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Cell-Fusion-Mediated Reprogramming: Pluripotency or Transdifferentiation? Implications for Regenerative Medicine

  • Daniela Sanges*
  • Frederic Lluis*
  • Maria Pia Cosma
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 713)

Abstract

Cell–cell fusion is a natural process that occurs not only during development, but as has emerged over the last few years, also with an important role in tissue regeneration. Interestingly, in-vitro studies have revealed that after fusion of two different cell types, the developmental potential of these cells can change. This suggests that the mechanisms by which cells differentiate during development to acquire their identities is not irreversible, as was considered until a few years ago. To date, it is well established that the fate of a cell can be changed by a process known as reprogramming. This mainly occurs in two different ways: the differentiated state of a cell can be reversed back into a pluripotent state (pluripotent reprogramming), or it can be switched directly to a different differentiated state (lineage reprogramming). In both cases, these possibilities of obtaining sources of autologous somatic cells to maintain, replace or rescue different tissues has provided new and fundamental insights in the stem-cell-therapy field. Most interestingly, the concept that cell reprogramming can also occur in vivo by spontaneous cell fusion events is also emerging, which suggests that this mechanism can be implicated not only in cellular plasticity, but also in tissue regeneration. In this chapter, we will summarize the present knowledge of the molecular mechanisms that mediate the restoration of pluripotency in vitro through cell fusion, as well as the studies carried out over the last 3 decades on lineage reprogramming, both in vitro and in vivo. How the outcome of these studies relate to regenerative medicine applications will also be discussed.

Keywords

Somatic Cell Cell Fusion Hybrid Cell Somatic Cell Nuclear Transfer Purkinje Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Chen EH, Grote E, Mohler W et al (2007) Cell-cell fusion. FEBS Lett 581:2181–2193PubMedGoogle Scholar
  2. 2.
    Lentz BR (2007) PEG as a tool to gain insight into membrane fusion. Eur Biophys J 36:315–326PubMedGoogle Scholar
  3. 3.
    Ogle BM, Cascalho M, Platt JL (2005) Biological implications of cell fusion. Nat Rev Mol Cell Biol 6:567–575PubMedGoogle Scholar
  4. 4.
    Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497PubMedGoogle Scholar
  5. 5.
    Ahkong QF, Howell JI, Lucy JA et al (1975) Fusion of hen erythrocytes with yeast protoplasts induced by polyethylene glycol. Nature 255:66–67PubMedGoogle Scholar
  6. 6.
    Arnold K, Herrmann A, Pratsch L et al (1985) The dielectric properties of aqueous solutions of poly(ethylene glycol) and their influence on membrane structure. Biochim Biophys Acta 815:515–518PubMedGoogle Scholar
  7. 7.
    Chiu DT (2001) A microfluidics platform for cell fusion. Curr Opin Chem Biol 5:609–612PubMedGoogle Scholar
  8. 8.
    Ramos C, Teissie J (2000) Electrofusion: a biophysical modification of cell membrane and a mechanism in exocytosis. Biochimie 82:511–518PubMedGoogle Scholar
  9. 9.
    Teissie J, Rols MP (1986) Fusion of mammalian cells in culture is obtained by creating the contact between cells after their electropermeabilization. Biochem Biophys Res Commun 140:258–266PubMedGoogle Scholar
  10. 10.
    Tweedell KS (2004) Embryos, clones, and stem cells: a scientific primer. Scientific World J 4:662–715Google Scholar
  11. 11.
    Wilmut I, Schnieke AE, McWhir J et al (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385:810–813PubMedGoogle Scholar
  12. 12.
    Wakayama T, Perry AC, Zuccotti M et al (1998) Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 394:369–374PubMedGoogle Scholar
  13. 13.
    Wakayama T, Yanagimachi R (1998) Development of normal mice from oocytes injected with freeze-dried spermatozoa. Nat Biotechnol 16:639–641PubMedGoogle Scholar
  14. 14.
    Onishi A, Iwamoto M, Akita T et al (2000) Pig cloning by microinjection of fetal fibroblast nuclei. Science 289:1188–1190PubMedGoogle Scholar
  15. 15.
    Morgan HD, Santos F, Green K et al (2005) Epigenetic reprogramming in mammals. Hum Mol Genet 14 Spec No 1:R47–58Google Scholar
  16. 16.
