Cell Therapy for Degenerative Retinal Disease: Special Focus on Cell Fusion-Mediated Regeneration

  • Francesco Sottile
  • Martina Pesaresi
  • Giacoma Simonte
  • Maria Pia CosmaEmail author
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


Millions of people worldwide suffer from visual disabilities as a result of retinal degeneration. Due to the poor regenerative capability of the central nervous system, retinal cell loss is essentially irreversible. Currently available therapies can only decelerate the degenerative process at late stages and are largely ineffective. However, the possibility of using stem cell-based therapy as cell rescue or cell replacement therapy is broadly being explored. While cell rescue is based on the secretion of biologically active molecules by the transplanted cells, cell replacement refers to the possibility of injected stem cells replacing the defective ones either via direct differentiation, transdifferentiation of the transplanted cells, or via cell fusion-mediated reprogramming of retinal cells.

Here, we will briefly introduce the most common degenerative retinal diseases, discuss the potential sources of stem cells for retinal disease treatment, and report the different mechanisms through which cell therapy can exert its beneficial effects.


Retinal degeneration Cell fusion BMDCs Reprogramming Regeneration Retinal neurons Glial cells 



We would like to thank the members of the M.P.C. lab for their valuable help with the critical reading of the book chapter. We apologize to the colleagues whose work could not be cited due to space limitations. Work in the M.P.C. lab is supported by an ERC grant (242630-RERE, to M.P.C.), the Ministerio de Economia y Competitividad and FEDER funds (SAF2011-28580, BFU2014-54717-P, and BFU2015-71984-ERC to M.P.C.), an AGAUR grant from Secretaria d’Universitats i Investigació del Departament d’Economia I Coneixement de la Generalitat de Catalunya (2014SGR1137 to M.P.C.), Velux Stiftung (M.P.C), the European Union’s Horizon 2020 research and innovation programme under grant agreement CellViewer No 686637 (to M.P.C.), and Fundació La Marató de TV3; grant 120530 (to M.P.C.). We acknowledge the support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership. We also acknowledge support of the CERCA Programme (Generalitat de Catalunya), and of the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa.” We are also grateful for support from La Caixa international PhD fellowship (to F.S.), and from the Subprograma estatal de Formación del Ministerio de Economía y Competitividad ref. BES-2015-075802 (to M.P.), the Boehringer Ingelheim Foundation Fellowship (to G.S.) and the co-finance of Fondo Social Europeo (FSE).


  1. 1.
    Bunce C, Wormald R. Leading causes of certification for blindness and partial sight in England & Wales. BMC Public Health. 2006;6:58.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308(5720):419–21.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Churchill AJ, Carter JG, Lovell HC, Ramsden C, Turner SJ, Yeung A, et al. VEGF polymorphisms are associated with neovascular age-related macular degeneration. Hum Mol Genet. 2006;15(19):2955–61.PubMedCrossRefGoogle Scholar
  4. 4.
    Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106–16.PubMedCrossRefGoogle Scholar
  5. 5.
    De Jong PTVM. Age-related macular degeneration. N Engl J Med. 2006;355(14):1474–85.PubMedCrossRefGoogle Scholar
  6. 6.
    Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008;358(24):2606–17.PubMedCrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    Wong TY, Liew G, Mitchell P. Clinical update: new treatments for age-related macular degeneration. Lancet. 2007;370(9583):204–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908.PubMedCrossRefGoogle Scholar
  10. 10.
    Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–31.PubMedCrossRefGoogle Scholar
  11. 11.
    Genead MA, Fishman GA, Stone EM, Allikmets R. The natural history of stargardt disease with specific sequence mutation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2009;50(12):5867–71.PubMedCrossRefGoogle Scholar
  12. 12.
    Bither PP, Berns LA. Stargardt’s disease: a review of the literature. J Am Optom Assoc. 1988;59(2):106–11.PubMedGoogle Scholar
  13. 13.
    Parmeggiani F. Clinics, epidemiology and genetics of retinitis pigmentosa. Curr Genomics. 2011;12(4):236–7.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368(9549):1795–809.PubMedCrossRefGoogle Scholar
  15. 15.
    Jasiak-Zatonska M, Kalinowska-Lyszczarz A, Michalak S, Kozubski W. The immunology of neuromyelitis optica—Current knowledge, clinical implications, controversies and future perspectives. Int J Mol Sci. 2016;17(3):273.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Chaon BC, Lee MS. Is there treatment for traumatic optic neuropathy? Curr Opin Ophthalmol. 2015;26(6):445–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Poss KD. Advances in understanding tissue regenerative capacity and mechanisms in animals. Nat Rev Genet. 2010;11(10):710–22.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Tamura K, Ohgo S, Yokoyama H. Limb blastema cell: a stem cell for morphological regeneration. Dev Growth Differ. 2010;52(1):89–99.PubMedCrossRefGoogle Scholar
  19. 19.
    Goss RJ. Kinetics of compensatory growth. Q Rev Biol. 1965;40:123–46.PubMedCrossRefGoogle Scholar
  20. 20.
    Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43(2 Suppl 1):S45–53.PubMedCrossRefGoogle Scholar
  21. 21.
    Costa RH, Kalinichenko VV, Holterman AX, Wang X. Transcription factors in liver development, differentiation, and regeneration. Hepatology. 2003;38(6):1331–47.PubMedCrossRefGoogle Scholar
  22. 22.
    Scadden DT. The stem-cell niche as an entity of action. Nature. 2006;441(7097):1075–9.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Moore KA, Lemischka IR. Stem cells and their niches. Science. 2006;311(5769):1880–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Cheung TH, Rando TA. Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol. 2013;14(6):329–40.PubMedCrossRefGoogle Scholar
  25. 25.
    Serakinci N, Keith WN. Therapeutic potential of adult stem cells. Eur J Cancer. 2006;42(9):1243–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Merrell AJ, Stanger BZ. Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol. 2016;17(7):413–25.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Merino D, Loza-Alvarez P. Adaptive optics scanning laser ophthalmoscope imaging: technology update. Clin Ophthalmol. 2016;10:743–55.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Scoles D, Flatter JA, Cooper RF, Langlo CS, Robison S, Neitz M, et al. Assessing photoreceptor structure associated with ellipsoid zone disruptions visualized with optical coherence tomography. Retina. 2016;36(1):91–103.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Zarbin MA, Casaroli-Marano RP, Rosenfeld PJ. Age-related macular degeneration: clinical findings, histopathology and imaging techniques, Cell-Based Therapy for Retinal Degenerative Disease, vol. 53. Basel: Karger Publishers; 2014. p. 1–32.Google Scholar
  30. 30.
