 117.
    Leach LL, Clegg DO (2015) Concise review: Making stem cells retinal: methods for deriving retinal pigment epithelium and implications for patients with ocular disease. Stem Cells 33(8):2363–2373CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Klimanskaya I, Hipp J, Rezai KA, West M, Atala A, Lanza R (2004) Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics. Cloning Stem Cells 6(3):217–245CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Choudhary P, Booth H, Gutteridge A, Surmacz B, Louca I, Steer J, Kerby J, Whiting PJ (2017) Directing differentiation of pluripotent stem cells toward retinal pigment epithelium lineage. Stem Cells Transl Med 6(2):490–501CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Lidgerwood GE, Lim SY, Crombie DE, Ali R, Gill KP, Hernandez D, Kie J, Conquest A, Waugh HS, Wong RC, Liang HH, Hewitt AW, Davidson KC, Pebay A (2016) Defined medium conditions for the induction and expansion of human pluripotent stem cell-derived retinal pigment epithelium. Stem Cell Rev 12(2):179–188CrossRefGoogle Scholar
  121. 121.
    Lamba DA, Karl MO, Ware CB, Reh TA (2006) Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A 103(34):12769–12774CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Buchholz DE, Pennington BO, Croze RH, Hinman CR, Coffey PJ, Clegg DO (2013) Rapid and efficient directed differentiation of human pluripotent stem cells into retinal pigmented epithelium. Stem Cells Transl Med 2(5):384–393CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Leach LL, Buchholz DE, Nadar VP, Lowenstein SE, Clegg DO (2015) Canonical/beta-catenin Wnt pathway activation improves retinal pigmented epithelium derivation from human embryonic stem cells. Invest Ophthalmol Vis Sci 56(2):1002–1013CrossRefGoogle Scholar
  124. 124.
    Bharti K, Miller SS, Arnheiter H (2011) The new paradigm: retinal pigment epithelium cells generated from embryonic or induced pluripotent stem cells. Pigment Cell Melanoma Res 24(1):21–34CrossRefGoogle Scholar
  125. 125.
    Buchholz DE, Hikita ST, Rowland TJ, Friedrich AM, Hinman CR, Johnson LV, Clegg DO (2009) Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells. Stem Cells 27(10):2427–2434CrossRefGoogle Scholar
  126. 126.
    Maruotti J, Sripathi SR, Bharti K, Fuller J, Wahlin KJ, Ranganathan V, Sluch VM, Berlinicke CA, Davis J, Kim C, Zhao L, Wan J, Qian J, Corneo B, Temple S, Dubey R, Olenyuk BZ, Bhutto I, Lutty GA, Zack DJ (2015) Small-molecule-directed, efficient generation of retinal pigment epithelium from human pluripotent stem cells. Proc Natl Acad Sci U S A 112(35):10950–10955CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Odorico JS, Kaufman DS, Thomson JA (2001) Multilineage differentiation from human embryonic stem cell lines. Stem Cells 19(3):193–204CrossRefGoogle Scholar
  128. 128.
    Itskovitz-Eldor J, Schuldiner M, Karsenti D, Eden A, Yanuka O, Amit M, Soreq H, Benvenisty N (2000) Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med 6(2):88–95CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Carr AJ, Smart MJ, Ramsden CM, Powner MB, da Cruz L, Coffey PJ (2013) Development of human embryonic stem cell therapies for age-related macular degeneration. Trends Neurosci 36(7):385–395CrossRefGoogle Scholar
  130. 130.