    Carlson LL, Page AW, Bestor TH (1992) Properties and localization of DNA methyltransferase in preimplantation mouse embryos: implications for genomic imprinting. Genes Dev 6:2536–2541PubMedGoogle Scholar
  17. 17.
    Bourc’his D, Le Bourhis D, Patin D et al (2001) Delayed and incomplete reprogramming of chromosome methylation patterns in bovine cloned embryos. Curr Biol 11:1542–1546PubMedGoogle Scholar
  18. 18.
    Dean W, Santos F, Stojkovic M et al (2001) Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proc Natl Acad Sci USA 98:13734–13738PubMedGoogle Scholar
  19. 19.
    Kang YK, Koo DB, Park JS et al (2001) Aberrant methylation of donor genome in cloned bovine embryos. Nat Genet 28:173–177PubMedGoogle Scholar
  20. 20.
    Miller RA, Ruddle FH (1976) Pluripotent teratocarcinoma-thymus somatic cell hybrids. Cell 9:45–55PubMedGoogle Scholar
  21. 21.
    Cowan CA, Atienza J, Melton DA et al (2005) Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309:1369–1373PubMedGoogle Scholar
  22. 22.
    Tada M, Takahama Y, Abe K et al (2001) Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr Biol 11:1553–1558PubMedGoogle Scholar
  23. 23.
    Blau HM, Chiu CP, Webster C (1983) Cytoplasmic activation of human nuclear genes in stable heterocaryons. Cell 32:1171–1180PubMedGoogle Scholar
  24. 24.
    Blau HM, Pavlath GK, Hardeman EC et al (1985) Plasticity of the differentiated state. Science 230:758–766PubMedGoogle Scholar
  25. 25.
    Baron MH, Maniatis T (1986) Rapid reprogramming of globin gene expression in transient heterokaryons. Cell 46:591–602PubMedGoogle Scholar
  26. 26.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedGoogle Scholar
  27. 27.
    Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells. Science 318:1917–1920Google Scholar
  28. 28.
    Aoi T, Yae K, Nakagawa M et al (2008) Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach Cells. Science 321:699–702Google Scholar
  29. 29.
    Hanna J, Markoulaki S, Schorderet P et al (2008) Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133:250–264PubMedGoogle Scholar
  30. 30.
    Cowling VH and Cole MD (2006) Mechanism of transcriptional activation by the Myc oncoproteins. Semin Cancer Biol 16:242–252PubMedGoogle Scholar
  31. 31.
    Knoepfler PS (2007) Myc goes global: new tricks for an old oncogene. Cancer Res 67:5061–5063PubMedGoogle Scholar
  32. 32.
    Lebofsky R, Walter JC (2007) New Myc-anisms for DNA replication and tumorigenesis? Cancer Cell 12:102–103PubMedGoogle Scholar
  33. 33.
    Nakagawa M, Koyanagi M, Tanabe K et al (2007) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26:101–106Google Scholar
  34. 34.
    Wernig M, Meissner A, Cassady JP et al (2008) c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2:10–12PubMedGoogle Scholar
  35. 35.
    Jiang J, Chan YS, Loh YH et al (2008) A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol 10:353–360PubMedGoogle Scholar
  36. 36.
    Nakatake Y, Fukui N, Iwamatsu Y et al (2006) Klf4 cooperates with Oct3/4 and Sox2 to activate the Lefty1 core promoter in embryonic stem cells. Mol Cell Biol 26:7772–7782PubMedGoogle Scholar
  37. 37.
    Feng B, Jiang J, Kraus P et al (2009) Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Biol Cell 11:197–203Google Scholar
  38. 38.
    Boyer LA, Mathur D and Jaenisch R (2006) Molecular control of pluripotency. Curr Opin Genet Dev 16:455–462PubMedGoogle Scholar
  39. 39.
    Niwa H (2007) How is pluripotency determined and maintained? Development 134:635–646PubMedGoogle Scholar
  40. 40.
    Nichols J, Zevnik B, Anastassiadis K et al (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379–391PubMedGoogle Scholar
  41. 41.
    Avilion AA, Nicolis SK, Pevny LH et al (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17:126–140PubMedGoogle Scholar
  42. 42.