    Menghini M, Duncan JL. Diagnosis and complementary examinations. Dev Ophthalmol. 2014;53:53–69.PubMedCrossRefGoogle Scholar
  31. 31.
    Zayit-Soudry S, Duncan JL, Syed R, Menghini M, Roorda AJ. Cone structure imaged with adaptive optics scanning laser ophthalmoscopy in eyes with nonneovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013;54(12):7498–509.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Zamiri P, Sugita S, Streilein JW. Immunosuppressive properties of the pigmented epithelial cells and the subretinal space. Chem Immunol Allergy. 2007;92:86–93.PubMedCrossRefGoogle Scholar
  33. 33.
    Streilein JW. Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation. J Leukoc Biol. 2003;74(2):179–85.PubMedCrossRefGoogle Scholar
  34. 34.
    Sugita S, Futagami Y, Smith SB, Naggar H, Mochizuki M. Retinal and ciliary body pigment epithelium suppress activation of T lymphocytes via transforming growth factor beta. Exp Eye Res. 2006;83(6):1459–71.PubMedCrossRefGoogle Scholar
  35. 35.
    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
  36. 36.
    Ferguson TA, Griffith TS. The role of Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL) in the ocular immune response. Chem Immunol Allergy. 2007;92:140–54.PubMedCrossRefGoogle Scholar
  37. 37.
    Sugita S, Horie S, Nakamura O, Futagami Y, Takase H, Keino H, et al. Retinal pigment epithelium-derived CTLA-2alpha induces TGFbeta-producing T regulatory cells. J Immunol. 2008;181(11):7525–36.PubMedCrossRefGoogle Scholar
  38. 38.
    Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell. 2008;132(4):661–80.PubMedCrossRefGoogle Scholar
  39. 39.
    Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981;78(12):7634–8.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Meyer JS, Katz ML, Maruniak JA, Kirk MD. Embryonic stem cell-derived neural progenitors incorporate into degenerating retina and enhance survival of host photoreceptors. Stem Cells. 2006;24(2):274–83.PubMedCrossRefGoogle Scholar
  42. 42.
    Wang S, Girman S, Lu B, Bischoff N, Holmes T, Shearer R, et al. Long-term vision rescue by human neural progenitors in a rat model of photoreceptor degeneration. Invest Ophthalmol Vis Sci. 2008;49(7):3201–6.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Gamm DM, Wang S, Lu B, Girman S, Holmes T, Bischoff N, et al. Protection of visual functions by human neural progenitors in a rat model of retinal disease. PLoS One. 2007;2(3):e338.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Chacko DM, Rogers JA, Turner JE, Ahmad I. Survival and differentiation of cultured retinal progenitors transplanted in the subretinal space of the rat. Biochem Biophys Res Commun. 2000;268(3):842–6.PubMedCrossRefGoogle Scholar
  45. 45.
    McGill TJ, Cottam B, Lu B, Wang S, Girman S, Tian C, et al. Transplantation of human central nervous system stem cells - neuroprotection in retinal degeneration. Eur J Neurosci. 2012;35(3):468–77.PubMedCrossRefGoogle Scholar
  46. 46.
    Jung G, Sun J, Petrowitz B, Riecken K, Kruszewski K, Jankowiak W, et al. Genetically modified neural stem cells for a local and sustained delivery of neuroprotective factors to the dystrophic mouse retina. Stem Cells Transl Med. 2013;2(12):1001–10.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Cuenca N, Fernández-Sánchez L, McGill TJ, Lu B, Wang S, Lund R, et al. Phagocytosis of photoreceptor outer segments by transplanted human neural stem cells as a neuroprotective mechanism in retinal degeneration. Invest Ophthalmol Vis Sci. 2013;54(10):6745–56.PubMedCrossRefGoogle Scholar
  48. 48.
    Grozdanic SD, Ast AM, Lazic T, Kwon YH, Kardon RH, Sonea IM, et al. Morphological integration and functional assessment of transplanted neural progenitor cells in healthy and acute ischemic rat eyes. Exp Eye Res. 2006;82(4):597–607.PubMedCrossRefGoogle Scholar
  49. 49.
    Mellough CB, Cui Q, Spalding KL, Symons NA, Pollett MA, Snyder EY, et al. Fate of multipotent neural precursor cells transplanted into mouse retina selectively depleted of retinal ganglion cells. Exp Neurol. 2004;186(1):6–19.PubMedCrossRefGoogle Scholar
  50. 50.
    Nishida A, Takahashi M, Tanihara H, Nakano I, Takahashi JB, Mizoguchi A, 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
  51. 51.
    Diniz B, Thomas P, Thomas B, Ribeiro R, Hu Y, Brant R, et al. Subretinal implantation of retinal pigment epithelial cells derived from human embryonic stem cells: improved survival when implanted as a monolayer. Invest Ophthalmol Vis Sci. 2013;54(7):5087–96.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Zhou S, Flamier A, Abdouh M, Tétreault N, Barabino A, Wadhwa S, et al. Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFß and Wnt signaling. Development. 2015;142(19):3294–306.PubMedCrossRefGoogle Scholar
  53. 53.
    Osakada F, Ikeda H, Mandai M, Wataya T, Watanabe K, Yoshimura N, 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
  54. 54.
    Decembrini S, Koch U, Radtke F, Moulin A, Arsenijevic Y. Derivation of traceable and transplantable photoreceptors from mouse embryonic stem cells. Stem Cell Reports. 2014;2(6):853–65.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    West EL, Gonzalez-Cordero A, Hippert C, Osakada F, Martinez-Barbera JP, Pearson RA, et al. Defining the integration capacity of embryonic stem cell-derived photoreceptor precursors. Stem Cells. 2012;30(7):1424–35.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Carr AJ, Vugler AA, Hikita ST, Lawrence JM, Gias C, Chen LL, et al. Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat. PLoS One. 2009;4(12):e8152.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Banin E, Obolensky A, Idelson M, Hemo I, Reinhardtz E, Pikarsky E, et al. Retinal incorporation and differentiation of neural precursors derived from human embryonic stem cells. Stem Cells. 2006;24(2):246–57.PubMedCrossRefGoogle Scholar
  58. 58.