    Idelson M, Alper R, Obolensky A, Ben-Shushan E, Hemo I, Yachimovich-Cohen N, Khaner H, Smith Y, Wiser O, Gropp M, Cohen MA, Even-Ram S, Berman-Zaken Y, Matzrafi L, Rechavi G, Banin E, Reubinoff B (2009) Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells. Cell Stem Cell 5(4):396–408CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Meyer JS, Howden SE, Wallace KA, Verhoeven AD, Wright LS, Capowski EE, Pinilla I, Martin JM, Tian S, Stewart R, Pattnaik B, Thomson JA, Gamm DM (2011) Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment. Stem Cells 29(8):1206–1218CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Reichman S, Slembrouck A, Gagliardi G, Chaffiol A, Terray A, Nanteau C, Potey A, Belle M, Rabesandratana O, Duebel J, Orieux G, Nandrot EF, Sahel JA, Goureau O (2017) Generation of storable retinal organoids and retinal pigmented epithelium from adherent human iPS cells in xeno-free and feeder-free conditions. Stem Cells 35(5):1176–1188CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Reichman S, Terray A, Slembrouck A, Nanteau C, Orieux G, Habeler W, Nandrot EF, Sahel JA, Monville C, Goureau O (2014) From confluent human iPS cells to self-forming neural retina and retinal pigmented epithelium. Proc Natl Acad Sci U S A 111(23):8518–8523CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Crombie DE, Daniszewski M, Liang HH, Kulkarni T, Li F, Lidgerwood GE, Conquest A, Hernandez D, Hung SS, Gill KP, De Smit E, Kearns LS, Clarke L, Sluch VM, Chamling X, Zack DJ, Wong RCB, Hewitt AW, Pebay A (2017) Development of a modular automated system for maintenance and differentiation of adherent human pluripotent stem cells. SLAS Discov 22(8):1016–1025PubMedPubMedCentralGoogle Scholar
  135. 135.
    Schwartz SD, Hubschman JP, Heilwell G, Franco-Cardenas V, Pan CK, Ostrick RM, Mickunas E, Gay R, Klimanskaya I, Lanza R (2012) Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379(9817):713–720CrossRefGoogle Scholar
  136. 136.
    Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, Fujihara M, Akimaru H, Sakai N, Shibata Y, Terada M, Nomiya Y, Tanishima S, Nakamura M, Kamao H, Sugita S, Onishi A, Ito T, Fujita K, Kawamata S, Go MJ, Shinohara C, Hata KI, Sawada M, Yamamoto M, Ohta S, Ohara Y, Yoshida K, Kuwahara J, Kitano Y, Amano N, Umekage M, Kitaoka F, Tanaka A, Okada C, Takasu N, Ogawa S, Yamanaka S, Takahashi M (2017) Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 376(11):1038–1046CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Xu RM, Carmel G, Kuret J, Cheng X (1996) Structural basis for selectivity of the isoquinoline sulfonamide family of protein kinase inhibitors. Proc Natl Acad Sci U S A 93(13):6308–6313CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Ben M’Barek K, Habeler W, Plancheron A, Jarraya M, Regent F, Terray A, Yang Y, Chatrousse L, Domingues S, Masson Y, Sahel JA, Peschanski M, Goureau O, Monville C (2017) Human ESC-derived retinal epithelial cell sheets potentiate rescue of photoreceptor cell loss in rats with retinal degeneration. Sci Transl Med 9(421):eaai7471CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Lustremant C, Habeler W, Plancheron A, Goureau O, Grenot L, de la Grange P, Audo I, Nandrot EF, Monville C (2013) Human induced pluripotent stem cells as a tool to model a form of Leber congenital amaurosis. Cell Reprogram 15(3):233–246CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ, Gregori NZ, Hubschman JP, Davis JL, Heilwell G, Spirn M, Maguire J, Gay R, Bateman J, Ostrick RM, Morris D, Vincent M, Anglade E, Del Priore LV, Lanza R (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):509–516CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Andrews PW, Baker D, Benvinisty N, Miranda B, Bruce K, Brustle O, Choi M, Choi YM, Crook JM, de Sousa PA, Dvorak P, Freund C, Firpo M, Furue MK, Gokhale P, Ha HY, Han E, Haupt S, Healy L, Hei DJ, Hovatta O, Hunt C, Hwang SM, Inamdar MS, Isasi RM, Jaconi M, Jekerle V, Kamthorn P, Kibbey MC, Knezevic I, Knowles BB, Koo SK, Laabi Y, Leopoldo L, Liu P, Lomax GP, Loring JF, Ludwig TE, Montgomery K, Mummery C, Nagy A, Nakamura Y, Nakatsuji N, Oh S, Oh SK, Otonkoski T, Pera M, Peschanski M, Pranke P, Rajala KM, Rao M, Ruttachuk