    Heng JC, Feng B, Han J et al (2010) The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Cell Stem Cell 6:167–174PubMedGoogle Scholar
  43. 43.
    Kim JB, Greber B, Arauzo-Bravo MJ et al (2009) Direct reprogramming of human neural stem cells by OCT4. Nature 461:649–643Google Scholar
  44. 44.
    Byrne JA, Pedersen DA, Clepper LL et al (2007) Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature 450:497–502PubMedGoogle Scholar
  45. 45.
    Han J, Sidhu KS (2008) Current concepts in reprogramming somatic cells to pluripotent state. Curr Stem Cell Res Ther 3:66–74PubMedGoogle Scholar
  46. 46.
    Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156PubMedGoogle Scholar
  47. 47.
    Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78:7634–7638PubMedGoogle Scholar
  48. 48.
    Donovan PJ (1994) Growth factor regulation of mouse primordial germ cell development. Curr Top Dev Biol 29:189–225PubMedGoogle Scholar
  49. 49.
    Jacob F (1978) The Leeuwenhoek Lecture, 1977. Mouse teratocarcinoma and mouse embryo. Proc R Soc Lond B Biol Sci 201:249–270PubMedGoogle Scholar
  50. 50.
    Papaioannou A, Lissaios B, Vasilaros S et al (1983) Pre- and postoperative chemoendocrine treatment with or without postoperative radiotherapy for locally advanced breast cancer. Cancer 51:1284–1290PubMedGoogle Scholar
  51. 51.
    Reubinoff BE, Pera MF, Fong CY et al (2000) Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 18:399–404PubMedGoogle Scholar
  52. 52.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147PubMedGoogle Scholar
  53. 53.
    Andrews PW, Goodfellow PN (1980) Antigen expression by somatic cell hybrids of a murine embryonal carcinoma cell with thymocytes and L cells. Somatic Cell Genet 6:271–284PubMedGoogle Scholar
  54. 54.
    Rousset JP, Bucchini D, Jami J (1983) Hybrids between F9 nullipotent teratocarcinoma and thymus cells produce multidifferentiated tumors in mice. Dev Biol 96:331–336PubMedGoogle Scholar
  55. 55.
    Do JT, Han DW, Gentile L et al (2007) Erasure of cellular memory by fusion with pluripotent cells. Stem Cells 25:1013–1020PubMedGoogle Scholar
  56. 56.
    Atsumi T, Shirayoshi Y, Takeichi M et al (1982) Nullipotent teratocarcinoma cells acquire the pluripotency for differentiation by fusion with somatic cells. Differentiation 23:83–86PubMedGoogle Scholar
  57. 57.
    Takagi N, Yoshida MA, Sugawara O et al (1983) Reversal of X-inactivation in female mouse somatic cells hybridized with murine teratocarcinoma stem cells in vitro. Cell 34:1053–1062PubMedGoogle Scholar
  58. 58.
    Flasza M, Shering AF, Smith K et al (2003) Reprogramming in inter-species embryonal carcinoma-somatic cell hybrids induces expression of pluripotency and differentiation markers. Cloning Stem Cells 5:339–354PubMedGoogle Scholar
  59. 59.
    Rousset JP, Dubois P, Lasserre C et al (1979) Phenotype and surface antigens of mouse teratocarcinoma x fibroblast cell hybrids. Somatic Cell Genet 5:739–752PubMedGoogle Scholar
  60. 60.
    Matveeva NM, Kuznetsov SB, Kaftanovskaya EM et al (2001) Segregation of parental chromosomes in hybrid cells obtained by fusion between embryonic stem cells and differentiated cells of adult animal. Dokl Biol Sci 379:399–401PubMedGoogle Scholar
  61. 61.
    Matveeva NM, Shilov AG, Kaftanovskaya EM et al (1998) 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 50:128–138PubMedGoogle Scholar
  62. 62.
    Tada M, Morizane A, Kimura H et al (2003) Pluripotency of reprogrammed somatic genomes in embryonic stem hybrid cells. Dev Dyn 227:504–510PubMedGoogle Scholar
  63. 63.
    Yu J, Vodyanik MA, He P et al (2006) Human embryonic stem cells reprogram myeloid precursors following cell-cell fusion. Stem Cells 24:168–176PubMedGoogle Scholar
  64. 64.
