Reprogramming of Somatic Cells to Pluripotency

  • Masato NakagawaEmail author
  • Shinya Yamanaka
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 695)


Reprogramming of somatic cells into pluripotent stem cells has been achieved by introducing four transcription factors, Sox2, Oct3/4, Klf4 and c-Myc, in 2006. These induced pluripotent stem (iPS) cells have raised hopes for a new era of regenerative medicine because they can avoid the ethical problems and innate immune rejection associated with embryonic stem cells. However, the underlying molecular mechanism of reprogramming still remains unclear. In this chapter, we look back at the history of reprogramming research ranging from amphibian to mammalian cells and discuss our recent understanding of the molecular mechanisms of reprogramming and the possibility of utilizing reprogrammed cells for regenerative medicine.


Somatic Cell Pluripotent Stem Cell Regenerative Medicine Cell Stem Cell Nuclear Reprogram 
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.


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  1. 1.
    Gurdon JB, Uehlinger V. “Fertile” intestine nuclei. Nature 1966; 210(5042):1240–1241.CrossRefPubMedGoogle Scholar
  2. 2.
    Briggs R, King TJ. Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs. Proc Natl Acad Sci USA 1952; 38(5):455–463.CrossRefPubMedGoogle Scholar
  3. 3.
    King TJ, Briggs R. Changes in the Nuclei of Differentiating Gastrula Cells, as Demonstrated by Nuclear Transplantation. Proc Natl Acad Sci USA 1955; 41(5):321–325.CrossRefPubMedGoogle Scholar
  4. 4.
    Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol 1962; 10:622–640.PubMedGoogle Scholar
  5. 5.
    Wilmut I, Schnieke AE, McWhir J et al. Viable offspring derived from fetal and adult mammalian cells. Nature 1997; 385(6619):810–813.CrossRefPubMedGoogle Scholar
  6. 6.
    Taylor SM, Jones PA. Multiple new phenotypes induced in 10T1/2 and 3T3 cells treated with 5-azacytidine. Cell 1979; 17(4):771–779.CrossRefPubMedGoogle Scholar
  7. 7.
    Tapscott SJ. The circuitry of a master switch: Myod and the regulation of skeletal muscle gene transcription. Development 2005; 132(12):2685–2695.CrossRefPubMedGoogle Scholar
  8. 8.
    Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 1987; 51(6):987–1000.CrossRefPubMedGoogle Scholar
  9. 9.
    Graf T, Enver T. Forcing cells to change lineages. Nature 2009; 462(7273):587–594.CrossRefPubMedGoogle Scholar
  10. 10.
    Kulessa H, Frampton J, Graf T. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts and erythroblasts. Genes Dev 1995; 9(10):1250–1262.CrossRefPubMedGoogle Scholar
  11. 11.
    Xie H, Ye M, Feng R et al reprogramming of B cells into macrophages. Cell 2004; 117(5):663–676.CrossRefPubMedGoogle Scholar
  12. 12.
    Nutt SL, Heavey B, Rolink AG et al. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 1999; 401(6753):556–562.CrossRefPubMedGoogle Scholar
  13. 13.
    Feng R, Desbordes SC, Xie H et al. PU.1 and C/EBPalpha/beta convert fibroblasts into macrophage-like cells. Proc Natl Acad Sci USA 2008; 105(16):6057–6062.CrossRefPubMedGoogle Scholar
  14. 14.
    Tada M, Takahama Y, Abe K et al. Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr Biol 2001; 11(19):1553–1558.CrossRefPubMedGoogle Scholar
  15. 15.
    Bhutani N, Brady JJ, Damian M et al. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 2010; 463(7284):1042–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981; 292(5819):154–156.CrossRefPubMedGoogle Scholar
  17. 17.
    Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 1981; 78(12):7634–7638.CrossRefPubMedGoogle Scholar
  18. 18.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS et al. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282(5391):1145–1147.CrossRefPubMedGoogle Scholar
  19. 19.
    Mitsui K, Tokuzawa Y, Itoh H et al. The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells. Cell 2003; 113(5):631–642.CrossRefPubMedGoogle Scholar
  20. 20.
    Chambers I, Silva J, Colby D et al. Nanog safeguards pluripotency and mediates germline development. Nature 2007; 450(7173):1230–1234.CrossRefPubMedGoogle Scholar
  21. 21.
    Boyer LA, Lee TI, Cole MF et al. Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells. Cell 2005; 122:947–956.CrossRefPubMedGoogle Scholar
  22. 22.
    Wang J, Rao S, Chu J et al. A protein interaction network for pluripotency of embryonic stem cells. Nature 2006; 444(7117):364–368.CrossRefPubMedGoogle Scholar
  23. 23.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126(4):663–676.CrossRefPubMedGoogle Scholar
  24. 24.
    Okita K, Ichisaka T, Yamanaka S. Generation of germ-line competent induced pluripotent stem cells. Nature 2007; 448:313–317.CrossRefPubMedGoogle Scholar
  25. 25.
    Maherali N, Sridharan R, Xie W et al. Directly reprogrammed fibroblasts show global epigenetic remodelling and widespread tissue contribution. Cell Stem Cell 2007; 1(1):55–70.CrossRefPubMedGoogle Scholar
  26. 26.