R, Reubinoff B, Ricco L, Rooke H, Sipp D, Stacey GN, Suemori H, Takahashi TA, Takada K, Talib S, Tannenbaum S, Yuan BZ, Zeng F, Zhou Q (2015) Points to consider in the development of seed stocks of pluripotent stem cells for clinical applications: International Stem Cell Banking Initiative (ISCBI). Regen Med 10(2 Suppl):1–44CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Kuroda T, Yasuda S, Kusakawa S, Hirata N, Kanda Y, Suzuki K, Takahashi M, Nishikawa S, Kawamata S, Sato Y (2012) Highly sensitive in vitro methods for detection of residual undifferentiated cells in retinal pigment epithelial cells derived from human iPS cells. PLoS One 7(5):e37342CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Kanemura H, Go MJ, Shikamura M, Nishishita N, Sakai N, Kamao H, Mandai M, Morinaga C, Takahashi M, Kawamata S (2014) Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration. PLoS One 9(1):e85336CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Bai Q, Ramirez JM, Becker F, Pantesco V, Lavabre-Bertrand T, Hovatta O, Lemaitre JM, Pellestor F, De Vos J (2015) Temporal analysis of genome alterations induced by single-cell passaging in human embryonic stem cells. Stem Cells Dev 24(5):653–662CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Weissbein U, Benvenisty N, Ben-David U (2014) Quality control: genome maintenance in pluripotent stem cells. J Cell Biol 204(2):153–163CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Garber K (2015) RIKEN suspends first clinical trial involving induced pluripotent stem cells. Nat Biotechnol 33(9):890–891CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Georgiadis A, Tschernutter M, Bainbridge JW, Balaggan KS, Mowat F, West EL, Munro PM, Thrasher AJ, Matter K, Balda MS, Ali RR (2010) The tight junction associated signalling proteins ZO-1 and ZONAB regulate retinal pigment epithelium homeostasis in mice. PLoS One 5(12):e15730CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Kannan R, Zhang N, Sreekumar PG, Spee CK, Rodriguez A, Barron E, Hinton DR (2006) Stimulation of apical and basolateral VEGF-A and VEGF-C secretion by oxidative stress in polarized retinal pigment epithelial cells. Mol Vis 12:1649–1659PubMedPubMedCentralGoogle Scholar
  149. 149.
    Nazari H, Zhang L, Zhu D, Chader GJ, Falabella P, Stefanini F, Rowland T, Clegg DO, Kashani AH, Hinton DR, Humayun MS (2015) Stem cell based therapies for age-related macular degeneration: the promises and the challenges. Prog Retin Eye Res 48:1–39CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Capeans C, Pineiro A, Pardo M, Sueiro-Lopez C, Blanco MJ, Dominguez F, Sanchez-Salorio M (2003) Amniotic membrane as support for human retinal pigment epithelium (RPE) cell growth. Acta Ophthalmol Scand 81(3):271–277CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Niknejad H, Peirovi H, Jorjani M, Ahmadiani A, Ghanavi J, Seifalian AM (2008) Properties of the amniotic membrane for potential use in tissue engineering. Eur Cell Mater 15:88–99CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Adds PJ, Hunt CJ, Dart JK (2001) Amniotic membrane grafts, “fresh” or frozen? A clinical and in vitro comparison. Br J Ophthalmol 85(8):905–907CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Kador KE, Goldberg JL (2012) Scaffolds and stem cells: delivery of cell transplants for retinal degenerations. Expert Rev Ophthalmol 7(5):459–470CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Hu Y, Liu L, Lu B, Zhu D, Ribeiro R, Diniz B, Thomas PB, Ahuja AK, Hinton DR, Tai YC, Hikita ST, Johnson LV, Clegg DO, Thomas BB, Humayun MS (2012) A novel approach for subretinal implantation of ultrathin substrates containing stem cell-derived retinal pigment epithelium monolayer. Ophthalmic Res 48(4):186–191CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    da Cruz L, Fynes K, Georgiadis O, Kerby J, Luo YH, Ahmado A, Vernon A, Daniels JT, Nommiste B, Hasan SM, Gooljar SB, Carr AF, Vugler A, Ramsden CM, Bictash M, Fenster M, Steer J, Harbinson T, Wilbrey A, Tufail A, Feng G, Whitlock M, Robson AG, Holder GE, Sagoo MS, Loudon PT, Whiting P, Coffey PJ (2018) Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol 36(4):328–337Google Scholar
  156. 156.