    Blau HM, Blakely BT (1999) Plasticity of cell fate: insights from heterokaryons. Semin Cell Dev Biol 10:267–272PubMedGoogle Scholar
  65. 65.
    Bhutani N, Brady JJ, Damian M et al (2010) Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463:1042–1047PubMedGoogle Scholar
  66. 66.
    Pereira CF, Terranova R, Ryan NK et al (2008) Heterokaryon-based reprogramming of human B lymphocytes for pluripotency requires Oct4 but not Sox2. PLoS Genet 4:e1000170PubMedGoogle Scholar
  67. 67.
    Matsui Y, Zsebo K, Hogan BL (1992) Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70:841–847PubMedGoogle Scholar
  68. 68.
    Resnick JL, Bixler LS, Cheng L et al (1992) Long-term proliferation of mouse primordial germ cells in culture. Nature 359:550–551PubMedGoogle Scholar
  69. 69.
    Hajkova P, Erhardt S, Lane N et al (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117:15–23PubMedGoogle Scholar
  70. 70.
    Monk M, Boubelik M, Lehnert S (1987) Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development 99:371–382PubMedGoogle Scholar
  71. 71.
    Tada T, Tada M, Hilton K et al (1998) Epigenotype switching of imprintable loci in embryonic germ cells. Dev Genes Evol 207:551–561PubMedGoogle Scholar
  72. 72.
    Tada M, Tada T, Lefebvre L et al (1997) Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. Embo J 16:6510–6520PubMedGoogle Scholar
  73. 73.
    Eggan K, Baldwin K, Tackett M et al (2004) Mice cloned from olfactory sensory neurons. Nature 428:44–49PubMedGoogle Scholar
  74. 74.
    Hochedlinger K, Jaenisch R (2006) Nuclear reprogramming and pluripotency. Nature 441:1061–1067PubMedGoogle Scholar
  75. 75.
    Hochedlinger K, Jaenisch R (2007) On the cloning of animals from terminally differentiated cells. Nat Genet 39:136–137; author reply 137–138PubMedGoogle Scholar
  76. 76.
    Jaenisch R, Hochedlinger K, Blelloch R et al (2004) Nuclear cloning, epigenetic reprogramming, and cellular differentiation. Cold Spring Harb Symp Quant Biol 69:19–27PubMedGoogle Scholar
  77. 77.
    Hansis C, Barreto G, Maltry N et al (2004) Nuclear reprogramming of human somatic cells by xenopus egg extract requires BRG1. Curr Biol 14:1475–1480PubMedGoogle Scholar
  78. 78.
    Taranger CK, Noer A, Sorensen AL et al (2005) Induction of dedifferentiation, genomewide transcriptional programming, and epigenetic reprogramming by extracts of carcinoma and embryonic stem cells. Mol Biol Cell 16:5719–5735PubMedGoogle Scholar
  79. 79.
    Do JT, Scholer HR (2004) Nuclei of embryonic stem cells reprogram somatic cells. Stem Cells 22:941–949PubMedGoogle Scholar
  80. 80.
    Chambers I, Colby D, Robertson M et al (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643–655PubMedGoogle Scholar
  81. 81.
    Mitsui K, Tokuzawa Y, Itoh H et al (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642PubMedGoogle Scholar
  82. 82.
    Silva J, Nichols J, Theunissen TW et al (2009) Nanog is the gateway to the pluripotent ground state. Cell 138:722–737PubMedGoogle Scholar
  83. 83.
    Silva J, Smith A (2008) Capturing pluripotency. Cell 132:532–536PubMedGoogle Scholar
  84. 84.
    Silva J, Chambers I, Pollard S et al (2006) Nanog promotes transfer of pluripotency after cell fusion. Nature 441:997–1001PubMedGoogle Scholar
  85. 85.
    Sato N, Meijer L, Skaltsounis L et al (2004) Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10:55–63PubMedGoogle Scholar
  86. 86.
    Cole MF, Johnstone SE, Newman JJ et al (2008) Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev 22:746–755PubMedGoogle Scholar
  87. 87.
    Willert K, Jones KA (2006) Wnt signaling: Is the party in the nucleus? Genes Dev 20:1394–1404PubMedGoogle Scholar
  88. 88.
