Delineating nuclear reprogramming

Abstract

Nuclear reprogramming is described as a molecular switch, triggered by the conversion of one cell type to another. Several key experiments in the past century have provided insight into the field of nuclear reprogramming. Previously deemed impossible, this research area is now brimming with new findings and developments. In this review, we aim to give a historical perspective on how the notion of nuclear reprogramming was established, describing main experiments that were performed, including (1) somatic cell nuclear transfer, (2) exposure to cell extracts and cell fusion, and (3) transcription factor induced lineage switch. Ultimately, we focus on (4) transcription factor induced pluripotency, as initiated by a landmark discovery in 2006, where the process of converting somatic cells to a pluripotent state was narrowed down to four transcription factors. The conception that somatic cells possess the capacity to revert to an immature status brings about huge clinical implications including personalized therapy, drug screening and disease modeling. Although this technology has potential to revolutionize the medical field, it is still impeded by technical and biological obstacles. This review describes the effervescent changes in this field, addresses bottlenecks hindering its advancement and in conclusion, applies the latest findings to overcome these issues.

Keywords

nuclear reprogramming / na?ve pluripotency

References

[1] Aasen, T., Raya, A., Barrero, M.J., Garreta, E., Consiglio, A., Gonzalez, F., Vassena, R., Bili?, J., Pekarik, V., Tiscornia, G., . (2008). Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 26, 1276-1284 .10.1038/nbt.1503
[2] Agarwal, S., Loh, Y.H., McLoughlin, E.M., Huang, J., Park, I.H., Miller, J.D., Huo, H., Okuka, M., Dos Reis, R.M., Loewer, S., . (2010). Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464, 292-296 .10.1038/nature08792
[3] Amps, K., Andrews, P.W., Anyfantis, G., Armstrong, L., Avery, S., Baharvand, H., Baker, J., Baker, D., Munoz, M.B., Beil, S., ., and the International Stem Cell Initiative. (2011). Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat Biotechnol 29, 1132-1144 .10.1038/nbt.2051
[4] Anokye-Danso, F., Trivedi, C.M., Juhr, D., Gupta, M., Cui, Z., Tian, Y., Zhang, Y., Yang, W., Gruber, P.J., Epstein, J.A., . (2011). Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8, 376-388 .10.1016/j.stem.2011.03.001
[5] Aoi, T., Yae, K., Nakagawa, M., Ichisaka, T., Okita, K., Takahashi, K., Chiba, T., and Yamanaka, S. (2008). Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 321, 699-702 .10.1126/science.1154884
[6] Avilion, A.A., Nicolis, S.K., Pevny, L.H., Perez, L., Vivian, N., and Lovell-Badge, R. (2003). Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17, 126-140 .10.1101/gad.224503
[7] Bao, S., Tang, F., Li, X., Hayashi, K., Gillich, A., Lao, K., and Surani, M.A. (2009). Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells. Nature 461, 1292-1295 .10.1038/nature08534
[8] Barnea, E., and Bergman, Y. (2000). Synergy of SF1 and RAR in activation of Oct-3/4 promoter. J Biol Chem 275, 6608-6619 .10.1074/jbc.275.9.6608
[9] Becker, M., Becker, A., Miyara, F., Han, Z., Kihara, M., Brown, D.T., Hager, G.L., Latham, K., Adashi, E.Y., and Misteli, T. (2005). Differential in vivo binding dynamics of somatic and oocyte-specific linker histones in oocytes and during ES cell nuclear transfer. Mol Biol Cell 16, 3887-3895 .10.1091/mbc.E05-04-0350
[10] Ben-Shushan, E., Sharir, H., Pikarsky, E., and Bergman, Y. (1995). A dynamic balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and retinoic acid receptor:retinoid X receptor heterodimers regulates Oct-3/4 expression in embryonal carcinoma cells. Mol Cell Biol 15, 1034-1048 .