    Seiler MJ, Aramant RB (2012) Cell replacement and visual restoration by retinal sheet transplants. Prog Retin Eye Res 31(6):661–687CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Bharti K, Rao M, Hull SC, Stroncek D, Brooks BP, Feigal E, van Meurs JC, Huang CA, Miller SS (2014) Developing cellular therapies for retinal degenerative diseases. Invest Ophthalmol Vis Sci 55(2):1191–1202CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Song WK, Park KM, Kim HJ, Lee JH, Choi J, Chong SY, Shim SH, Del Priore LV, Lanza R (2015) Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients. Stem Cell Rep 4(5):860–872CrossRefGoogle Scholar
  159. 159.
    Ramsden CM, Powner MB, Carr AJ, Smart MJ, da Cruz L, Coffey PJ (2013) Stem cells in retinal regeneration: past, present and future. Development 140(12):2576–2585CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Brandl C, Grassmann F, Riolfi J, Weber BH (2015) Tapping stem cells to target AMD: challenges and prospects. J Clin Med 4(2):282–303CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE II, Parrott MB, Rosenfeld PJ, Flynn HW Jr, Goldberg JL (2017) Vision loss after intravitreal injection of autologous “stem cells” for AMD. N Engl J Med 376(11):1047–1053CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Forrester JV (2009) Privilege revisited: an evaluation of the eye’s defence mechanisms. Eye (Lond) 23(4):756–766CrossRefGoogle Scholar
  163. 163.
    Streilein JW, Ma N, Wenkel H, Ng TF, Zamiri P (2002) Immunobiology and privilege of neuronal retina and pigment epithelium transplants. Vision Res 42(4):487–495CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Sauve Y, Klassen H, Whiteley SJ, Lund RD (1998) Visual field loss in RCS rats and the effect of RPE cell transplantation. Exp Neurol 152(2):243–250CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Araki R, Uda M, Hoki Y, Sunayama M, Nakamura M, Ando S, Sugiura M, Ideno H, Shimada A, Nifuji A, Abe M (2013) Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 494(7435):100–104CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Drukker M, Katz G, Urbach A, Schuldiner M, Markel G, Itskovitz-Eldor J, Reubinoff B, Mandelboim O, Benvenisty N (2002) Characterization of the expression of MHC proteins in human embryonic stem cells. Proc Natl Acad Sci U S A 99(15):9864–9869CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Wu KH, Wu HP, Chan CK, Hwang SM, Peng CT, Chao YH (2013) The role of mesenchymal stem cells in hematopoietic stem cell transplantation: from bench to bedsides. Cell Transplant 22(4):723–729CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Sohn EH, Jiao C, Kaalberg E, Cranston C, Mullins RF, Stone EM, Tucker BA (2015) Allogenic iPSC-derived RPE cell transplants induce immune response in pigs: a pilot study. Sci Rep 5:11791CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Xian B, Huang B (2015) The immune response of stem cells in subretinal transplantation. Stem Cell Res Ther 6:161CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Zamiri P, Sugita S, Streilein JW (2007) Immunosuppressive properties of the pigmented epithelial cells and the subretinal space. Chem Immunol Allergy 92:86–93CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Wenkel H, Streilein JW (1998) Analysis of immune deviation elicited by antigens injected into the subretinal space. Invest Ophthalmol Vis Sci 39(10):1823–1834PubMedPubMedCentralGoogle Scholar
  172. 172.