    Lluis F, Pedone E, Pepe S et al (2008) Periodic activation of Wnt/beta-catenin signaling enhances somatic cell reprogramming mediated by cell fusion. Cell Stem Cell 3:493–507PubMedGoogle Scholar
  89. 89.
    He TC, Sparks AB, Rago C et al (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512PubMedGoogle Scholar
  90. 90.
    Tam WL, Lim CY, Han J et al (2008) T-cell factor 3 regulates embryonic stem cell pluripotency and self-renewal by the transcriptional control of multiple lineage pathways. Stem Cells 26:2019–2031PubMedGoogle Scholar
  91. 91.
    Yi F, Pereira L, Merrill BJ (2008) Tcf3 functions as a steady-state limiter of transcriptional programs of mouse embryonic stem cell self-renewal. Stem Cells 26:1951–1960PubMedGoogle Scholar
  92. 92.
    Lluis F, Cosma MP (2009) Somatic cell reprogramming control: signaling pathway modulation versus transcription factor activities. Cell Cycle 8:1138–1144PubMedGoogle Scholar
  93. 93.
    Nakamura T, Inoue K, Ogawa S et al (2008) Effects of Akt signaling on nuclear reprogramming. Genes Cells 13:1269–1277Google Scholar
  94. 94.
    Watanabe S, Umehara H, Murayama K et al (2006) Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells. Oncogene 25:2697–2707PubMedGoogle Scholar
  95. 95.
    Frei E, Schuh R, Baumgartner S et al (1988) Molecular characterization of spalt, a homeotic gene required for head and tail development in the Drosophila embryo. EMBO J 7:197–204PubMedGoogle Scholar
  96. 96.
    Elling U, Klasen C, Eisenberger T et al (2006) Murine inner cell mass-derived lineages depend on Sall4 function. Proc Natl Acad Sci USA 103:16319–16324PubMedGoogle Scholar
  97. 97.
    Zhang J, Tam WL, Tong GQ et al (2006) Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 8:1114–1123PubMedGoogle Scholar
  98. 98.
    Wong CC, Gaspar-Maia A, Ramalho-Santos M et al (2008) High-efficiency stem cell fusion-mediated assay reveals Sall4 as an enhancer of reprogramming. PLoS ONE 3:e1955PubMedGoogle Scholar
  99. 99.
    Meissner A, Mikkelsen TS, Gu H et al (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454:766–770PubMedGoogle Scholar
  100. 100.
    Ooi SK, Bestor TH (2008) The colorful history of active DNA demethylation. Cell 133:1145–1148PubMedGoogle Scholar
  101. 101.
    Morgan HD, Dean W, Coker HA et al (2004) Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J Biol Chem 279:52353–52360PubMedGoogle Scholar
  102. 102.
    Rai K, Huggins IJ, James SR et al (2008) DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 135:1201–1212PubMedGoogle Scholar
  103. 103.
    Gehring M, Reik W, Henikoff S (2009) DNA demethylation by DNA repair. Trends Genet 25:82–90PubMedGoogle Scholar
  104. 104.
    Ringrose L, Paro R (2004) Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 38:413–443PubMedGoogle Scholar
  105. 105.
    Chamberlain SJ, Yee D, Magnuson T (2008) Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. Stem Cells 26:1496–1505PubMedGoogle Scholar
  106. 106.
    Faust C, Schumacher A, Holdener B et al (1995) The eed mutation disrupts anterior mesoderm production in mice. Development 121:273–285PubMedGoogle Scholar
  107. 107.
    O’Carroll D, Erhardt S, Pagani M et al (2001) The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 21:4330–4336PubMedGoogle Scholar
  108. 108.
    Pasini D, Bracken AP, Hansen JB et al (2007) The polycomb group protein Suz12 is required for embryonic stem cell differentiation. Mol Cell Biol 27:3769–3779PubMedGoogle Scholar
  109. 109.
    Boyer LA, Lee TI, Cole MF et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956PubMedGoogle Scholar
  110. 110.
    Lee TI, Jenner RG, Boyer LA et al (2006) Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125:301–313PubMedGoogle Scholar
  111. 111.
    Yang J, Chai L, Fowles TC et al (2008) Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells. Proc Natl Acad Sci USA 105:19756–19761PubMedGoogle Scholar
  112. 112.
    Azuara V, Perry P, Sauer S et al (2006) Chromatin signatures of pluripotent cell lines. Nat Cell Biol 8:532–538PubMedGoogle Scholar
  113. 113.