[11] Blau, H.M., Chiu, C.P., and Webster, C. (1983). Cytoplasmic activation of human nuclear genes in stable heterocaryons. Cell 32, 1171-1180 .10.1016/0092-8674(83)90300-8
[12] Bouchard, C., Dittrich, O., Kiermaier, A., Dohmann, K., Menkel, A., Eilers, M., and Lüscher, B. (2001). Regulation of cyclin D2 gene expression by the Myc/Max/Mad network: Myc-dependent TRRAP recruitment and histone acetylation at the cyclin D2 promoter. Genes Dev 15, 2042-2047 .10.1101/gad.907901
[13] Boyer, L.A., Lee, T.I., Cole, M.F., Johnstone, S.E., Levine, S.S., Zucker, J.P., Guenther, M.G., Kumar, R.M., Murray, H.L., Jenner, R.G., . (2005). Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947-956 .10.1016/j.cell.2005.08.020
[14] Briggs, R., and King, T.J. (1952). Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs. Proc Natl Acad Sci U S A 38, 455-463 .10.1073/pnas.38.5.455
[15] Brimble, S.N., Zeng, X., Weiler, D.A., Luo, Y., Liu, Y., Lyons, I.G., Freed, W.J., Robins, A.J., Rao, M.S., and Schulz, T.C. (2004). Karyotypic stability, genotyping, differentiation, feeder-free maintenance, and gene expression sampling in three human embryonic stem cell lines derived prior to August 9, 2001. Stem Cells Devel 13, 585-597 .10.1089/scd.2004.13.585
[16] Brons, I.G., Smithers, L.E., Trotter, M.W., Rugg-Gunn, P., Sun, B., Chuva de Sousa Lopes, S.M., Howlett, S.K., Clarkson, A., Ahrlund-Richter, L., Pedersen, R.A., . (2007). Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448, 191-195 .10.1038/nature05950
[17] Buecker, C., Chen, H.H., Polo, J.M., Daheron, L., Bu, L., Barakat, T.S., Okwieka, P., Porter, A., Gribnau, J., Hochedlinger, K., . (2010). A murine ESC-like state facilitates transgenesis and homologous recombination in human pluripotent stem cells. Cell Stem Cell 6, 535-546 .10.1016/j.stem.2010.05.003
[18] Buzzard, J.J., Gough, N.M., Crook, J.M., and Colman, A. (2004). Karyotype of human ES cells during extended culture. Nat Biotechnol 22, 381-382 , author reply 382.10.1038/nbt0404-381
[19] Byrne, J.A., Simonsson, S., Western, P.S., and Gurdon, J.B. (2003). Nuclei of adult mammalian somatic cells are directly reprogrammed to oct-4 stem cell gene expression by amphibian oocytes. Curr Biol 13, 1206-1213 .10.1016/S0960-9822(03)00462-7
[20] Carey, B.W., Markoulaki, S., Hanna, J., Saha, K., Gao, Q., Mitalipova, M., and Jaenisch, R. (2009). Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc Natl Acad Sci U S A 106, 157-162 .10.1073/pnas.0811426106
[21] Carey, B.W., Markoulaki, S., Hanna, J.H., Faddah, D.A., Buganim, Y., Kim, J., Ganz, K., Steine, E.J., Cassady, J.P., Creyghton, M.P., . (2011). Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Cell Stem Cell 9, 588-598 .10.1016/j.stem.2011.11.003
[22] Cartwright, P., McLean, C., Sheppard, A., Rivett, D., Jones, K., and Dalton, S. (2005). LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 132, 885-896 .10.1242/dev.01670
[23] Chambers, I., Silva, J., Colby, D., Nichols, J., Nijmeijer, B., Robertson, M., Vrana, J., Jones, K., Grotewold, L., and Smith, A. (2007). Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230-1234 .10.1038/nature06403
[24] Chen, J., Liu, J., Yang, J., Chen, Y., Chen, J., Ni, S., Song, H., Zeng, L., Ding, K., and Pei, D. (2011). BMPs functionally replace Klf4 and support efficient reprogramming of mouse fibroblasts by Oct4 alone. Cell Res 21, 205-212 .10.1038/cr.2010.172
[25] Chen, X., Xu, H., Yuan, P., Fang, F., Huss, M., Vega, V.B., Wong, E., Orlov, Y.L., Zhang, W., Jiang, J., . (2008). Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, 1106-1117 .10.1016/j.cell.2008.04.043
[26] Chew, J.L., Loh, Y.H., Zhang, W., Chen, X., Tam, W.L., Yeap, L.S., Li, P., Ang, Y.S., Lim, B., Robson, P., . (2005). Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. Mol Cell Biol 25, 6031-6046 .10.1128/MCB.25.14.6031-6046.2005
[27] Chickarmane, V., Enver, T., and Peterson, C. (2009). Computational modeling of the hematopoietic erythroid-myeloid switch reveals insights into cooperativity, priming, and irreversibility. PloS Comput Biol 5, e1000268.10.1371/journal.pcbi.1000268
[28] Chiu, C.P., and Blau, H.M. (1985). 5-Azacytidine permits gene activation in a previously noninducible cell type. Cell 40, 417-424 .10.1016/0092-8674(85)90155-2
[29] Claassen, G.F., and Hann, S.R. (2000). A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta-induced cell-cycle arrest. Proc Natl Acad Sci U S A 97, 9498-9503 .10.1073/pnas.150006697
[30] Cowan, C.A., Atienza, J., Melton, D.A., and Eggan, K. (2005). Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309, 1369-1373 .10.1126/science.1116447
[31] Dejosez, M., Krumenacker, J.S., Zitur, L.J., Passeri, M., Chu, L.F., Songyang, Z., Thomson, J.A., and Zwaka, T.P. (2008). Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell 133, 1162-1174 .10.1016/j.cell.2008.05.047
[32] DiBerardino, M.A., and Hoffner, N.J. (1983). Gene reactivation in erythrocytes: nuclear transplantation in oocytes and eggs of Rana. Science 219, 862-864 .10.1126/science.6600520
[33] Dimos, J.T., Rodolfa, K.T., Niakan, K.K., Weisenthal, L.M., Mitsumoto, H., Chung, W., Croft, G.F., Saphier, G., Leibel, R., Goland, R., . (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218-1221 .10.1126/science.1158799
[34] Do, J.T., and Scholer, H.R. (2010). Cell fusion-induced reprogramming. Meth Mol Biol 636, 179-190 .10.1007/978-1-60761-691-7_11
[35] Driesch, H. (1894). Analytische theorie der organischen entwicklung (Leipzig, W. Engelmann).