    Sugita S, Futagami Y, Smith SB, Naggar H, Mochizuki M (2006) Retinal and ciliary body pigment epithelium suppress activation of T lymphocytes via transforming growth factor beta. Exp Eye Res 83(6):1459–1471CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Zamiri P, Masli S, Streilein JW, Taylor AW (2006) Pigment epithelial growth factor suppresses inflammation by modulating macrophage activation. Invest Ophthalmol Vis Sci 47(9):3912–3918CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Wenkel H, Streilein JW (2000) Evidence that retinal pigment epithelium functions as an immune-privileged tissue. Invest Ophthalmol Vis Sci 41(11):3467–3473PubMedPubMedCentralGoogle Scholar
  175. 175.
    Hirsch L, Nazari H, Sreekumar PG, Kannan R, Dustin L, Zhu D, Barron E, Hinton DR (2015) TGF-beta2 secretion from RPE decreases with polarization and becomes apically oriented. Cytokine 71(2):394–396CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Zamiri P, Masli S, Kitaichi N, Taylor AW, Streilein JW (2005) Thrombospondin plays a vital role in the immune privilege of the eye. Invest Ophthalmol Vis Sci 46(3):908–919CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Enzmann V, Stadler M, Wiedemann P, Kohen L (1998) In-vitro methods to decrease MHC class II-positive cells in retinal pigment epithelium cell grafts. Ocul Immunol Inflamm 6(3):145–153CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Horie S, Sugita S, Futagami Y, Yamada Y, Mochizuki M (2010) Human retinal pigment epithelium-induced CD4+CD25+ regulatory T cells suppress activation of intraocular effector T cells. Clin Immunol 136(1):83–95CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Sugita S, Horie S, Nakamura O, Maruyama K, Takase H, Usui Y, Takeuchi M, Ishidoh K, Koike M, Uchiyama Y, Peters C, Yamamoto Y, Mochizuki M (2009) Acquisition of T regulatory function in cathepsin L-inhibited T cells by eye-derived CTLA-2alpha during inflammatory conditions. J Immunol 183(8):5013–5022CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Sugita S, Horie S, Yamada Y, Mochizuki M (2010) Inhibition of B-cell activation by retinal pigment epithelium. Invest Ophthalmol Vis Sci 51(11):5783–5788CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Sugita S, Usui Y, Horie S, Futagami Y, Yamada Y, Ma J, Kezuka T, Hamada H, Usui T, Mochizuki M, Yamagami S (2009) Human corneal endothelial cells expressing programmed death-ligand 1 (PD-L1) suppress PD-1+ T helper 1 cells by a contact-dependent mechanism. Invest Ophthalmol Vis Sci 50(1):263–272CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Osusky R, Dorio RJ, Arora YK, Ryan SJ, Walker SM (1997) MHC class II positive retinal pigment epithelial (RPE) cells can function as antigen-presenting cells for microbial superantigen. Ocul Immunol Inflamm 5(1):43–50CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Imai A, Sugita S, Kawazoe Y, Horie S, Yamada Y, Keino H, Maruyama K, Mochizuki M (2012) Immunosuppressive properties of regulatory T cells generated by incubation of peripheral blood mononuclear cells with supernatants of human RPE cells. Invest Ophthalmol Vis Sci 53(11):7299–7309CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Futagami Y, Sugita S, Vega J, Ishida K, Takase H, Maruyama K, Aburatani H, Mochizuki M (2007) Role of thrombospondin-1 in T cell response to ocular pigment epithelial cells. J Immunol 178(11):6994–7005CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Diniz B, Thomas P, Thomas B, Ribeiro R, Hu Y, Brant R, Ahuja A, Zhu D, Liu L, Koss M, Maia M, Chader G, Hinton DR, Humayun MS (2013) Subretinal implantation of retinal pigment epithelial cells derived from human embryonic stem cells: improved survival when implanted as a monolayer. Invest Ophthalmol Vis Sci 54(7):5087–5096CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Hambright D, Park KY, 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
  187. 187.