    Bernstein BE, Mikkelsen TS, Xie X et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326PubMedGoogle Scholar
  114. 114.
    Bernstein E, Duncan EM, Masui O et al (2006) Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol Cell Biol 26:2560–2569PubMedGoogle Scholar
  115. 115.
    Boyer LA, Plath K, Zeitlinger J et al (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441:349–353PubMedGoogle Scholar
  116. 116.
    Pereira CF, Piccolo FM, Tsubouchi T et al (2010) ESCs Require PRC2 to Direct the Successful Reprogramming of Differentiated Cells toward Pluripotency. Cell Stem Cell 6:547–556PubMedGoogle Scholar
  117. 117.
    Ma DK, Chiang CH, Ponnusamy K et al (2008) G9a and Jhdm2a regulate embryonic stem cell fusion-induced reprogramming of adult neural stem cells. Stem Cells 26:2131–2141PubMedGoogle Scholar
  118. 118.
    Wright WE (1984) Control of differentiation in heterokaryons and hybrids involving differentiation-defective myoblast variants. J Cell Biol 98:436–443PubMedGoogle Scholar
  119. 119.
    Darlington GJ, Bernard HP, Ruddle FH (1974) Human serum albumin phenotype activation in mouse hepatoma–human leukocyte cell hybrids. Science 185:859–862PubMedGoogle Scholar
  120. 120.
    Aurade F, Pinset C, Chafey P et al (1994) Myf5, MyoD, myogenin and MRF4 myogenic derivatives of the embryonic mesenchymal cell line C3H10T1/2 exhibit the same adult muscle phenotype. Differentiation 55:185–192PubMedGoogle Scholar
  121. 121.
    Choi J, Costa ML, Mermelstein CS et al (1990) MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes. Proc Natl Acad Sci USA 87:7988–7992PubMedGoogle Scholar
  122. 122.
    Davis C, Kannan MS (1987) Sympathetic innervation of human tracheal and bronchial smooth muscle. Respir Physiol 68:53–61PubMedGoogle Scholar
  123. 123.
    Weintraub H, Tapscott SJ, Davis RL et al (1989) Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proc Natl Acad Sci USA 86:5434–5438PubMedGoogle Scholar
  124. 124.
    Lluis F, Perdiguero E, Nebreda AR et al (2006) Regulation of skeletal muscle gene expression by p38 MAP kinases. Trends Cell Biol 16:36–44PubMedGoogle Scholar
  125. 125.
    Xie H, Ye M, Feng R et al (2004) Stepwise reprogramming of B cells into macrophages. Cell 117:663–676PubMedGoogle Scholar
  126. 126.
    Bussmann LH, Schubert A, Vu Manh TP et al (2009) A robust and highly efficient immune cell reprogramming system. Cell Stem Cell 5:554–566PubMedGoogle Scholar
  127. 127.
    Vierbuchen T, Ostermeier A, Pang ZP et al (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463:1035–1041PubMedGoogle Scholar
  128. 128.
    Tapscott SJ, Davis RL, Thayer MJ et al (1988) MyoD1:a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science 242:405–411PubMedGoogle Scholar
  129. 129.
    Pomerantz JH, Mukherjee S, Palermo AT et al (2009) Reprogramming to a muscle fate by fusion recapitulates differentiation. J Cell Sci 122:1045–1053PubMedGoogle Scholar
  130. 130.
    Blau HM (1989) How fixed is the differentiated state? Lessons from heterokaryons. Trends Genet 5:268–272PubMedGoogle Scholar
  131. 131.
    Deisseroth A, Hendrick D (1979) Activation of phenotypic expression of human globin genes from nonerythroid cells by chromosome-dependent transfer to tetraploid mouse erythroleukemia cells. Proc Natl Acad Sci USA 76:2185–2189PubMedGoogle Scholar
  132. 132.
    Willing MC, Nienhuis AW, Anderson WF (1979) Selective activation of human beta-but not gamma-globin gene in human fibroblast x mouse erythroleukaemia cell hybrids. Nature 277:534–538PubMedGoogle Scholar
  133. 133.
    Papayannopoulou T, Enver T, Takegawa S et al (1988) Activation of developmentally mutated human globin genes by cell fusion. Science 242:1056–1058PubMedGoogle Scholar
  134. 134.