[36] Ebert, A.D., Yu, J., Rose, F.F. Jr, Mattis, V.B., Lorson, C.L., Thomson, J.A., and Svendsen, C.N. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277-280 .10.1038/nature07677
[37] Eilken, H.M., Nishikawa, S., and Schroeder, T. (2009). Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 457, 896-900 .10.1038/nature07760
[38] Esteban, M.A., Wang, T., Qin, B., Yang, J., Qin, D., Cai, J., Li, W., Weng, Z., Chen, J., Ni, S., . (2010). Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6, 71-79 .10.1016/j.stem.2009.12.001
[39] Esteban, M.A., Xu, J., Yang, J., Peng, M., Qin, D., Li, W., Jiang, Z., Chen, J., Deng, K., Zhong, M., . (2009). Generation of induced pluripotent stem cell lines from Tibetan miniature pig. J Biol Chem 284, 17634-17640 .10.1074/jbc.M109.008938
[40] Evans, M.J., and Kaufman, M.H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154-156 .10.1038/292154a0
[41] Ezashi, T., Das, P., and Roberts, R.M. (2005). Low O2 tensions and the prevention of differentiation of hES cells. Proc Natl Acad Sci U S A 102, 4783-4788 .10.1073/pnas.0501283102
[42] Feng, B., Jiang, J., Kraus, P., Ng, J.H., Heng, J.C., Chan, Y.S., Yaw, L.P., Zhang, W., Loh, Y.H., Han, J., . (2009). Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Cell Biol 11, 197-203 .10.1038/ncb1827
[43] Flasza, M., Shering, A.F., Smith, K., Andrews, P.W., Talley, P., and Johnson, P.A. (2003). Reprogramming in inter-species embryonal carcinoma-somatic cell hybrids induces expression of pluripotency and differentiation markers. Cloning Stem Cells 5, 339-354 .10.1089/153623003772032844
[44] Forsyth, N.R., Musio, A., Vezzoni, P., Simpson, A.H., Noble, B.S., and McWhir, J. (2006). Physiologic oxygen enhances human embryonic stem cell clonal recovery and reduces chromosomal abnormalities. Cloning Stem Cells 8, 16-23 .10.1089/clo.2006.8.16
[45] Frank, S.R., Schroeder, M., Fernandez, P., Taubert, S., and Amati, B. (2001). Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation. Genes Dev 15, 2069-2082 .10.1101/gad.906601
[46] Freberg, C.T., Dahl, J.A., Timoskainen, S., and Collas, P. (2007). Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract. Mol Biol Cell 18, 1543-1553 .10.1091/mbc.E07-01-0029
[47] French, A.J., Adams, C.A., Anderson, L.S., Kitchen, J.R., Hughes, M.R., and Wood, S.H. (2008). Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts. Stem Cells 26, 485-493 .10.1634/stemcells.2007-0252
[48] Fusaki, N., Ban, H., Nishiyama, A., Saeki, K., and Hasegawa, M. (2009). Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci 85, 348-362 .10.2183/pjab.85.348
[49] Gao, S., Chung, Y.G., Parseghian, M.H., King, G.J., Adashi, E.Y., and Latham, K.E. (2004). Rapid H1 linker histone transitions following fertilization or somatic cell nuclear transfer: evidence for a uniform developmental program in mice. Dev Biol 266, 62-75 .10.1016/j.ydbio.2003.10.003
[50] Giorgetti, A., Montserrat, N., Aasen, T., Gonzalez, F., Rodríguez-Pizà, I., Vassena, R., Raya, A., Boué, S., Barrero, M.J., Corbella, B.A., . (2009). Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 5, 353-357 .10.1016/j.stem.2009.09.008
[51] Gore, A., Li, Z., Fung, H.L., Young, J.E., Agarwal, S., Antosiewicz-Bourget, J., Canto, I., Giorgetti, A., Israel, M.A., Kiskinis, E., . (2011). Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63-67 .10.1038/nature09805
[52] Guo, G., and Smith, A. (2010). A genome-wide screen in EpiSCs identifies Nr5a nuclear receptors as potent inducers of ground state pluripotency. Development 137, 3185-3192 .10.1242/dev.052753
[53] Guo, G., Yang, J., Nichols, J., Hall, J.S., Eyres, I., Mansfield, W., and Smith, A. (2009). Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136, 1063-1069 .10.1242/dev.030957
[54] Gurdon, J.B. (1962a). Adult frogs derived from the nuclei of single somatic cells. Dev Biol 4, 256-273 .10.1016/0012-1606(62)90043-X
[55] Gurdon, J.B. (1962b). The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol 10, 622-640 .