    Tucker BA, Park IH, Qi SD, Klassen HJ, Jiang C, Yao J, et al. Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS One. 2011;6(4):e18992.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U. Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci. 2004;45(12):4251–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Vugler A, Carr AJ, Lawrence J, Chen LL, Burrell K, Wright A, et al. Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation. Exp Neurol. 2008;214(2):347–61.PubMedCrossRefGoogle Scholar
  61. 61.
    Lu B, Malcuit C, Wang S, Girman S, Francis P, Lemieux L, et al. Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration. Stem Cells. 2009;27(9):2126–35.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.CrossRefPubMedGoogle Scholar
  63. 63.
    Araki R, Uda M, Hoki Y, Sunayama M, Nakamura M, Ando S, et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature. 2013;494(7435):100–4.PubMedCrossRefGoogle Scholar
  64. 64.
    Zhao T, Zhang ZN, Rong Z, Xu Y. Immunogenicity of induced pluripotent stem cells. Nature. 2011;474(7350):212–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Fairchild PJ. The challenge of immunogenicity in the quest for induced pluripotency. Nat Rev Immunol. 2010;10(12):868–75.PubMedCrossRefGoogle Scholar
  66. 66.
    Doi A, Park IH, Wen B, Murakami P, Aryee MJ, Irizarry R, et al. Differential methylation of tissue-and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet. 2009;41(12):1350–3.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Liao JL, Yu J, Huang K, Hu J, Diemer T, Ma Z, et al. Molecular signature of primary retinal pigment epithelium and stem-cell-derived RPE cells. Hum Mol Genet. 2010;19(21):4229–38.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2008;26(1):101–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Zhu S, Li W, Zhou H, Wei W, Ambasudhan R, Lin T, et al. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell. 2010;7(6):651–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol. 2008;26(11):1269–75.PubMedCrossRefGoogle Scholar
  71. 71.
    Shi Y, Desponts C, Do JT, Hahm HS, Schöler HR, Ding S. Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Oct4 and Klf4 with Small-Molecule Compounds. Cell Stem Cell. 2008;3(5):568–74.PubMedCrossRefGoogle Scholar
  72. 72.
    Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008;322(5903):949–53.PubMedCrossRefGoogle Scholar
  73. 73.
    Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature. 2009;458(7239):771–5.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010;7(5):618–30.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell. 2009;4(6):472–6.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Ballios BG, Clarke L, Coles BLK, Shoichet MS, Van Der Kooy D. The adult retinal stem cell is a rare cell in the ciliary epithelium whose progeny can differentiate into photoreceptors. Biol Open. 2012;1(3):237–46.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Ahmad I, Tang L, Pham H. Identification of neural progenitors in the adult mammalian eye. Biochem Biophys Res Commun. 2000;270(2):517–21.PubMedCrossRefGoogle Scholar
  78. 78.
    Tropepe V, Coles BLK, Chiasson BJ, Horsford DJ, Elia AJ, McInnes RR, et al. Retinal stem cells in the adult mammalian eye. Science. 2000;287(5460):2032–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Pearson RA, Barber AC, Rizzi M, Hippert C, Xue T, West EL, et al. Restoration of vision after transplantation of photoreceptors. Nature. 2012;485(7396):99–103.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    MacLaren RE, Pearson RA, MacNeil A, Douglas RH, Salt TE, Akimoto M, et al. Retinal repair by transplantation of photoreceptor precursors. Nature. 2006;444(7116):203–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Humayun MS, De Juan E Jr, Del Cerro M, Dagnelie G, Radner W, Sadda SR, et al. Human neural retinal transplantation. Invest Ophthalmol Vis Sci. 2000;41(10):3100–6.PubMedGoogle Scholar
  82. 82.
    Coles BLK, Angénieux B, Inoue T, Del Rio-Tsonis K, Spence JR, McInnes RR, et al. Facile isolation and the characterization of human retinal stem cells. Proc Natl Acad Sci U S A. 2004;101(44):15772–7.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Liu B, Hunter DJ, Rooker S, Chan A, Paulus YM, Leucht P, et al. Wnt signaling promotes Müller cell proliferation and survival after injury. Invest Ophthalmol Vis Sci. 2013;54(1):444–53.PubMedCrossRefGoogle Scholar
  84. 84.
    Das AV, Mallya KB, Zhao X, Ahmad F, Bhattacharya S, Thoreson WB, et al. Neural stem cell properties of Müller glia in the mammalian retina: regulation by Notch and Wnt signaling. Dev Biol. 2006;299(1):283–302.PubMedCrossRefGoogle Scholar
  85. 85.
    Ooto S, Akagi T, Kageyama R, Akita J, Mandai M, Honda Y, et al. 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
  86. 86.
    Fischer AJ, Reh TA. Müller glia are a potential source of neural regeneration in the postnatal chicken retina. Nat Neurosci. 2001;4(3):247–52.PubMedCrossRefGoogle Scholar
  87. 87.
    Singhal S, Bhatia B, Jayaram H, Becker S, Jones MF, Cottrill PB, et al. Human müller glia with stem cell characteristics differentiate into retinal ganglion cell (RGC) precursors in vitro and partially restore RGC function in vivo following transplantation. Stem Cells Transl Med. 2012;1(3):188–99.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829–34.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276(5309):71–4.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Gregory CA, Prockop DJ, Spees JL. Non-hematopoietic bone marrow stem cells: molecular control of expansion and differentiation. Exp Cell Res. 2005;306(2):330–5.PubMedCrossRefGoogle Scholar
  92. 92.
    Dezawa M, Kanno H, Hoshino M, Cho H, Matsumoto N, Itokazu Y, et al. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Investig. 2004;113(12):1701–10.PubMedCrossRefGoogle Scholar
  93. 93.
    Kicic A, Shen WY, Wilson AS, Constable IJ, Robertson T, Rakoczy PE. Differentiation of marrow stromal cells into photoreceptors in the rat eye. J Neurosci. 2003;23(21):7742–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Lu B, Wang S, Girman S, McGill T, Ragaglia V, Lund R. Human adult bone marrow-derived somatic cells rescue vision in a rodent model of retinal degeneration. Exp Eye Res. 2010;91(3):449–55.PubMedCrossRefGoogle Scholar
  95. 95.
    Arnhold S, Absenger Y, Klein H, Addicks K, Schraermeyer U. Transplantation of bone marrow-derived mesenchymal stem cells rescue photoreceptor cells in the dystrophic retina of the rhodopsin knockout mouse. Graefes Arch Clin Exp Ophthalmol. 2007;245(3):414–22.PubMedCrossRefGoogle Scholar
  96. 96.
