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Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration

Nature Reviews Molecular Cell Biology volume 12, pages 79–89 (2011)Cite this article

Subjects

Key Points

  • The ultimate goal of regenerative medicine is to replace lost or damaged cells. This can potentially be accomplished using the processes of dedifferentiation, transdifferentiation or reprogramming.

  • During dedifferentiation, a terminally differentiated cell reverts back to a less-differentiated stage from within its own lineage, which allows it to proliferate. Many regenerative processes have been associated with dedifferentiation.

  • Transdifferentiation sees cells regress to a point when they can switch lineages or can also occur directly between two different cell types.

  • Reprogramming aims to induce differentiated cells into reverting to pluripotency. From here, they can differentiate into almost any cell type.

  • During dedifferentiation and transdifferentiation, well-defined intermediate cell types have been identified. The process of reprogramming seems to be largely stochastic.

  • Dedifferentiation and transdifferentiation can be successfully achieved in vivo, and reprogramming facilitates genetic manipulation such as correcting disease-inducing mutations.

Abstract

The ultimate goal of regenerative medicine is to replace lost or damaged cells. This can potentially be accomplished using the processes of dedifferentiation, transdifferentiation or reprogramming. Recent advances have shown that the addition of a group of genes can not only restore pluripotency in a fully differentiated cell state (reprogramming) but can also induce the cell to proliferate (dedifferentiation) or even switch to another cell type (transdifferentiation). Current research aims to understand how these processes work and to eventually harness them for use in regenerative medicine.

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Figure 1: Overview of reprogramming, transdifferentiation and dedifferentiation.
Figure 2: Natural dedifferentiation during zebrafish heart regeneration.
Figure 3: Natural and artificial transdifferentiation.
Figure 4: The induction of pluripotency.

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References

  1. Brockes, J. P. & Kumar, A. Plasticity and reprogramming of differentiated cells in amphibian regeneration. Nature Rev. Mol. Cell Biol. 3, 566–574 (2002).

    CAS  Google Scholar 

  2. Wolff, G. Entwicklungsphysiologische Studien. I. Die Regeneration der. Urodelenlinse. Wilhelm Roux' Arch. Entwickl-Mech. Org. 1, 380–390 (1895).

    Google Scholar 

  3. de Vries, W. N. et al. Reprogramming and differentiation in mammals: motifs and mechanisms. Cold Spring Harb. Symp. Quant. Biol. 73, 33–38 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science 298, 2188–2190 (2002).

    CAS  PubMed  Google Scholar 

  5. Raya, A. et al. Activation of Notch signaling pathway precedes heart regeneration in zebrafish. Proc. Natl Acad. Sci. USA 100, 11889–11895 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Jopling, C. et al. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464, 606–609 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Kikuchi, K. et al. Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes. Nature 464, 601–605 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sleep, E. et al. Transcriptomics approach to investigate zebrafish heart regeneration. J. Cardiovasc. Med. 11, 369–380 (2010).

    Google Scholar 

  9. Lien, C. L., Schebesta, M., Makino, S., Weber, G. J. & Keating, M. T. Gene expression analysis of zebrafish heart regeneration. PLoS Biol. 4, e260 (2006).

    PubMed  PubMed Central  Google Scholar 

  10. Lepilina, A. et al. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127, 607–619 (2006).

    CAS  PubMed  Google Scholar 

  11. Ahuja, P., Sdek, P. & MacLellan, W. R. Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol. Rev. 87, 521–544 (2007).

    CAS  PubMed  Google Scholar 

  12. Poss, K. D. Advances in understanding tissue regenerative capacity and mechanisms in animals. Nature Rev. Genet. 11, 710–722 (2010).

    CAS  PubMed  Google Scholar 

  13. Burkhart, D. L. & Sage, J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nature Rev. Cancer 8, 671–682 (2008).

    CAS  Google Scholar 

  14. Tanaka, E. M., Gann, A. A., Gates, P. B. & Brockes, J. P. Newt myotubes reenter the cell cycle by phosphorylation of the retinoblastoma protein. J. Cell Biol. 136, 155–165 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Nye, H. L., Cameron, J. A., Chernoff, E. A. & Stocum, D. L. Regeneration of the urodele limb: a review. Dev. Dyn. 226, 280–294 (2003).