[56] Gurdon, J.B., Brennan, S., Fairman, S., and Mohun, T.J. (1984). Transcription of muscle-specific actin genes in early Xenopus development: nuclear transplantation and cell dissociation. Cell 38, 691-700 .10.1016/0092-8674(84)90264-2
[57] Gurdon, J.B., Elsdale, T.R., and Fischberg, M. (1958). Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei. Nature 182, 64-65 .10.1038/182064a0
[58] Gurdon, J.B., Laskey, R.A., and Reeves, O.R. (1975). The developmental capacity of nuclei transplanted from keratinized skin cells of adult frogs. J Embryol Exp Morphol 34, 93-112 .
[59] Hall, J., Guo, G., Wray, J., Eyres, I., Nichols, J., Grotewold, L., Morfopoulou, S., Humphreys, P., Mansfield, W., Walker, R., . (2009). Oct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell 5, 597-609 .10.1016/j.stem.2009.11.003
[60] Hall, V.J., Compton, D., Stojkovic, P., Nesbitt, M., Herbert, M., Murdoch, A., and Stojkovic, M. (2007). Developmental competence of human in vitro aged oocytes as host cells for nuclear transfer. Hum Reprod 22, 52-62 .10.1093/humrep/del345
[61] Han, J., Yuan, P., Yang, H., Zhang, J., Soh, B.S., Li, P., Lim, S.L., Cao, S., Tay, J., Orlov, Y.L., . (2010). Tbx3 improves the germ-line competency of induced pluripotent stem cells. Nature 463, 1096-1100 .10.1038/nature08735
[62] Hanna, J., Cheng, A.W., Saha, K., Kim, J., Lengner, C.J., Soldner, F., Cassady, J.P., Muffat, J., Carey, B.W., and Jaenisch, R. (2010). Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc Natl Acad Sci U S A 107, 9222-9227 .10.1073/pnas.1004584107
[63] Hanna, J., Markoulaki, S., Schorderet, P., Carey, B.W., Beard, C., Wernig, M., Creyghton, M.P., Steine, E.J., Cassady, J.P., Foreman, R., . (2008). Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133, 250-264 .10.1016/j.cell.2008.03.028
[64] Hanna, J., Saha, K., Pando, B., van Zon, J., Lengner, C.J., Creyghton, M.P., van Oudenaarden, A., and Jaenisch, R. (2009). Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462, 595-601 .10.1038/nature08592
[65] Hanna, J., Wernig, M., Markoulaki, S., Sun, C.W., Meissner, A., Cassady, J.P., Beard, C., Brambrink, T., Wu, L.C., Townes, T.M., . (2007). Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920-1923 .10.1126/science.1152092
[66] Hansis, C., Barreto, G., Maltry, N., and Niehrs, C. (2004). Nuclear reprogramming of human somatic cells by xenopus egg extract requires BRG1. Curr Biol 14, 1475-1480 .10.1016/j.cub.2004.08.031
[67] Harris, H. (1965). Behaviour of differentiated nuclei in heterokaryons of animal cells from different species. Nature 206, 583-588 .10.1038/206583a0
[68] Harris, H., Watkins, J.F., Ford, C.E., and Schoefl, G.I. (1966). Artificial heterokaryons of animal cells from different species. J Cell Sci 1, 1-30 .