    Johnson TV, Dekorver NW, Levasseur VA, Osborne A, Tassoni A, Lorber B, et al. Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome. Brain. 2014;137(2):503–19.PubMedCrossRefGoogle Scholar
  97. 97.
    Taghi GM, Maryam HGK, Taghi L, Leili H, Leyla M. Characterization of in vitro cultured bone marrow and adipose tissue-derived mesenchymal stem cells and their ability to express neurotrophic factors. Cell Biol Int. 2012;36(12):1239–49.PubMedCrossRefGoogle Scholar
  98. 98.
    Sakai K, Yamamoto A, Matsubara K, Nakamura S, Naruse M, Yamagata M, et al. Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms. J Clin Investig. 2012;122(1):80–90.PubMedGoogle Scholar
  99. 99.
    Wilkins A, Kemp K, Ginty M, Hares K, Mallam E, Scolding N. Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res. 2009;3(1):63–70.PubMedCrossRefGoogle Scholar
  100. 100.
    Dormady SP, Bashayan O, Dougherty R, Zhang XM, Basch RS. Immortalized multipotential mesenchymal cells and the hematopoietic microenvironment. J Hematother Stem Cell Res. 2001;10(1):125–40.PubMedCrossRefGoogle Scholar
  101. 101.
    Singer NG, Caplan AI. Mesenchymal stem cells: mechanisms of inflammation. Ann Rev Pathol. 2011;6:457–78.CrossRefGoogle Scholar
  102. 102.
    Johnson TV, Bull ND, Martin KR. Transplantation prospects for the inner retina. Eye. 2009;23(10):1980–4.PubMedCrossRefGoogle Scholar
  103. 103.
    Levkovitch-Verbin H, Sadan O, Vander S, Rosner M, Barhum Y, Melamed E, et al. Intravitreal injections of neurotrophic factors secreting mesenchymal stem cells are neuroprotective in rat eyes following optic nerve transaction. Invest Ophthalmol Vis Sci. 2010;51(12):6394–400.PubMedCrossRefGoogle Scholar
  104. 104.
    Abumaree MH, Al Jumah MA, Kalionis B, Jawdat D, Al Khaldi A, Abomaray FM, et al. Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti-inflammatory M2 macrophages. Stem Cell Rev Rep. 2013;9(5):620–41.CrossRefGoogle Scholar
  105. 105.
    Ribeiro A, Laranjeira P, Mendes S, Velada I, Leite C, Andrade P, et al. Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. Stem Cell Res Ther. 2013;4(5):125.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Siqueira RC, Voltarelli JC, Messias AMV, Jorge R. Possible mechanisms of retinal function recovery with the use of cell therapy with bone marrow-derived stem cells. Arq Bras Oftalmol. 2010;73(5):474–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Joo YO, Mee KK, Mi SS, Hyun JL, Jung HK, Won RW, et al. The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. Stem Cells. 2008;26(4):1047–55.CrossRefGoogle Scholar
  108. 108.
    Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood. 2005;105(10):4120–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Zhang W, Ge W, Li C, You S, Liao L, Han Q, et al. Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev. 2004;13(3):263–71.PubMedCrossRefGoogle Scholar
  110. 110.
    Nicola MD, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838–43.PubMedCrossRefGoogle Scholar
  111. 111.
    Jacobs SA, Roobrouck VD, Verfaillie CM, Van Gool SW. Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol. 2013;91(1):32–9.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Han KH, Kang HG, Gil HJ, Lee EM, Ahn C, Yang J. The immunosuppressive effect of embryonic stem cells and mesenchymal stem cells on both primary and secondary alloimmune responses. Transpl Immunol. 2010;23(3):141–6.PubMedCrossRefGoogle Scholar
  113. 113.
    Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110(10):3499–506.PubMedCrossRefGoogle Scholar
  114. 114.
    Vega A, Martín-Ferrero MA, Canto FD, Alberca M, García V, Munar A, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015;99(8):1681–90.PubMedCrossRefGoogle Scholar
  115. 115.
    Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012;150(6):1264–73.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Schwartz SD, Hubschman JP, Heilwell G, Franco-Cardenas V, Pan CK, Ostrick RM, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012;379(9817):713–20.PubMedCrossRefGoogle Scholar
  117. 117.
    Cummings BJ, Uchida N, Tamaki SJ, Salazar DL, Hooshmand M, Summers R, et al. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc Natl Acad Sci U S A. 2005;102(39):14069–74.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Otani A, Dorrell MI, Kinder K, Moreno SK, Nusinowitz S, Banin E, et al. Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells. J Clin Investig. 2004;114(6):765–74.PubMedCrossRefGoogle Scholar
  119. 119.
    Greco R, Bondanza A, Vago L, Moiola L, Rossi P, Furlan R, et al. Allogeneic hematopoietic stem cell transplantation for neuromyelitis optica. Ann Neurol. 2014;75(3):447–53.PubMedCrossRefGoogle Scholar
  120. 120.
    Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998;279(5356):1528–30.PubMedCrossRefGoogle Scholar
  121. 121.
    Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001;107(11):1395–402.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410(6829):701–5.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, et al. Bone marrow as a potential source of hepatic oval cells. Science. 1999;284(5417):1168–70.PubMedCrossRefGoogle Scholar
  124. 124.
    Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000;6(11):1229–34.PubMedCrossRefGoogle Scholar
  125. 125.
    Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: expression of neuronal phenotypes in adult mice. Science. 2000;290(5497):1775–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000;290(5497):1779–82.PubMedCrossRefGoogle Scholar
  127. 127.
    Priller J, Persons DA, Klett FF, Kempermann G, Kreutzberg GW, Dirnagl U. Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J Cell Biol. 2001;155(5):733–8.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001;105(3):369–77.PubMedCrossRefGoogle Scholar
  129. 129.
    Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci U S A. 1997;94(8):4080–5.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Sottile F, Aulicino F, Theka I, Cosma MP. Mesenchymal stem cells generate distinct functional hybrids in vitro via cell fusion or entosis. Sci Rep. 2016;6:36863.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Cantone I, Bagci H, Dormann D, Dharmalingam G, Nesterova T, Brockdorff N, et al. Ordered chromatin changes and human X chromosome reactivation by cell fusion-mediated pluripotent reprogramming. Nat Commun. 2016;7:12354.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Harris H, Watkins JF. Hybrid cells derived from mouse and man: artificial heterokaryons of mammalian cells from different species. Nature. 1965;205:640–6.PubMedCrossRefGoogle Scholar
  133. 133.