    PubMed  Google Scholar 

  16. Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kragl, M. et al. Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature 460, 60–65 (2009).

    CAS  PubMed  Google Scholar 

  18. Chen, Z. L., Yu, W. M. & Strickland, S. Peripheral regeneration. Annu. Rev. Neurosci. 30, 209–233 (2007).

    PubMed  Google Scholar 

  19. Mirsky, R. et al. Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation. J. Peripher. Nerv. Syst. 13, 122–135 (2008).

    PubMed  Google Scholar 

  20. Woodhoo, A. et al. Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nature Neurosci. 12, 839–847 (2009).

    CAS  PubMed  Google Scholar 

  21. Wolff, T. & Ready, D. F. The beginning of pattern formation in the Drosophila compound eye: the morphogenetic furrow and the second mitotic wave. Development 113, 841–850 (1991).

    CAS  PubMed  Google Scholar 

  22. Harvey, K. & Tapon, N. The Salvador–Warts–Hippo pathway — an emerging tumour-suppressor network. Nature Rev. Cancer 7, 182–191 (2007).

    CAS  Google Scholar 

  23. Nicolay, B. N., Bayarmagnai, B., Moon, N. S., Benevolenskaya, E. V. & Frolov, M. V. Combined inactivation of pRB and Hippo pathways induces dedifferentiation in the Drosophila retina. PLoS Genet. 6, e1000918 (2010).

    PubMed  PubMed Central  Google Scholar 

  24. Monje, P. V., Soto, J., Bacallao, K. & Wood, P. M. Schwann cell dedifferentiation is independent of mitogenic signaling and uncoupled to proliferation: role of cAMP and JNK in the maintenance of the differentiated state. J. Biol. Chem. 285, 31024–31036 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. McGann, C. J., Odelberg, S. J. & Keating, M. T. Mammalian myotube dedifferentiation induced by newt regeneration extract. Proc. Natl Acad. Sci. USA 98, 13699–13704 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Camarda, G. et al. A pRb-independent mechanism preserves the postmitotic state in terminally differentiated skeletal muscle cells. J. Cell Biol. 167, 417–423 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Sherr, C. J. et al. p53-dependent and -independent functions of the Arf tumor suppressor. Cold Spring Harb. Symp. Quant. Biol. 70, 129–137 (2005).

    CAS  PubMed  Google Scholar 

  28. Pajcini, K. V., Corbel, S. Y., Sage, J., Pomerantz, J. H. & Blau, H. M. Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle. Cell Stem Cell 7, 198–213 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bicknell, K. A., Coxon, C. H. & Brooks, G. Can the cardiomyocyte cell cycle be reprogrammed? J. Mol. Cell Cardiol. 42, 706–721 (2007).

    CAS  PubMed  Google Scholar 

  30. MacLellan, W. R. et al. Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb. Mol. Cell Biol. 25, 2486–2497 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee, J. et al. Activation of p38 MAPK induces cell cycle arrest via inhibition of Raf/ERK pathway during muscle differentiation. Biochem. Biophys. Res. Commun. 298, 765–771 (2002).

    CAS  PubMed  Google Scholar 

  32. Engel, F. B. et al. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev. 19, 1175–1187 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rumyantsev, P. P. Interrelations of the proliferation and differentiation processes during cardiact myogenesis and regeneration. Int. Rev. Cytol. 51, 186–273 (1977).

    CAS  PubMed  Google Scholar 

  34. Gassmann, M. et al. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378, 390–394 (1995).

    CAS  PubMed  Google Scholar 

  35. Lee, K. F. et al. Requirement for neuregulin receptor ErbB2 in neural and cardiac development. Nature 378, 394–398 (1995).