[69] Heng, J.C., Feng, B., Han, J., Jiang, J., Kraus, P., Ng, J.H., Orlov, Y.L., Huss, M., Yang, L., Lufkin, T., . (2010). The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Cell Stem Cell 6, 167-174 .10.1016/j.stem.2009.12.009
[70] Hochedlinger, K., and Plath, K. (2009). Epigenetic reprogramming and induced pluripotency. Development 136, 509-523 .10.1242/dev.020867
[71] Hong, H., Takahashi, K., Ichisaka, T., Aoi, T., Kanagawa, O., Nakagawa, M., Okita, K., and Yamanaka, S. (2009). Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460, 1132-1135 .10.1038/nature08235
[72] Huangfu, D., Maehr, R., Guo, W., Eijkelenboom, A., Snitow, M., Chen, A.E., and Melton, D.A. (2008a). Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 26, 795-797 .10.1038/nbt1418
[73] Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., Muhlestein, W., and Melton, D.A. (2008b). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 26, 1269-1275 .10.1038/nbt.1502
[74] Hussein, S.M., Batada, N.N., Vuoristo, S., Ching, R.W., Autio, R., N?rv?, E., Ng, S., Sourour, M., H?m?l?inen, R., Olsson, C., . (2011). Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58-62 .10.1038/nature09871
[75] Ichida, J.K., Blanchard, J., Lam, K., Son, E.Y., Chung, J.E., Egli, D., Loh, K.M., Carter, A.C., Di Giorgio, F.P., Koszka, K., . (2009). A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell 5, 491-503 .10.1016/j.stem.2009.09.012
[76] Ieda, M., Fu, J.D., Delgado-Olguin, P., Vedantham, V., Hayashi, Y., Bruneau, B.G., and Srivastava, D. (2010). Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375-386 .10.1016/j.cell.2010.07.002
[77] Inoue, A., and Zhang, Y. (2011). Replication-dependent loss of 5-hydroxymethylcytosine in mouse preimplantation embryos. Science 334, 194.10.1126/science.1212483
[78] Itzhaki, I., Maizels, L., Huber, I., Zwi-Dantsis, L., Caspi, O., Winterstern, A., Feldman, O., Gepstein, A., Arbel, G., Hammerman, H., . (2011). Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225-229 .10.1038/nature09747
[79] Iwasaki, H., Mizuno, S., Arinobu, Y., Ozawa, H., Mori, Y., Shigematsu, H., Takatsu, K., Tenen, D.G., and Akashi, K. (2006). The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev 20, 3010-3021 .10.1101/gad.1493506
[80] Jang, J., Kang, H.C., Kim, H.S., Kim, J.Y., Huh, Y.J., Kim, D.S., Yoo, J.E., Lee, J.A., Lim, B., Lee, J., . (2011). Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients. Ann Neurol 70, 402-409 .10.1002/ana.22486
[81] Jiang, J., Chan, Y.S., Loh, Y.H., Cai, J., Tong, G.Q., Lim, C.A., Robson, P., Zhong, S., and Ng, H.H. (2008). A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol 10, 353-360 .10.1038/ncb1698
[82] Judson, R.L., Babiarz, J.E., Venere, M., and Blelloch, R. (2009). Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol 27, 459-461 .10.1038/nbt.1535
[83] Jullien, J., Astrand, C., Halley-Stott, R.P., Garrett, N., and Gurdon, J.B. (2010). Characterization of somatic cell nuclear reprogramming by oocytes in which a linker histone is required for pluripotency gene reactivation. Proc Natl Acad Sci U S A 107, 5483-5488 .10.1073/pnas.1000599107
[84] Kajimura, S., Seale, P., Kubota, K., Lunsford, E., Frangioni, J.V., Gygi, S.P., and Spiegelman, B.M. (2009). Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature 460, 1154-1158 .10.1038/nature08262
[85] Kawamura, T., Suzuki, J., Wang, Y.V., Menendez, S., Morera, L.B., Raya, A., Wahl, G.M., and Izpisúa Belmonte, J.C. (2009). Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460, 1140-1144 .10.1038/nature08311
[86] Kim, D., Kim, C.H., Moon, J.I., Chung, Y.G., Chang, M.Y., Han, B.S., Ko, S., Yang, E., Cha, K.Y., Lanza, R., . (2009a). Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4, 472-476 .10.1016/j.stem.2009.05.005