    Harris H, Miller OJ, Klein G, Worst P, Tachibana T. Suppression of malignancy by cell fusion. Nature. 1969;223(5204):363–8.PubMedCrossRefGoogle Scholar
  134. 134.
    Rao PN, Johnson RT. Mammalian cell fusion: studies on the regulation of DNA synthesis and mitosis. Nature. 1970;225(5228):159–64.PubMedCrossRefGoogle Scholar
  135. 135.
    Miller RA, Ruddle FH. Pluripotent teratocarcinoma-thymus somatic cell hybrids. Cell. 1976;9(1):45–55.PubMedCrossRefGoogle Scholar
  136. 136.
    Miller RA, Ruddle FH. Properties of teratocarcinoma-thymus somatic cell hybrids. Somatic Cell Genet. 1977;3(3):247–61.PubMedCrossRefGoogle Scholar
  137. 137.
    Andrews PW, Goodfellow PN. Antigen expression by somatic cell hybrids of a murine embryonal carcinoma cell with thymocytes and L cells. Somatic Cell Genet. 1980;6(2):271–84.PubMedCrossRefGoogle Scholar
  138. 138.
    Duran C, Talley PJ, Walsh J, Pigott C, Morton IE, Andrews PW. Hybrids of pluripotent and nullipotent human embryonal carcinoma cells: partial retention of a pluripotent phenotype. Int J Cancer. 2001;93(3):324–32.PubMedCrossRefGoogle Scholar
  139. 139.
    Takagi N, Yoshida MA, Sugawara O, Sasaki M. Reversal of X-inactivation in female mouse somatic cells hybridized with murine teratocarcinoma stem cells in vitro. Cell. 1983;34(3):1053–62.PubMedCrossRefGoogle Scholar
  140. 140.
    Atsumi T, Shirayoshi Y, Takeichi M, Okada TS. Nullipotent teratocarcinoma cells acquire the pluripotency for differentiation by fusion with somatic cells. Differentiation. 1982;23(1):83–6.PubMedCrossRefGoogle Scholar
  141. 141.
    Rousset JP, Bucchini D, Jami J. Hybrids between F9 nullipotent teratocarcinoma and thymus cells produce multidifferentiated tumors in mice. Dev Biol. 1983;96(2):331–6.PubMedCrossRefGoogle Scholar
  142. 142.
    Matveeva NM, Shilov AG, Kaftanovskaya EM, Maximovsky LP, Zhelezova AI, Golubitsa AN, et al. In vitro and in vivo study of pluripotency in intraspecific hybrid cells obtained by fusion of murine embryonic stem cells with splenocytes. Mol Reprod Dev. 1998;50(2):128–38.PubMedCrossRefGoogle Scholar
  143. 143.
    Matveeva NM, Kuznetsov SB, Kaftanovskaya EM, Serov OL. Segregation of parental chromosomes in hybrid cells obtained by fusion between embryonic stem cells and differentiated cells of adult animal. Dokl Biol Sci. 2001;379:399–401.PubMedCrossRefGoogle Scholar
  144. 144.
    Tada M, Morizane A, Kimura H, Kawasaki H, Ainscough JF, Sasai Y, et al. Pluripotency of reprogrammed somatic genomes in embryonic stem hybrid cells. Dev Dyn. 2003;227(4):504–10.PubMedCrossRefGoogle Scholar
  145. 145.
    Silva J, Chambers I, Pollard S, Smith A. Nanog promotes transfer of pluripotency after cell fusion. Nature. 2006;441(7096):997–1001.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Ying QL, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion. Nature. 2002;416(6880):545–8.CrossRefPubMedGoogle Scholar
  147. 147.
    Lluis F, Pedone E, Pepe S, Cosma MP. Periodic activation of Wnt/beta-catenin signaling enhances somatic cell reprogramming mediated by cell fusion. Cell Stem Cell. 2008;3(5):493–507.PubMedCrossRefGoogle Scholar
  148. 148.
    Nakamura T, Inoue K, Ogawa S, Umehara H, Ogonuki N, Miki H, et al. Effects of Akt signaling on nuclear reprogramming. Genes Cells. 2008;13(12):1269–77.PubMedCrossRefGoogle Scholar
  149. 149.
    Lluis F, Pedone E, Pepe S, Cosma MP. The Wnt/beta-catenin signaling pathway tips the balance between apoptosis and reprograming of cell fusion hybrids. Stem Cells. 2010;28(11):1940–9.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature. 2010;463(7284):1042–7.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Pereira CF, Terranova R, Ryan NK, Santos J, Morris KJ, Cui W, et al. Heterokaryon-based reprogramming of human B lymphocytes for pluripotency requires Oct4 but not Sox2. PLoS Genet. 2008;4(9):e1000170.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Pereira CF, Piccolo FM, Tsubouchi T, Sauer S, Ryan NK, Bruno L, et al. ESCs require PRC2 to direct the successful reprogramming of differentiated cells toward pluripotency. Cell Stem Cell. 2010;6(6):547–56.PubMedCrossRefGoogle Scholar
  153. 153.
    Tsubouchi T, Soza-Ried J, Brown K, Piccolo FM, Cantone I, Landeira D, et al. DNA synthesis is required for reprogramming mediated by stem cell fusion. Cell. 2013;152(4):873–83.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Cowan CA, Atienza J, Melton DA, Eggan K. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science. 2005;309(5739):1369–73.PubMedCrossRefGoogle Scholar
  155. 155.
    Matsui Y, Zsebo K, Hogan BL. Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell. 1992;70(5):841–7.PubMedCrossRefGoogle Scholar
  156. 156.
    Resnick JL, Bixler LS, Cheng L, Donovan PJ. Long-term proliferation of mouse primordial germ cells in culture. Nature. 1992;359(6395):550–1.PubMedCrossRefGoogle Scholar
  157. 157.
    Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, Reik W, et al. Epigenetic reprogramming in mouse primordial germ cells. Mech Dev. 2002;117(1–2):15–23.PubMedCrossRefGoogle Scholar
  158. 158.
    Monk M, Boubelik M, Lehnert S. Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development. 1987;99(3):371–82.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Tada M, Tada T, Lefebvre L, Barton SC, Surani MA. Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. EMBO J. 1997;16(21):6510–20.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Blau HM, Chiu CP, Webster C. Cytoplasmic activation of human nuclear genes in stable heterocaryons. Cell. 1983;32(4):1171–80.PubMedCrossRefGoogle Scholar
  161. 161.