    CAS  PubMed  Google Scholar 

  36. Meyer, D. & Birchmeier, C. Multiple essential functions of neuregulin in development. Nature 378, 386–390 (1995).

    CAS  PubMed  Google Scholar 

  37. Bersell, K., Arab, S., Haring, B. & Kühn, B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 138, 257–270 (2009).

    CAS  PubMed  Google Scholar 

  38. Tsonis, P. A., Madhavan, M., Tancous, E. E. & Del Rio-Tsonis, K. A newt's eye view of lens regeneration. Int. J. Dev. Biol. 48, 975–980 (2004).

    PubMed  Google Scholar 

  39. Thitoff, A. R., Call, M. K., Del Rio-Tsonis, K. & Tsonis, P. A. Unique expression patterns of the retinoblastoma (Rb) gene in intact and lens regeneration-undergoing newt eyes. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 271, 185–188 (2003).

    PubMed  Google Scholar 

  40. Maki, N. et al. Expression profiles during dedifferentiation in newt lens regeneration revealed by expressed sequence tags. Mol. Vis. 16, 72–78 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Tsonis, P. A. et al. Effects of a CDK inhibitor on lens regeneration. Wound Repair Regen. 12, 24–29 (2004).

    PubMed  Google Scholar 

  42. Xie, H., Ye, M., Feng, R. & Graf, T. Stepwise reprogramming of B cells into macrophages. Cell 117, 663–676 (2004).

    CAS  PubMed  Google Scholar 

  43. McKercher, S. R. et al. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 15, 5647–5658 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Nutt, S. L., Heavey, B., Rolink, A. G. & Busslinger, M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401, 556–562 (1999).

    CAS  PubMed  Google Scholar 

  45. Offield, M. F. et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122, 983–995 (1996).

    CAS  PubMed  Google Scholar 

  46. Meivar-Levy, I. et al. Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/enhancer-binding protein β. Hepatology 46, 898–905 (2007).

    CAS  PubMed  Google Scholar 

  47. Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J. & Melton, D. A. In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature 455, 627–632 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gradwohl, G., Dierich, A., LeMeur, M. & Guillemot, F. neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc. Natl Acad. Sci. USA 97, 1607–1611 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Bernardo, A. S., Hay, C. W. & Docherty, K. Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell. Mol. Cell. Endocrinol. 294, 1–9 (2008).

    CAS  PubMed  Google Scholar 

  50. Kataoka, K. et al. MafA is a glucose-regulated and pancreatic β-cell-specific transcriptional activator for the insulin gene. J. Biol. Chem. 277, 49903–49910 (2002).

    CAS  PubMed  Google Scholar 

  51. Thorel, F. et al. Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss. Nature 464, 1149–1154 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Vierbuchen, T. et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Romm, E., Nielsen, J. A., Kim, J. G. & Hudson, L. D. Myt1 family recruits histone deacetylase to regulate neural transcription. J. Neurochem. 93, 1444–1453 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Ieda, M. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Ghosh, T. K. et al. Physical interaction between TBX5 and MEF2C is required for early heart development. Mol. Cell. Biol. 29, 2205–2218 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Garg, V. et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424, 443–447 (2003).

    CAS  PubMed  Google Scholar 

  57. Lin, Q., Schwarz, J., Bucana, C. & Olson, E. N. Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276, 1404–1407 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Cirillo, L. A. et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol. Cell 9, 279–289 (2002).

    CAS  PubMed  Google Scholar 

  59. Yamanaka, S. & Blau, H. M. Nuclear reprogramming to a pluripotent state by three approaches. Nature 465, 704–712 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    CAS  PubMed  Google Scholar 

  61. van den Berg, D. L. et al. An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell 6, 369–381 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Pardo, M. et al. An expanded Oct4 interaction network: implications for stem cell biology, development, and disease. Cell Stem Cell 6, 382–395 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391 (1998).

    CAS  PubMed  Google Scholar 

  64. Ellis, P. et al. SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. Dev. Neurosci. 26, 148–165 (2004).

    CAS  PubMed  Google Scholar 

  65. Kondoh, H. & Kamachi, Y. SOX-partner code for cell specification: regulatory target selection and underlying molecular mechanisms. Int. J. Biochem. Cell Biol. 42, 391–399 (2010).