[87] Kim, J., Chu, J., Shen, X., Wang, J., and Orkin, S.H. (2008). An extended transcriptional network for pluripotency of embryonic stem cells. Cell 132, 1049-1061 .10.1016/j.cell.2008.02.039
[88] Kim, J.B., Greber, B., Araúzo-Bravo, M.J., Meyer, J., Park, K.I., Zaehres, H., and Sch?ler, H.R. (2009b). Direct reprogramming of human neural stem cells by OCT4. Nature 461, 649-653 .10.1038/nature08436
[89] Kim, J.B., Sebastiano, V., Wu, G., Araúzo-Bravo, M.J., Sasse, P., Gentile, L., Ko, K., Ruau, D., Ehrich, M., van den Boom, D., . (2009c). Oct4-induced pluripotency in adult neural stem cells. Cell 136, 411-419 .10.1016/j.cell.2009.01.023
[90] Kim, K., Doi, A., Wen, B., Ng, K., Zhao, R., Cahan, P., Kim, J., Aryee, M.J., Ji, H., Ehrlich, L.I., . (2010). Epigenetic memory in induced pluripotent stem cells. Nature 467, 285-290 .10.1038/nature09342
[91] King, T.J., and Briggs, R. (1955). Changes in the Nuclei of Differentiating Gastrula Cells, as Demonstrated by Nuclear Transplantation. Proc Natl Acad Sci U S A 41, 321-325 .10.1073/pnas.41.5.321
[92] Klein, G. (1983). Specific chromosomal translocations and the genesis of B-cell-derived tumors in mice and men. Cell 32, 311-315 .10.1016/0092-8674(83)90449-X
[93] Kopp, J.L., Ormsbee, B.D., Desler, M., and Rizzino, A. (2008). Small increases in the level of Sox2 trigger the differentiation of mouse embryonic stem cells. Stem Cells 26, 903-911 .10.1634/stemcells.2007-0951
[94] Kuijk, E.W., van Tol, L.T., Van de Velde, H., Wubbolts, R., Welling, M., Geijsen, N., and Roelen, B.A. (2012). The roles of FGF and MAP kinase signaling in the segregation of the epiblast and hypoblast cell lineages in bovine and human embryos. Development 139, 871-882 .10.1242/dev.071688
[95] Kulessa, H., Frampton, J., and Graf, T. (1995). GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. Genes Dev 9, 1250-1262 .10.1101/gad.9.10.1250
[96] Laiosa, C.V., Stadtfeld, M., Xie, H., de Andres-Aguayo, L., and Graf, T. (2006). Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBP alpha and PU.1 transcription factors. Immunity 25, 731-744 .10.1016/j.immuni.2006.09.011
[97] Laskey, R.A., and Gurdon, J.B. (1970). Genetic content of adult somatic cells tested by nuclear transplantation from cultured cells. Nature 228, 1332-1334 .10.1038/2281332a0
[98] Lee, G., Papapetrou, E.P., Kim, H., Chambers, S.M., Tomishima, M.J., Fasano, C.A., Ganat, Y.M., Menon, J., Shimizu, F., Viale, A., . (2009). Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461, 402-406 .10.1038/nature08320
[99] Lefort, N., Feyeux, M., Bas, C., Féraud, O., Bennaceur-Griscelli, A., Tachdjian, G., Peschanski, M., and Perrier, A.L. (2008). Human embryonic stem cells reveal recurrent genomic instability at 20q11.21. Nat Biotechnol 26, 1364-1366 .10.1038/nbt.1509
[100] Lengner, C.J., Gimelbrant, A.A., Erwin, J.A., Cheng, A.W., Guenther, M.G., Welstead, G.G., Alagappan, R., Frampton, G.M., Xu, P., Muffat, J., . (2010). Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations. Cell 141, 872-883 .10.1016/j.cell.2010.04.010
[101] Li, H., Collado, M., Villasante, A., Strati, K., Ortega, S., Ca?amero, M., Blasco, M.A., and Serrano, M. (2009a). The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460, 1136-1139 .10.1038/nature08290
[102] Li, R., Liang, J., Ni, S., Zhou, T., Qing, X., Li, H., He, W., Chen, J., Li, F., Zhuang, Q., . (2010). A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7, 51-63 .10.1016/j.stem.2010.04.014
[103] Li, W., Wei, W., Zhu, S., Zhu, J., Shi, Y., Lin, T., Hao, E., Hayek, A., Deng, H., and Ding, S. (2009b). Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 4, 16-19 .10.1016/j.stem.2008.11.014
[104] Liao, B., Bao, X., Liu, L., Feng, S., Zovoilis, A., Liu, W., Xue, Y., Cai, J., Guo, X., Qin, B., . (2011). MicroRNA cluster 302-367 enhances somatic cell reprogramming by accelerating a mesenchymal-to-epithelial transition. J Biol Chem 286, 17359-17364 .10.1074/jbc.C111.235960
