Evans, M. J. & Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).
Martin, G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78, 7634–7638 (1981).
Hadorn, E. Constancy, variation and type of determination and differentiation in cells from male genitalia rudiments of Drosophila melanogaster in permanent culture in vivo [in German with English abstract]. Dev. Biol. 13, 424–509 (1966).
Gehring, W. Clonal analysis of determination dynamics in cultures of imaginal disks in Drosophila melanogaster. Dev. Biol. 16, 438–456 (1967).
Le Lievre, C. S. & Le Douarin, N. M. Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos. J. Embryol. Exp. Morphol. 34, 125–154 (1975).
Briggs, R. & King, T. J. Transplantation of living nuclei from blastula cells into enucleated frogs' eggs. Proc. Natl Acad. Sci. USA 38, 455–463 (1952).
Gurdon, J. B. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10, 622–640 (1962).
Gurdon, J. B. Adult frogs derived from the nuclei of single somatic cells. Dev. Biol. 4, 256–273 (1962).
In this study, using nuclear transfer, differentiated intestinal cells in amphibians were shown to retain all of the genetic information to produce an entire frog.
Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J. & Campbell, K. H. Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813 (1997).
In this study, the first cloned mammal, Dolly the Sheep, was generated using nuclear transfer.
Wakayama, T., Perry, A. C., Zuccotti, M., Johnson, K. R. & Yanagimachi, R. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 394, 369–374 (1998).
In this study, the first cloned mice, the most widely used experimental animal, were generated using nuclear transfer.
Hochedlinger, K. & Jaenisch, R. Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature 415, 1035–1038 (2002).
Eggan, K. et al. Mice cloned from olfactory sensory neurons. Nature 428, 44–49 (2004).
Egli, D., Rosains, J., Birkhoff, G. & Eggan, K. Developmental reprogramming after chromosome transfer into mitotic mouse zygotes. Nature 447, 679–685 (2007).
Thuan, N. V., Kishigami, S. & Wakayama, T. How to improve the success rate of mouse cloning technology. J. Reprod. Dev. 56, 20–30 (2010).
Wakayama, S. et al. Production of healthy cloned mice from bodies frozen at −20 degrees C for 16 years. Proc. Natl Acad. Sci. USA 105, 17318–17322 (2008).
Yang, X. et al. Nuclear reprogramming of cloned embryos and its implications for therapeutic cloning. Nature Genet. 39, 295–302 (2007).
Byrne, J. A. et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature 450, 497–502 (2007).
Simonsson, S. & Gurdon, J. DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nature Cell Biol. 6, 984–990 (2004).
Kucharski, R., Maleszka, J., Foret, S. & Maleszka, R. Nutritional control of reproductive status in honeybees via DNA methylation. Science 319, 1827–1830 (2008).
Blau, H. M., Chiu, C. P. & Webster, C. Cytoplasmic activation of human nuclear genes in stable heterocaryons. Cell 32, 1171–1180 (1983).
This paper shows that differentiated mammalian cells are plastic: their differentiated state can be reversed by fusing them to another cell to form a stable, non-dividing heterokaryon.
Blau, H. M. et al. Plasticity of the differentiated state. Science 230, 758–766 (1985).
Blau, H. M. & Baltimore, D. Differentiation requires continuous regulation. J. Cell Biol. 112, 781–783 (1991).
Davidson, R. L., Ephrussi, B. & Yamamoto, K. Regulation of pigment synthesis in mammalian cells, as studied by somatic hybridization. Proc. Natl Acad. Sci. USA 56, 1437–1440 (1966).
Weiss, M. C. & Chaplain, M. Expression of differentiated functions in hepatoma cell hybrids: reappearance of tyrosine aminotransferase inducibility after the loss of chromosomes. Proc. Natl Acad. Sci. USA 68, 3026–3030 (1971).
Ringertz, N. R. & Savage, R. E. Cell Hybrids (Academic, 1977).
Harris, H., Miller, O. J., Klein, G., Worst, P. & Tachibana, T. Suppression of malignancy by cell fusion. Nature 223, 363–368 (1969).
Peterson, J. A. & Weiss, M. C. Expression of differentiated functions in hepatoma cell hybrids: induction of mouse albumin production in rat hepatoma–mouse fibroblast hybrids. Proc. Natl Acad. Sci. USA 69, 571–575 (1972).