    Blau HM, Pavlath GK, Hardeman EC, Chiu CP, Silberstein L, Webster SG, et al. Plasticity of the differentiated state. Science. 1985;230(4727):758–66.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Davidson RL, Ephrussi B, Yamamoto K. Regulation of pigment synthesis in mammalian cells, as studied by somatic hybridization. Proc Natl Acad Sci U S A. 1966;56(5):1437–40.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Weiss MC, Chaplain M. Expression of differentiated functions in hepatoma cell hybrids: reappearance of tyrosine aminotransferase inducibility after the loss of chromosomes. Proc Natl Acad Sci U S A. 1971;68(12):3026–30.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Peterson JA, Weiss MC. Expression of differentiated functions in hepatoma cell hybrids: induction of mouse albumin production in rat hepatoma-mouse fibroblast hybrids. Proc Natl Acad Sci U S A. 1972;69(3):571–5.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Darlington GJ, Bernard HP, Ruddle FH. Human serum albumin phenotype activation in mouse hepatoma--human leukocyte cell hybrids. Science. 1974;185(4154):859–62.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Davidson RL. Regulation of malanin synthesis in mammalian cells: effect of gene dosage on the expression of differentiation. Proc Natl Acad Sci U S A. 1972;69(4):951–5.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Pavlath GK, Blau HM. Expression of muscle genes in heterokaryons depends on gene dosage. J Cell Biol. 1986;102(1):124–30.PubMedCrossRefGoogle Scholar
  168. 168.
    Wright WE. Induction of muscle genes in neural cells. J Cell Biol. 1984;98(2):427–35.PubMedCrossRefGoogle Scholar
  169. 169.
    Palermo A, Doyonnas R, Bhutani N, Pomerantz J, Alkan O, Blau HM. Nuclear reprogramming in heterokaryons is rapid, extensive, and bidirectional. FASEB J. 2009;23(5):1431–40.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Gibson AJ, Karasinski J, Relvas J, Moss J, Sherratt TG, Strong PN, et al. Dermal fibroblasts convert to a myogenic lineage in mdx mouse muscle. J Cell Sci. 1995;108(Pt 1):207–14.PubMedGoogle Scholar
  171. 171.
    Gussoni E, Bennett RR, Muskiewicz KR, Meyerrose T, Nolta JA, Gilgoff I, et al. Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation. J Clin Invest. 2002;110(6):807–14.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature. 1999;401(6751):390–4.PubMedGoogle Scholar
  173. 173.
    Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003;422(6934):901–4.PubMedCrossRefGoogle Scholar
  174. 174.
    Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003;422(6934):897–901.PubMedCrossRefGoogle Scholar
  175. 175.
    Willenbring H, Bailey AS, Foster M, Akkari Y, Dorrell C, Olson S, et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med. 2004;10(7):744–8.PubMedCrossRefGoogle Scholar
  176. 176.
    Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. 2003;425(6961):968–73.PubMedCrossRefGoogle Scholar
  177. 177.
    Weimann JM, Johansson CB, Trejo A, Blau HM. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol. 2003;5(11):959–66.PubMedCrossRefGoogle Scholar
  178. 178.
    Weimann JM, Charlton CA, Brazelton TR, Hackman RC, Blau HM. Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci U S A. 2003;100(4):2088–93.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Lluis F, Cosma MP. Cell-fusion-mediated somatic-cell reprogramming: a mechanism for tissue regeneration. J Cell Physiol. 2010;223(1):6–13.PubMedGoogle Scholar
  180. 180.
    Corbel SY, Lee A, Yi L, Duenas J, Brazelton TR, Blau HM, et al. Contribution of hematopoietic stem cells to skeletal muscle. Nat Med. 2003;9(12):1528–32.PubMedCrossRefGoogle Scholar
  181. 181.
    Camargo FD, Green R, Capetanaki Y, Jackson KA, Goodell MA. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med. 2003;9(12):1520–7.PubMedCrossRefGoogle Scholar
  182. 182.
    Nygren JM, Jovinge S, Breitbach M, Sawen P, Roll W, Hescheler J, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med. 2004;10(5):494–501.PubMedCrossRefGoogle Scholar
  183. 183.
    Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, et al. Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther. 2006;14(6):840–50.PubMedCrossRefGoogle Scholar
  184. 184.
    Freeman BT, Kouris NA, Ogle BM. Tracking fusion of human mesenchymal stem cells after transplantation to the heart. Stem Cells Transl Med. 2015;4(6):685–94.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Piquer-Gil M, Garcia-Verdugo JM, Zipancic I, Sanchez MJ, Alvarez-Dolado M. Cell fusion contributes to pericyte formation after stroke. J Cereb Blood Flow Metab. 2009;29(3):480–5.PubMedCrossRefGoogle Scholar
  186. 186.
    Herzog EL, Van Arnam J, Hu B, Zhang J, Chen Q, Haberman AM, et al. Lung-specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation. FASEB J. 2007;21(10):2592–601.PubMedCrossRefGoogle Scholar
  187. 187.
    Rizvi AZ, Swain JR, Davies PS, Bailey AS, Decker AD, Willenbring H, et al. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc Natl Acad Sci U S A. 2006;103(16):6321–5.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Davies PS, Powell AE, Swain JR, Wong MH. Inflammation and proliferation act together to mediate intestinal cell fusion. PLoS One. 2009;4(8):e6530.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Ferrand J, Noel D, Lehours P, Prochazkova-Carlotti M, Chambonnier L, Menard A, et al. Human bone marrow-derived stem cells acquire epithelial characteristics through fusion with gastrointestinal epithelial cells. PLoS One. 2011;6(5):e19569.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Camargo FD, Finegold M, Goodell MA. Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. J Clin Invest. 2004;113(9):1266–70.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Pedone E, Olteanu VA, Marucci L, Munoz-Martin MI, Youssef SA, de Bruin A, et al. Modeling Dynamics and Function of Bone Marrow Cells in Mouse Liver Regeneration. Cell Rep. 2017;18(1):107–21.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Johansson CB, Youssef S, Koleckar K, Holbrook C, Doyonnas R, Corbel SY, et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat Cell Biol. 2008;10(5):575–83.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Bae JS, Furuya S, Shinoda Y, Endo S, Schuchman EH, Hirabayashi Y, et al. Neurodegeneration augments the ability of bone marrow-derived mesenchymal stem cells to fuse with Purkinje neurons in Niemann-Pick type C mice. Hum Gene Ther. 2005;16(8):1006–11.PubMedCrossRefGoogle Scholar
  194. 194.