[105] Liao, J., Cui, C., Chen, S., Ren, J., Chen, J., Gao, Y., Li, H., Jia, N., Cheng, L., Xiao, H., . (2009). Generation of induced pluripotent stem cell lines from adult rat cells. Cell Stem Cell 4, 11-15 .10.1016/j.stem.2008.11.013
[106] Lister, R., Pelizzola, M., Kida, Y.S., Hawkins, R.D., Nery, J.R., Hon, G., Antosiewicz-Bourget, J., O’Malley, R., Castanon, R., Klugman, S., . (2011). Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68-73 .10.1038/nature09798
[107] Liu, H., Ye, Z., Kim, Y., Sharkis, S., and Jang, Y.Y. (2010). Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes. Hepatology 51, 1810-1819 .10.1002/hep.23626
[108] Liu, H., Zhu, F., Yong, J., Zhang, P., Hou, P., Li, H., Jiang, W., Cai, J., Liu, M., Cui, K., . (2008). Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell 3, 587-590 .10.1016/j.stem.2008.10.014
[109] Loewer, S., Cabili, M.N., Guttman, M., Loh, Y.H., Thomas, K., Park, I.H., Garber, M., Curran, M., Onder, T., Agarwal, S., . (2010). Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet 42, 1113-1117 .10.1038/ng.710
[110] Loh, Y.H., Agarwal, S., Park, I.H., Urbach, A., Huo, H., Heffner, G.C., Kim, K., Miller, J.D., Ng, K., and Daley, G.Q. (2009). Generation of induced pluripotent stem cells from human blood. Blood 113, 5476-5479 .10.1182/blood-2009-02-204800
[111] Loh, Y.H., Wu, Q., Chew, J.L., Vega, V.B., Zhang, W., Chen, X., Bourque, G., George, J., Leong, B., Liu, J., . (2006). The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38, 431-440 .10.1038/ng1760
[112] Maekawa, M., Yamaguchi, K., Nakamura, T., Shibukawa, R., Kodanaka, I., Ichisaka, T., Kawamura, Y., Mochizuki, H., Goshima, N., and Yamanaka, S. (2011). Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1. Nature 474, 225-229 .10.1038/nature10106
[113] Maherali, N., Sridharan, R., Xie, W., Utikal, J., Eminli, S., Arnold, K., Stadtfeld, M., Yachechko, R., Tchieu, J., Jaenisch, R., . (2007). Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55-70 .10.1016/j.stem.2007.05.014
[114] Maki, N., Suetsugu-Maki, R., Sano, S., Nakamura, K., Nishimura, O., Tarui, H., Del Rio-Tsonis, K., Ohsumi, K., Agata, K., and Tsonis, P.A. (2010). Oocyte-type linker histone B4 is required for transdifferentiation of somatic cells in vivo. FASEB J 24, 3462-3467 .10.1096/fj.10-159285
[115] Marión, R.M., Strati, K., Li, H., Murga, M., Blanco, R., Ortega, S., Fernandez-Capetillo, O., Serrano, M., and Blasco, M.A. (2009). A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460, 1149-1153 .10.1038/nature08287
[116] Masui, S., Nakatake, Y., Toyooka, Y., Shimosato, D., Yagi, R., Takahashi, K., Okochi, H., Okuda, A., Matoba, R., Sharov, A.A., . (2007). Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 9, 625-635 .10.1038/ncb1589
[117] Mayshar, Y., Ben-David, U., Lavon, N., Biancotti, J.C., Yakir, B., Clark, A.T., Plath, K., Lowry, W.E., and Benvenisty, N. (2010). Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7, 521-531 .10.1016/j.stem.2010.07.017
[118] McGrath, J., and Solter, D. (1983). Nuclear transplantation in the mouse embryo by microsurgery and cell fusion. Science 1300-1302 .10.1126/science.6857250
[119] Mikkelsen, T.S., Hanna, J., Zhang, X., Ku, M., Wernig, M., Schorderet, P., Bernstein, B.E., Jaenisch, R., Lander, E.S., and Meissner, A. (2008). Dissecting direct reprogramming through integrative genomic analysis. Nature 454, 49-55 .10.1038/nature07056
[120] Miyoshi, N., Ishii, H., Nagano, H., Haraguchi, N., Dewi, D.L., Kano, Y., Nishikawa, S., Tanemura, M., Mimori, K., Tanaka, F., . (2011). Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 8, 633-638 .10.1016/j.stem.2011.05.001