Davidson, R. L. Regulation of melanin synthesis in mammalian cells: effect of gene dosage on the expression of differentiation. Proc. Natl Acad. Sci. USA 69, 951–955 (1972).
Harris, H., Watkins, J. F., Ford, C. E. & Schoefl, G. I. Artificial heterokaryons of animal cells from different species. J. Cell Sci. 1, 1–30 (1966).
Pavlath, G. K. & Blau, H. M. Expression of muscle genes in heterokaryons depends on gene dosage. J. Cell Biol. 102, 124–130 (1986).
Chiu, C. P. & Blau, H. M. Reprogramming cell differentiation in the absence of DNA synthesis. Cell 37, 879–887 (1984).
Miller, S. C., Pavlath, G. K., Blakely, B. T. & Blau, H. M. Muscle cell components dictate hepatocyte gene expression and the distribution of the Golgi apparatus in heterokaryons. Genes Dev. 2, 330–340 (1988).
Chiu, C. P. & Blau, H. M. 5-Azacytidine permits gene activation in a previously noninducible cell type. Cell 40, 417–424 (1985).
Wright, W. E. Induction of muscle genes in neural cells. J. Cell Biol. 98, 427–435 (1984).
Baron, M. H. & Maniatis, T. Rapid reprogramming of globin gene expression in transient heterokaryons. Cell 46, 591–602 (1986).
Spear, B. T. & Tilghman, S. M. Role of α-fetoprotein regulatory elements in transcriptional activation in transient heterokaryons. Mol. Cell Biol. 10, 5047–5054 (1990).
Johansson, C. B. et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nature Cell Biol. 10, 575–583 (2008).
Weimann, J. M., Charlton, C. A., Brazelton, T. R., Hackman, R. C. & Blau, H. M. Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc. Natl Acad. Sci. USA 100, 2088–2093 (2003).
Tada, M., Tada, T., Lefebvre, L., Barton, S. C. & Surani, M. A. Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. EMBO J. 16, 6510–6520 (1997).
This report shows that fusing embryonic germ cells with somatic cells results in the reprogramming of epigenetic marks on imprinted genes in the somatic cell.
Tada, M., Takahama, Y., Abe, K., Nakatsuji, N. & Tada, T. Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr. Biol. 11, 1553–1558 (2001).
Kimura, H., Tada, M., Nakatsuji, N. & Tada, T. Histone code modifications on pluripotential nuclei of reprogrammed somatic cells. Mol. Cell. Biol. 24, 5710–5720 (2004).
Cowan, C. A., Atienza, J., Melton, D. A. & Eggan, K. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309, 1369–1373 (2005).
Silva, J., Chambers, I., Pollard, S. & Smith, A. Nanog promotes transfer of pluripotency after cell fusion. Nature 441, 997–1001 (2006).
Pereira, C. F. et al. Heterokaryon-based reprogramming of human B lymphocytes for pluripotency requires Oct4 but not Sox2. PLoS Genet. 4, e1000170 (2008).
Bhutani, N. et al. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463, 1042–1047 (2010).
This report shows that the enzyme AID is essential for the demethylation of DNA and for the induction of pluripotency by forming heterokaryons.
Agarwal, S. & Daley, G. Q. AID for reprogramming. Cell Res. 20, 253–255 (2010).
Schneuwly, S., Klemenz, R. & Gehring, W. J. Redesigning the body plan of Drosophila by ectopic expression of the homoeotic gene Antennapedia. Nature 325, 816–818 (1987).
Gehring, W. J. The master control gene for morphogenesis and evolution of the eye. Genes Cells 1, 11–15 (1996).
Davis, R. L., Weintraub, H. & Lassar, A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987–1000 (1987).
Taylor, S. M. & Jones, P. A. Multiple new phenotypes induced in 10T1/2 and 3T3 cells treated with 5-azacytidine. Cell 17, 771–779 (1979).
Xie, H., Ye, M., Feng, R. & Graf, T. Stepwise reprogramming of B cells into macrophages. Cell 117, 663–676 (2004).
Cobaleda, C., Jochum, W. & Busslinger, M. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 449, 473–477 (2007).
Graf, T. & Enver, T. Forcing cells to change lineages. Nature 462, 587–594 (2009).
Farah, M. H. et al. Generation of neurons by transient expression of neural bHLH proteins in mammalian cells. Development 127, 693–702 (2000).