    Bae JS, Han HS, Youn DH, Carter JE, Modo M, Schuchman EH, et al. Bone marrow-derived mesenchymal stem cells promote neuronal networks with functional synaptic transmission after transplantation into mice with neurodegeneration. Stem Cells. 2007;25(5):1307–16.PubMedCrossRefGoogle Scholar
  195. 195.
    Nern C, Wolff I, Macas J, von Randow J, Scharenberg C, Priller J, et al. Fusion of hematopoietic cells with Purkinje neurons does not lead to stable heterokaryon formation under noninvasive conditions. J Neurosci. 2009;29(12):3799–807.PubMedCrossRefGoogle Scholar
  196. 196.
    Altarche-Xifro W, di Vicino U, Munoz-Martin MI, Bortolozzi A, Bove J, Vila M, et al. Functional rescue of dopaminergic neuron loss in Parkinson’s disease mice after transplantation of hematopoietic stem and progenitor cells. EBioMedicine. 2016;8:83–95.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Sanges D, Romo N, Simonte G, Di Vicino U, Tahoces AD, Fernandez E, et al. Wnt/beta-catenin signaling triggers neuron reprogramming and regeneration in the mouse retina. Cell Rep. 2013;4(2):271–86.PubMedCrossRefGoogle Scholar
  198. 198.
    Sanges D, Simonte G, Di Vicino U, Romo N, Pinilla I, Nicolas M, et al. Reprogramming Muller glia via in vivo cell fusion regenerates murine photoreceptors. J Clin Invest. 2016;126(8):3104–16.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    DeLeve LD, Wang X, Wang L. VEGF-sdf1 recruitment of CXCR7+ bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration. Am J Physiol Gastrointest Liver Physiol. 2016;310(9):G739–46.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Lima e Silva R, Shen J, Hackett SF, Kachi S, Akiyama H, Kiuchi K, et al. The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization. FASEB J. 2007;21(12):3219–30.PubMedCrossRefGoogle Scholar
  201. 201.
    Wang Y, Deng Y, Zhou GQ. SDF-1alpha/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. Brain Res. 2008;1195:104–12.PubMedCrossRefGoogle Scholar
  202. 202.
    Pesaresi M, Bonilla-Pons SA, Simonte G, Sanges D, Di Vicino U, Cosma MP. Endogenous mobilization of bone-marrow cells into the murine retina induces fusion-mediated reprogramming of Muller Glia cells. EBioMedicine. 2018;30:38–51.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Duncan AW, Hickey RD, Paulk NK, Culberson AJ, Olson SB, Finegold MJ, et al. Ploidy reductions in murine fusion-derived hepatocytes. PLoS Genet. 2009;5(2):e1000385.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Assis ACM, Carvalho JL, Jacoby BA, Ferreira RLB, Castanheira P, Diniz SOF, et al. Time-dependent migration of systemically delivered bone marrow mesenchymal stem cells to the infarcted heart. Cell Transplant. 2010;19(2):219–30.PubMedCrossRefGoogle Scholar
  205. 205.
    Yu S, Tanabe T, Dezawa M, Ishikawa H, Yoshimura N. Effects of bone marrow stromal cell injection in an experimental glaucoma model. Biochem Biophys Res Commun. 2006;344(4):1071–9.PubMedCrossRefGoogle Scholar
  206. 206.
    Hambright D, Park KY, Brooks M, McKay R, Swaroop A, Nasonkin IO. Long-term survival and differentiation of retinal neurons derived from human embryonic stem cell lines in un-immunosuppressed mouse retina. Mol Vis. 2012;18:920–36.PubMedPubMedCentralGoogle Scholar
  207. 207.
    Tzameret A, Sher I, Belkin M, Treves AJ, Meir A, Nagler A, et al. 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. 2014;118:135–44.PubMedCrossRefGoogle Scholar
  208. 208.
    Barber AC, Hippert C, Duran Y, West EL, Bainbridge JWB, Warre-Cornish K, et al. Repair of the degenerate retina by photoreceptor transplantation. Proc Natl Acad Sci U S A. 2013;110(1):354–9.PubMedCrossRefGoogle Scholar
  209. 209.
    Singh MS, Issa PC, Butler R, Martin C, Lipinski DM, Sekaran S, et al. Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation. Proc Natl Acad Sci U S A. 2013;110(3):1101–6.PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Whiting P, Kerby J, Coffey P, da Cruz L, McKernan R. Progressing a human embryonic stem-cell-based regenerative medicine therapy towards the clinic. Philos Trans R Soc B Biol Sci. 2015;370(1680):20140375.CrossRefGoogle Scholar
  211. 211.
    Stanzel BV, Liu Z, Somboonthanakij S, Wongsawad W, Brinken R, Eter N, et al. Human RPE stem cells grown into polarized RPE monolayers on a polyester matrix are maintained after grafting into rabbit subretinal space. Stem Cell Reports. 2014;2(1):64–77.PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Kundu J, Michaelson A, Baranov P, Young MJ, Carrier RL. Approaches to cell delivery: substrates and scaffolds for cell therapy. Dev Ophthalmol. 2014;53:143–54.PubMedCrossRefGoogle Scholar
  213. 213.
    Lu B, Tai YC, Humayun MS. Microdevice-based cell therapy for age-related macular degeneration. Dev Ophthalmol. 2014;53:155–66.PubMedCrossRefGoogle Scholar
  214. 214.
    Tsukahara I, Ninomiya S, Castellarin A, Yagi F, Sugino IK, Zarbin MA. Early attachment of uncultured retinal pigment epithelium from aged donors onto Bruch’s membrane explants. Exp Eye Res. 2002;74(2):255–66.PubMedCrossRefGoogle Scholar
  215. 215.
    Jiang C, Klassen H, Zhang X, Young M. Laser injury promotes migration and integration of retinal progenitor cells into host retina. Mol Vis. 2010;16:983–90.PubMedPubMedCentralGoogle Scholar
  216. 216.
    Inoue Y, Iriyama A, Ueno S, Takahashi H, Kondo M, Tamaki Y, et al. Subretinal transplantation of bone marrow mesenchymal stem cells delays retinal degeneration in the RCS rat model of retinal degeneration. Exp Eye Res. 2007;85(2):234–41.PubMedCrossRefGoogle Scholar
  217. 217.
    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(6):340–8.PubMedCrossRefGoogle Scholar
  218. 218.
    Young MJ, Ray J, Whiteley SJO, Klassen H, Gage FH. 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
  219. 219.