    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(9):2126–2135CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Hewitt Z, Priddle H, Thomson AJ, Wojtacha D, McWhir J (2007) Ablation of undifferentiated human embryonic stem cells: exploiting innate immunity against the Gal alpha1-3Galbeta1-4GlcNAc-R (alpha-Gal) epitope. Stem Cells 25(1):10–18CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Sugita S, Makabe K, Fujii S, Iwasaki Y, Kamao H, Shiina T, Ogasawara K, Takahashi M (2017) Detection of retinal pigment epithelium-specific antibody in iPSC-derived retinal pigment epithelium transplantation models. Stem Cell Rep 9(5):1501–1515CrossRefGoogle Scholar
  190. 190.
    Sonoda S, Sreekumar PG, Kase S, Spee C, Ryan SJ, Kannan R, Hinton DR (2010) Attainment of polarity promotes growth factor secretion by retinal pigment epithelial cells: relevance to age-related macular degeneration. Aging (Albany NY) 2(1):28–42CrossRefGoogle Scholar
  191. 191.
    Hsiung J, Zhu D, Hinton DR (2015) Polarized human embryonic stem cell-derived retinal pigment epithelial cell monolayers have higher resistance to oxidative stress-induced cell death than nonpolarized cultures. Stem Cells Transl Med 4(1):10–20CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Kawazoe Y, Sugita S, Keino H, Yamada Y, Imai A, Horie S, Mochizuki M (2012) Retinoic acid from retinal pigment epithelium induces T regulatory cells. Exp Eye Res 94(1):32–40CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Sugita S, Horie S, Nakamura O, Futagami Y, Takase H, Keino H, Aburatani H, Katunuma N, Ishidoh K, Yamamoto Y, Mochizuki M (2008) Retinal pigment epithelium-derived CTLA-2alpha induces TGFbeta-producing T regulatory cells. J Immunol 181(11):7525–7536CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Sugita S, Kamao H, Iwasaki Y, Okamoto S, Hashiguchi T, Iseki K, Hayashi N, Mandai M, Takahashi M (2015) Inhibition of T-cell activation by retinal pigment epithelial cells derived from induced pluripotent stem cells. Invest Ophthalmol Vis Sci 56(2):1051–1062CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Ferguson TA, Griffith TS (2007) The role of Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL) in the ocular immune response. Chem Immunol Allergy 92:140–154CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Sugita S, Kawazoe Y, Imai A, Usui Y, Takahashi M, Mochizuki M (2013) Suppression of IL-22-producing T helper 22 cells by RPE cells via PD-L1/PD-1 interactions. Invest Ophthalmol Vis Sci 54(10):6926–6933CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Zhang X, Bok D (1998) Transplantation of retinal pigment epithelial cells and immune response in the subretinal space. Invest Ophthalmol Vis Sci 39(6):1021–1027PubMedPubMedCentralGoogle Scholar
  198. 198.
    Bhatt NS, Newsome DA, Fenech T, Hessburg TP, Diamond JG, Miceli MV, Kratz KE, Oliver PD (1994) Experimental transplantation of human retinal pigment epithelial cells on collagen substrates. Am J Ophthalmol 117(2):214–221CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Crafoord S, Algvere PV, Kopp ED, Seregard S (2000) Cyclosporine treatment of RPE allografts in the rabbit subretinal space. Acta Ophthalmol Scand 78(2):122–129CrossRefPubMedPubMedCentralGoogle Scholar
  200. 200.