Schafer, B. W., Blakely, B. T., Darlington, G. J. & Blau, H. M. Effect of cell history on response to helix–loop–helix family of myogenic regulators. Nature 344, 454–458 (1990).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
This report shows that the introduction of four transcription factors into somatic mouse cells is sufficient to make these cells (now known as iPS cells) pluripotent.
Yamanaka, S. Strategies and new developments in the generation of patient-specific 57 stem cells. Cell Stem Cell 1, 39–49 (2007).
Tokuzawa, Y. et al. Fbx15 is a novel target of Oct3/4 but is dispensable for embryonic stem cell self-renewal and mouse development. Mol. Cell. Biol. 23, 2699–2708 (2003).
Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).
Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).
Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnol. 26, 101–106 (2008).
Wernig, M., Meissner, A., Cassady, J. P. & Jaenisch, R. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2, 10–12 (2008).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
This report shows that human somatic cells can be made pluripotent (converted to iPS cells) solely by introducing four transcription factors.
Park, I. H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008).
Aasen, T. et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nature Biotechnol. 26, 1276–1284 (2008).
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
Yamanaka, S. A fresh look at iPS cells. Cell 137, 13–17 (2009).
Yoshida, Y., Takahashi, K., Okita, K., Ichisaka, T. & Yamanaka, S. Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 5, 237–241 (2009).
Esteban, M. A. et al. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6, 71–79 (2010).
Li, H. et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460, 1136–1139 (2009).
Marion, R. M. et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460, 1149–1153 (2009).
Utikal, J. et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460, 1145–1148 (2009).
Kawamura, T. et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460, 1140–1144 (2009).
Hong, H. et al. Suppression of induced pluripotent stem cell generation by the p53–p21 pathway. Nature 460, 1132–1135 (2009).
Judson, R. L., Babiarz, J. E., Venere, M. & Blelloch, R. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nature Biotechnol. 27, 459–461 (2009).
Eminli, S. et al. Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nature Genet. 41, 968–976 (2009).
Wernig, M. et al. A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types. Nature Biotechnol. 26, 916–924 (2008).
Woltjen, K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766–770 (2009).
Hanna, J. et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462, 595–601 (2009).
Yamanaka, S. Elite and stochastic models for induced pluripotent stem cell generation. Nature 460, 49–52 (2009).
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).
Vierbuchen, T. et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010).
Palermo, A. et al. Nuclear reprogramming in heterokaryons is rapid, extensive, and bidirectional. FASEB J. 23, 1431–1440 (2009).
Zhang, F., Pomerantz, J. H., Sen, G., Palermo, A. T. & Blau, H. M. Active tissue-specific DNA demethylation conferred by somatic cell nuclei in stable heterokaryons. Proc. Natl Acad. Sci. USA 104, 4395–4400 (2007).
Pomerantz, J. H., Mukherjee, S., Palermo, A. T. & Blau, H. M. Reprogramming to a muscle fate by fusion recapitulates differentiation. J. Cell Sci. 122, 1045–1053 (2009).
Terranova, R., Pereira, C. F., Du Roure, C., Merkenschlager, M. & Fisher, A. G. Acquisition and extinction of gene expression programs are separable events in heterokaryon reprogramming. J. Cell Sci. 119, 2065–2072 (2006).
Jacob, F. & Monod, J. Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3, 318–356 (1961).
Ptashne, M. A Genetic Switch: Gene Control and Phage Lambda (Blackwell Science, 1986).
Blau, H. M. Differentiation requires continuous active control. Annu. Rev.Biochem. 61, 1213–1230 (1992).
Rideout, W. M., Eggan, K. & Jaenisch, R. Nuclear cloning and epigenetic reprogramming of the genome. Science 293, 1093–1098 (2001).
Wakayama, T. et al. Cloning of mice to six generations. Nature 407, 318–319 (2000).
Marion, R. M. et al. Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 4, 141–154 (2009).
Eggan, K. et al. X-chromosome inactivation in cloned mouse embryos. Science 290, 1578–1581 (2000).
Nolen, L. D. et al. X chromosome reactivation and regulation in cloned embryos. Dev. Biol. 279, 525–540 (2005).
Maherali, N. et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55–70 (2007).
Dimos, J. T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221 (2008).
Park, I. H. et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008).
Daley, G. Q. Stem cells: roadmap to the clinic. J. Clin. Invest. 120, 8–10 (2010).