    CAS  PubMed  Google Scholar 

  66. Masui, S. et al. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nature Cell Biol. 9, 625–635 (2007).

    CAS  PubMed  Google Scholar 

  67. Niwa, H., Miyazaki, J. & Smith, A. G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nature Genet. 24, 372–376 (2000).

    CAS  PubMed  Google Scholar 

  68. Silva, J. et al. Nanog is the gateway to the pluripotent ground state. Cell 138, 722–737 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Chambers, I. et al. Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230–1234 (2007).

    CAS  PubMed  Google Scholar 

  70. Jaenisch, R. & Young, R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132, 567–582 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Niwa, H. How is pluripotency determined and maintained? Development 134, 635–646 (2007).

    CAS  PubMed  Google Scholar 

  72. Loh, Y. H. et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nature Genet. 38, 431–440 (2006).

    CAS  PubMed  Google Scholar 

  73. Kuroda, T. et al. Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression. Mol. Cell. Biol. 25, 2475–2485 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Kashyap, V. et al. Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Dev. 18, 1093–1108 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Hochedlinger, K. & Plath, K. Epigenetic reprogramming and induced pluripotency. Development 136, 509–523 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Sridharan, R. et al. Role of the murine reprogramming factors in the induction of pluripotency. Cell 136, 364–377 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotech. 26, 101–106 (2008).

    CAS  Google Scholar 

  78. Giorgetti, A. et al. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 5, 353–357 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kim, J. B. et al. Direct reprogramming of human neural stem cells by OCT4. Nature 461, 649–643 (2009).

    CAS  PubMed  Google Scholar 

  80. Heng, J. C. et al. The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Cell Stem Cell 6, 167–174 (2010).

    CAS  PubMed  Google Scholar 

  81. Hanna, J. et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462, 595–601 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Mikkelsen, T. S. et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 454, 49–55 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Lowry, W. E. et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc. Natl Acad. Sci. USA 105, 2883–2888 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Ying, Q. L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Smith, Z. D., Nachman, I., Regev, A. & Meissner, A. Dynamic single-cell imaging of direct reprogramming reveals an early specifying event. Nature Biotech. 28, 521–526 (2010).

    CAS  Google Scholar 

  86. Stadtfeld, M., Maherali, N., Breault, D. T. & Hochedlinger, K. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell 2, 230–240 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Huangfu, D. et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nature Biotech. 26, 795–797 (2008).

    CAS  Google Scholar 

  88. Wernig, M. et al. A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types. Nature Biotech. 26, 916–924 (2008).

    CAS  Google Scholar 

  89. Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996).

    CAS  PubMed  Google Scholar 

  90. Yin, T. & Li, L. The stem cell niches in bone. J. Clin. Invest. 116, 1195–1201 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).

    CAS  PubMed  Google Scholar 

  92. Wilson, A. et al. Dormant and self-renewing hematopoietic stem cells and their niches. Ann. N. Y. Acad. Sci. 1106, 64–75 (2007).

    CAS  PubMed  Google Scholar 

  93. Kopp, H. G., Avecilla, S. T., Hooper, A. T. & Rafii, S. The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology 20, 349–356 (2005).

    CAS  PubMed  Google Scholar 

  94. Flanagan, J. G., Chan, D. C. & Leder, P. Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant. Cell 64, 1025–1035 (1991).

    CAS  PubMed  Google Scholar 

  95. Broudy, V. C. Stem cell factor and hematopoiesis. Blood 90, 1345–1364 (1997).

    CAS  PubMed  Google Scholar 

  96. Heissig, B. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625–637 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Weber, J. M. & Calvi, L. M. Notch signaling and the bone marrow hematopoietic stem cell niche. Bone 46, 281–285 (2010).

    CAS  PubMed  Google Scholar 

  98. Meshorer, E. & Misteli, T. Chromatin in pluripotent embryonic stem cells and differentiation. Nature Rev. Mol. Cell Biol. 7, 540–546 (2006).