    Wernig M, Meissner A, Foreman R et al. In vitro reprogramming of fibroblasts into a pluripotent ES cell-like state. Nature 2007; 448:318–324.CrossRefPubMedGoogle Scholar
  27. 27.
    Aoi T, Yae K, Nakagawa M et al. Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach Cells Science 2008; 321:699–702.CrossRefPubMedGoogle Scholar
  28. 28.
    Takahashi K, Tanabe K, Ohnuki M et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131(5):861–872.CrossRefPubMedGoogle Scholar
  29. 29.
    Yu J, Vodyanik MA, Smuga-Otto K et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318(5858):1917–1920.CrossRefPubMedGoogle Scholar
  30. 30.
    Nakagawa M, Koyanagi M, Tanabe K et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 2008; 26(1):101–106.CrossRefPubMedGoogle Scholar
  31. 31.
    Wernig M, Meissner A, Cassady JP et al. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2008; 2(1):10–12.CrossRefPubMedGoogle Scholar
  32. 32.
    Han J, Yuan P, Yang H et al. Tbx3 improves the germ-line competency of induced pluripotent stem cells. Nature 463(7284):1096–1100.Google Scholar
  33. 33.
    Okita K, Nakagawa M, Hyenjong H et al. Generation of Mouse Induced Pluripotent Stem Cells Without Viral Vectors. Science 2008; 322(5903):949–953.CrossRefPubMedGoogle Scholar
  34. 34.
    Carey BW, Markoulaki S, Hanna J et al. Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc Natl Acad Sci USA 2008.Google Scholar
  35. 35.
    Sommer CA, Stadtfeld M, Murphy GJ et al. iPS Cell Generation Using a Single Lentiviral Stem Cell Cassette. Stem Cells. 2009; 27(3):543–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Stadtfeld M, Nagaya M, Utikal J et al. Induced Pluripotent Stem Cells Generated Without Viral Integration. Science 2008; 322(5903):945–949.CrossRefPubMedGoogle Scholar
  37. 37.
    Gonzalez F, Barragan Monasterio M, Tiscornia G et al. Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector. Proc Natl Acad Sci USA 2009.Google Scholar
  38. 38.
    Hotta A, Cheung AYL, Farra N et al. Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nature Methods. 2009; advance online publication.Google Scholar
  39. 39.
    Kaji K, Norrby K, Paca A et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009.Google Scholar
  40. 40.
    Lyssiotis CA, Foreman RK, Staerk J et al. Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4. Proc Natl Acad Sci USA 2009.Google Scholar
  41. 41.
    Shao L, Feng W, Sun Y et al. Generation of iPS cells using defined factors linked via the self-cleaving 2A sequences in a single open reading frame. Cell Research. 2009; advance online publication.Google Scholar
  42. 42.
    Soldner F, Hockemeyer D, Beard C et al. Parkinson’s Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors. Cell 2009; 136:964–977.CrossRefPubMedGoogle Scholar
  43. 43.
    Sommer CA, Stadtfeld M, Murphy GJ et al. Induced pluripotent stem cell generation using a single lentiviral stem cell cassette. Stem Cells 2009; 27(3):543–549.CrossRefPubMedGoogle Scholar
  44. 44.
    Woltjen K, Michael IP, Mohseni P et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009.Google Scholar
  45. 45.
    Zhou W, Freed CR. Adenoviral Gene Delivery Can Reprogram Human Fibroblasts to Induced Pluripotent Stem Cells. Stem Cells 2009.Google Scholar
  46. 46.
    Kim D, Kim CH, Moon JI et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 2009; 4(6):472–476.CrossRefPubMedGoogle Scholar
  47. 47.
    Zhou H, Wu S, Joo JY et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 2009; 4(5):381–384.CrossRefPubMedGoogle Scholar
  48. 48.
    Jia F, Wilson KD, Sun N et al. A nonviral minicircle vector for deriving human iPS cells. Nat Methods; 7(3):197–199.Google Scholar
  49. 49.
    Chen L, Liu L. Current progress and prospects of induced pluripotent stem cells. Sci China C Life Sci 2009; 52(7):622–636.CrossRefPubMedGoogle Scholar
  50. 50.
    Zhao W, Hisamuddin IM, Nandan MO et al. Identification of Kruppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene 2004; 23(2):395–402.CrossRefPubMedGoogle Scholar
  51. 51.
    Rowland BD, Bernards R, Peeper DS. The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat Cell Biol 2005; 7(11):1074–1082.CrossRefPubMedGoogle Scholar
  52. 52.
    Cartwright P, McLean C, Sheppard A et al. LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 2005; 132(5):885–896.CrossRefPubMedGoogle Scholar
  53. 53.
    Sumi T, Tsuneyoshi N, Nakatsuji N et al. Apoptosis and differentiation of human embryonic stem cells induced by sustained activation of c-Myc. Oncogene 2007; 26(38):5564–5576.CrossRefPubMedGoogle Scholar
  54. 54.
    Zhou Q, Brown J, Kanarek A et al. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008; 455(7213):627–632.CrossRefPubMedGoogle Scholar
  55. 55.
    Vierbuchen T, Ostermeier A, Pang ZP et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010; 463(7284):1035–41CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Center for iPS Research and Application Institute for Integrated Cell-Material SciencesKyoto UniversityKyotoJapan

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