    Ahmad ZM, Hughes BA, Abrams GW, Mahmoud TH (2012) Combined posterior chamber intraocular lens, vitrectomy, Retisert, and pars plana tube in noninfectious uveitis. Arch Ophthalmol 130(7):908–913CrossRefPubMedPubMedCentralGoogle Scholar
  201. 201.
    Tomkins-Netzer O, Taylor SR, Bar A, Lula A, Yaganti S, Talat L, Lightman S (2014) Treatment with repeat dexamethasone implants results in long-term disease control in eyes with noninfectious uveitis. Ophthalmology 121(8):1649–1654CrossRefPubMedPubMedCentralGoogle Scholar
  202. 202.
    Grafft CA, Cornell LD, Gloor JM, Cosio FG, Gandhi MJ, Dean PG, Stegall MD, Amer H (2010) Antibody-mediated rejection following transplantation from an HLA-identical sibling. Nephrol Dial Transplant 25(1):307–310CrossRefPubMedPubMedCentralGoogle Scholar
  203. 203.
    Taylor CJ, Bolton EM, Pocock S, Sharples LD, Pedersen RA, Bradley JA (2005) Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet 366(9502):2019–2025CrossRefPubMedPubMedCentralGoogle Scholar
  204. 204.
    Copelan EA (2006) Hematopoietic stem-cell transplantation. N Engl J Med 354(17):1813–1826CrossRefPubMedPubMedCentralGoogle Scholar
  205. 205.
    de Rham C, Villard J (2014) Potential and limitation of HLA-based banking of human pluripotent stem cells for cell therapy. J Immunol Res 2014:518135PubMedPubMedCentralGoogle Scholar
  206. 206.
    Okita K, Nagata N, Yamanaka S (2011) Immunogenicity of induced pluripotent stem cells. Circ Res 109(7):720–721CrossRefPubMedPubMedCentralGoogle Scholar
  207. 207.
    Opelz G, Dohler B (2010) Impact of HLA mismatching on incidence of posttransplant non-hodgkin lymphoma after kidney transplantation. Transplantation 89(5):567–572CrossRefPubMedPubMedCentralGoogle Scholar
  208. 208.
    Sugita S, Iwasaki Y, Makabe K, Kimura T, Futagami T, Suegami S, Takahashi M (2016) Lack of T cell response to iPSC-derived retinal pigment epithelial cells from HLA homozygous donors. Stem Cell Rep 7(4):619–634CrossRefGoogle Scholar
  209. 209.
    Sugita S, Iwasaki Y, Makabe K, Kamao H, Mandai M, Shiina T, Ogasawara K, Hirami Y, Kurimoto Y, Takahashi M (2016) Successful transplantation of retinal pigment epithelial cells from MHC homozygote iPSCs in MHC-matched models. Stem Cell Rep 7(4):635–648CrossRefGoogle Scholar
  210. 210.
    Nakajima F, Tokunaga K, Nakatsuji N (2007) Human leukocyte antigen matching estimations in a hypothetical bank of human embryonic stem cell lines in the Japanese population for use in cell transplantation therapy. Stem Cells 25(4):983–985CrossRefPubMedPubMedCentralGoogle Scholar
  211. 211.
    Gourraud PA, Gilson L, Girard M, Peschanski M (2012) The role of human leukocyte antigen matching in the development of multiethnic “haplobank” of induced pluripotent stem cell lines. Stem Cells 30(2):180–186CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Karim Ben M’Barek
    • 1
    • 2
    • 3
  • Walter Habeler
    • 1
    • 2
    • 3
  • Florian Regent
    • 1
    • 2
  • Christelle Monville
    • 1
    • 2
    Email author
  1. 1.INSERM U861, I-Stem, AFMInstitute for Stem Cell Therapy and Exploration of Monogenic DiseasesCorbeil-EssonnesFrance
  2. 2.UEVE UMR861Corbeil-EssonnesFrance
  3. 3.CECS, Association Française contre les MyopathiesCorbeil-EssonnesFrance

Personalised recommendations