    CAS  Google Scholar 

  99. Mallanna, S. K. & Rizzino, A. Emerging roles of microRNAs in the control of embryonic stem cells and the generation of induced pluripotent stem cells. Dev. Biol. 344, 16–25 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).

    CAS  PubMed  Google Scholar 

  101. Fouse, S. D. et al. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2, 160–169 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Francis, N. J., Kingston, R. E. & Woodcock, C. L. Chromatin compaction by a polycomb group protein complex. Science 306, 1574–1577 (2004).

    CAS  PubMed  Google Scholar 

  103. Nagy, P. L., Griesenbeck, J., Kornberg, R. D. & Cleary, M. L. A trithorax-group complex purified from Saccharomyces cerevisiae is required for methylation of histone H3. Proc. Natl Acad. Sci. USA 99, 90–94 (2002).

    CAS  PubMed  Google Scholar 

  104. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhao, X. D. et al. Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinc genomic compartments in human embryonic stem cells. Cell Stem Cell 1, 286–298 (2007).

    CAS  PubMed  Google Scholar 

  106. Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Loh, Y. H., Zhang, W., Chen, X., George, J. & Ng, H. H. Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev. 21, 2545–2557 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Kloosterman, W. P. & Plasterk, R. H. The diverse functions of microRNAs in animal development and disease. Dev. Cell 11, 441–450 (2006).

    CAS  PubMed  Google Scholar 

  109. Sinkkonen, L. et al. MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nature Struct. Mol. Biol. 15, 259–267 (2008).

    CAS  Google Scholar 

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Acknowledgements

We apologize to our colleagues whose research could not be included in this article owing to size limitations. We thank A. Faucherre and M. J. Barrero for constructive criticism of the manuscript and the members of the laboratory for discussions. Work in the laboratory of J.C.I.B. was supported by grants from MICINN, Fundacion Cellex, Sanofi-Aventis and the G. Harold and Leila Y. Mathers Charitable Foundation.

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  1. Center of Regenerative Medicine in Barcelona, Dr. Aiguader, 88, 08003, Barcelona, Spain

    Chris Jopling, Stephanie Boue & Juan Carlos Izpisua Belmonte

  2. Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Juan Carlos Izpisua Belmonte

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Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration

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Glossary

Pluripotency

The ability of a cell to give rise to all cells of the embryo. Cells of the inner cell mass and its derivative embryonic stem cells are pluripotent.

Totipotent

Pertaining to the ability of a cell to give rise to all cells of an organism, including embryonic and extra-embryonic tissues. Zygotes are totipotent.

Hyperplasia

Growth that is due to an increase in the number of cells.

Hypertrophic growth

Growth that is due to an increase in the size of cells.

Multipotent

Pertaining to the ability of a cell to give rise to different cell types of a given cell lineage. Most adult stem cells, such as gut stem cells, skin stem cells, haematopoietic stem cells and neural stem cells, are multipotent.

Schwann cell

A cell type that wraps around the axons of peripheral nerves and forms the insulating myelin sheath.

Neural crest cell

A cell type that migrates during neurulation and forms most of the peripheral nervous system (and many other structures) in the embryo.

Myotube

An elongated multinucleate cell (with three or more nuclei) that contains some peripherally located myofibrils. Myotubes are formed in vivo or in vitro by the fusion of myoblasts; they eventually develop into mature muscle fibres that have peripherally located nuclei and most of their cytoplasm filled with myofibrils.

β-cell

A cell type in the pancreas, found in the islets of Langerhans, that produces insulin.

Pancreatic exocrine cell

A pancreatic cell type that is responsible for the secretion of bicarbonate ions and digestive enzymes.

DNA methyltransferase

An enzyme that catalyses the addition of a methyl group to C or A. DNMT1 is a maintenance DNA methyltransferase, DNMT3a and DNMT3b are de novo DNA methyltransferases.

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Jopling, C., Boue, S. & Belmonte, J. Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat Rev Mol Cell Biol 12, 79–89 (2011). https://doi.org/10.1038/nrm3043

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