    Dupuy-Coin AM, Ege T, Bouteille M et al (1976) Ultrastructure of chick erythrocyte nuclei undergoing reactivation in heterokaryons and enucleated cells. Exp Cell Res 101:355–369PubMedGoogle Scholar
  135. 135.
    Chiu CP, Blau HM (1984) Reprogramming cell differentiation in the absence of DNA synthesis. Cell 37:879–887PubMedGoogle Scholar
  136. 136.
    Chiu CP, Blau HM (1985) 5-Azacytidine permits gene activation in a previously noninducible cell type. Cell 40:417–424PubMedGoogle Scholar
  137. 137.
    Palermo A, Doyonnas R, Bhutani N et al (2009) Nuclear reprogramming in heterokaryons is rapid, extensive, and bidirectional. Faseb J 23:1431–1440PubMedGoogle Scholar
  138. 138.
    Lanfranchi G, Linder S, Ringertz NR (1984) Globin synthesis in heterokaryons formed between chick erythrocytes and human K562 cells or rat L6 myoblasts. J Cell Sci 66:309–319PubMedGoogle Scholar
  139. 139.
    Brown DD (1984) The role of stable complexes that repress and activate eucaryotic genes. Cell 37:359–365PubMedGoogle Scholar
  140. 140.
    Smale ST, Fisher AG (2002) Chromatin structure and gene regulation in the immune system. Annu Rev Immunol 20:427–462PubMedGoogle Scholar
  141. 141.
    Orlando V (2003) Polycomb, epigenomes, and control of cell identity. Cell 112:599–606PubMedGoogle Scholar
  142. 142.
    Terranova R, Pereira CF, Du Roure C et al (2006) Acquisition and extinction of gene expression programs are separable events in heterokaryon reprogramming. J Cell Sci 119:2065–2072PubMedGoogle Scholar
  143. 143.
    Ferrari G, Cusella-De Angelis G, Coletta M et al (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279:1528–1530PubMedGoogle Scholar
  144. 144.
    Petersen BE, Bowen WC, Patrene KD et al (1999) Bone marrow as a potential source of hepatic oval cells. Science 284:1168–1170PubMedGoogle Scholar
  145. 145.
    Mezey E, Chandross KJ, Harta G et al (2000) Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290:1779–1782PubMedGoogle Scholar
  146. 146.
    Krause DS, Theise ND, Collector MI et al (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105:369–377PubMedGoogle Scholar
  147. 147.
    LaBarge MA, Blau HM (2002) Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111:589–601PubMedGoogle Scholar
  148. 148.
    Terada N, Hamazaki T, Oka M et al (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545PubMedGoogle Scholar
  149. 149.
    Weimann JM, Charlton CA, Brazelton TR et al (2003) Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci USA 100:2088–2093PubMedGoogle Scholar
  150. 150.
    Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM et al (2003) Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968–973PubMedGoogle Scholar
  151. 151.
    Eglitis MA, Mezey E (1997) Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 94:4080–4085PubMedGoogle Scholar
  152. 152.
    Weimann JM, Johansson CB, Trejo A et al (2003) Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol 5:959–966PubMedGoogle Scholar
  153. 153.
    Johansson CB, Youssef S, Koleckar K et al (2008) Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat Cell Biol 10:575–583PubMedGoogle Scholar
  154. 154.
    Vassilopoulos G, Wang PR, Russell DW (2003) Transplanted bone marrow regenerates liver by cell fusion. Nature 422:901–904PubMedGoogle Scholar
  155. 155.
    Herzog EL, Van Arnam J, Hu B et al (2007) Lung-specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation. FASEB J 21:2592–2601PubMedGoogle Scholar
  156. 156.
    Gibson AJ, Karasinski J, Relvas J et al (1995) Dermal fibroblasts convert to a myogenic lineage in mdx mouse muscle. J Cell Sci 108 (Pt 1):207–214PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Daniela Sanges*
    • 1
  • Frederic Lluis*
    • 1
  • Maria Pia Cosma
    • 2
    • 1
  1. 1.Center for Genomic Regulation (CRG)BarcelonaSpain
  2. 2.Institució Catalana de Recerca i Estudis Avançats (ICREA)BarcelonaSpain

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