    Qiu G, Seiler MJ, Mui C, Arai S, Aramant RB, De Juan E Jr, et al. Photoreceptor differentiation and integration of retinal progenitor cells transplanted into transgenic rats. Exp Eye Res. 2005;80(4):515–25.PubMedCrossRefGoogle Scholar
  220. 220.
    Klassen HJ, Ng TF, Kurimoto Y, Kirov I, Shatos M, Coffey P, et al. Multipotent retinal progenitors express developmental markers, differentiate into retinal neurons, and preserve light-mediated behavior. Invest Ophthalmol Vis Sci. 2004;45(11):4167–73.PubMedCrossRefGoogle Scholar
  221. 221.
    West EL, Pearson RA, Tschernutter M, Sowden JC, MacLaren RE, Ali RR. Pharmacological disruption of the outer limiting membrane leads to increased retinal integration of transplanted photoreceptor precursors. Exp Eye Res. 2008;86(4):601–11.PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Karlstetter M, Ebert S, Langmann T. Microglia in the healthy and degenerating retina: insights from novel mouse models. Immunobiology. 2010;215(9–10):685–91.PubMedCrossRefGoogle Scholar
  223. 223.
    Sellés-Navarro I, Ellezam B, Fajardo R, Latour M, McKerracher L. Retinal ganglion cell and nonneuronal cell responses to a microcrush lesion of adult rat optic nerve. Exp Neurol. 2001;167(2):282–9.PubMedCrossRefGoogle Scholar
  224. 224.
    Singhal S, Lawrence JM, Bhatia B, Ellis JS, Kwan AS, MacNeil A, et al. Chondroitin sulfate proteoglycans and microglia prevent migration and integration of grafted müller stem cells into degenerating retina. Stem Cells. 2008;26(4):1074–82.PubMedCrossRefGoogle Scholar
  225. 225.
    Tassoni A, Gutteridge A, Barber AC, Osborne A, Martin KR. Molecular mechanisms mediating retinal reactive gliosis following bone marrow mesenchymal stem cell transplantation. Stem Cells. 2015;33(10):3006–16.PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Bradbury EJ, Moon LDF, Popat RJ, King VR, Bennett GS, Patel PN, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature. 2002;416(6881):636–40.PubMedCrossRefGoogle Scholar
  227. 227.
    Zhang Y, Klassen HJ, Tucker BA, Perez MTR, Young MJ. CNS progenitor cells promote a permissive environment for neurite outgrowth via a matrix metalloproteinase-2-dependent mechanism. J Neurosci. 2007;27(17):4499–506.PubMedCrossRefGoogle Scholar
  228. 228.
    Jones LL, Margolis RU, Tuszynski MH. The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. Exp Neurol. 2003;182(2):399–411.PubMedCrossRefGoogle Scholar
  229. 229.
    Busch SA, Silver J. The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol. 2007;17(1):120–7.PubMedCrossRefGoogle Scholar
  230. 230.
    Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci. 2004;5(2):146–56.PubMedCrossRefGoogle Scholar
  231. 231.
    Suzuki T, Akimoto M, Imai H, Ueda Y, Mandai M, Yoshimura N, et al. Chondroitinase ABC treatment enhances synaptogenesis between transplant and host neurons in model of retinal degeneration. Cell Transplant. 2007;16(5):493–503.PubMedCrossRefGoogle Scholar
  232. 232.
    Park SS, Bauer G, Abedi M, Pontow S, Panorgias A, Jonnal R, et al. Intravitreal autologous bone marrow cd34+ cell therapy for ischemic and degenerative retinal disorders: preliminary phase 1 clinical trial findings. Invest Ophthalmol Vis Sci. 2015;56(1):81–9.PubMedCentralCrossRefGoogle Scholar
  233. 233.
    Siqueira RC, Messias A, Messias K, Arcieri RS, Ruiz MA, Souza NF, et al. Quality of life in patients with retinitis pigmentosa submitted to intravitreal use of bone marrow-derived stem cells (Reticell -clinical trial). Stem Cell Res Ther. 2015;6(1):29.PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Lund RD, Wang S, Lu B, Girman S, Holmes T, Sauve Y, et al. Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells. 2007;25(3):602–11.PubMedCrossRefGoogle Scholar
  235. 235.
    Zhang Y, Wang W. Effects of bone marrow mesenchymal stem cell transplantation on light-damaged retina. Invest Ophthalmol Vis Sci. 2010;51(7):3742–8.PubMedCrossRefGoogle Scholar
  236. 236.
    Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci. 2010;51(4):2051–9.PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Mead B, Logan A, Berry M, Leadbeater W, Scheven BA. Intravitreally transplanted dental pulp stem cells promote neuroprotection and axon regeneration of retinal ganglion cells after optic nerve injury. Invest Ophthalmol Vis Sci. 2013;54(12):7544–56.PubMedCrossRefGoogle Scholar
  238. 238.
    Sanges D, Simonte G, Di Vicino U, Romo N, Pinilla I, Farres MN, et al. Reprogramming Muller glia via in vivo cell fusion regenerates murine photoreceptors. J Clin Invest. 2016;126(8):3104–16.PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Wang HC, Brown J, Alayon H, Stuck BE. Transplantation of quantum dot-labelled bone marrow-derived stem cells into the vitreous of mice with laser-induced retinal injury: survival, integration and differentiation. Vision Res. 2010;50(7):665–73.PubMedCrossRefGoogle Scholar
  240. 240.
    Park SS, Caballero S, Bauer G, Shibata B, Roth A, Fitzgerald PG, et al. Long-term effects of intravitreal injection of GMP-grade bone-marrow-derived CD34+ cells in NOD-SCID mice with acute ischemia-reperfusion injury. Invest Ophthalmol Vis Sci. 2012;53(2):986–94.PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Lund RD, Wang S, Klimanskaya I, Holmes T, Ramos-Kelsey R, Lu B, 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
  242. 242.
    Wang S, Lu B, Girman S, Holmes T, Bischoff N, Lund RD. Morphological and functional rescue in RCS rats after RPE cell line transplantation at a later stage of degeneration. Invest Ophthalmol Vis Sci. 2008;49(1):416–21.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Francesco Sottile
    • 1
  • Martina Pesaresi
    • 1
  • Giacoma Simonte
    • 1
  • Maria Pia Cosma
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyBarcelonaSpain
  2. 2.Universitat Pompeu Fabra (UPF)BarcelonaSpain
  3. 3.Institució Catalana de Recerca i Estudis Avançat (ICREA), Pg. Lluís Companys 23BarcelonaSpain
  4. 4.Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of ScienceGuangzhouChina

Personalised recommendations