[121] Moretti, A., Bellin, M., Welling, A., Jung, C.B., Lam, J.T., Bott-Flügel, L., Dorn, T., Goedel, A., H?hnke, C., Hofmann, F., . (2010). Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med 363, 1397-1409 .10.1056/NEJMoa0908679
[122] Nagamatsu, G., Kosaka, T., Kawasumi, M., Kinoshita, T., Takubo, K., Akiyama, H., Sudo, T., Kobayashi, T., Oya, M., and Suda, T. (2011). A germ cell-specific gene, Prmt5, works in somatic cell reprogramming. J Biol Chem 286, 10641-10648 .10.1074/jbc.M110.216390
[123] Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., and Yamanaka, S. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26, 101-106 .10.1038/nbt1374
[124] Nichols, J., Silva, J., Roode, M., and Smith, A. (2009). Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 136, 3215-3222 .10.1242/dev.038893
[125] Nichols, J., Zevnik, B., Anastassiadis, K., Niwa, H., Klewe-Nebenius, D., Chambers, I., Sch?ler, H., and Smith, A. (1998). Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379-391 .10.1016/S0092-8674(00)81769-9
[126] Niwa, H., Miyazaki, J., and Smith, A.G. (2000). Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24, 372-376 .10.1038/74199
[127] Noggle, S., Fung, H.L., Gore, A., Martinez, H., Satriani, K.C., Prosser, R., Oum, K., Paull, D., Druckenmiller, S., Freeby, M., . (2011). Human oocytes reprogram somatic cells to a pluripotent state. Nature 478, 70-75 .10.1038/nature10397
[128] Nori, S., Okada, Y., Yasuda, A., Tsuji, O., Takahashi, Y., Kobayashi, Y., Fujiyoshi, K., Koike, M., Uchiyama, Y., Ikeda, E., . (2011). Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc Natl Acad Sci U S A 108, 16825-16830 .10.1073/pnas.1108077108
[129] Ohi, Y., Qin, H., Hong, C., Blouin, L., Polo, J.M., Guo, T., Qi, Z., Downey, S.L., Manos, P.D., Rossi, D.J., . (2011). Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol 13, 541-549 .10.1038/ncb2239
[130] Okita, K., Ichisaka, T., and Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317 .10.1038/nature05934
[131] Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T., and Yamanaka, S. (2008). Generation of mouse induced pluripotent stem cells without viral vectors. Science 322, 949-953 .10.1126/science.1164270
[132] Pander, C.H. (1817). Beitr?ge zur Entwickelungsgeschichte des Hühnchens im Eye (Wurzburg).
[133] Park, I.H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., Lensch, M.W., Cowan, C., Hochedlinger, K., and Daley, G.Q. (2008). Disease-specific induced pluripotent stem cells. Cell 134, 877-886 .10.1016/j.cell.2008.07.041
[134] Pavlath, G.K., and Blau, H.M. (1986). Expression of muscle genes in heterokaryons depends on gene dosage. J Cell Biol 102, 124-130 .10.1083/jcb.102.1.124
[135] Pereira, C.F., Terranova, R., Ryan, N.K., Santos, J., Morris, K.J., Cui, W., Merkenschlager, M., and Fisher, A.G. (2008). Heterokaryon-based reprogramming of human B lymphocytes for pluripotency requires Oct4 but not Sox2. PLoS Genet 4, e1000170.10.1371/journal.pgen.1000170
[136] Phanstiel, D.H., Brumbaugh, J., Wenger, C.D., Tian, S., Probasco, M.D., Bailey, D.J., Swaney, D.L., Tervo, M.A., Bolin, J.M., Ruotti, V., . (2011). Proteomic and phosphoproteomic comparison of human ES and iPS cells. Nat Methods 8, 821-827 .10.1038/nmeth.1699
[137] Polo, J.M., Liu, S., Figueroa, M.E., Kulalert, W., Eminli, S., Tan, K.Y., Apostolou, E., Stadtfeld, M., Li, Y., Shioda, T., . (2010). Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol 28, 848-855 .10.1038/nbt.1667
[138] Prasad, S.M., Czepiel, M., Cetinkaya, C., Smigielska, K., Weli, S.C., Lysdahl, H., Gabrielsen, A., Petersen, K., Ehlers, N., Fink, T., . (2009). Continuous hypoxic culturing maintains activation of Notch and allows long-term propagation of human embryonic stem cells without spontaneous differentiation. Cell Prolif 42, 63-74 .10.1111/j.1365-2184.2008.00571.x
[139] Rahl, P.B., Lin, C.Y., Seila, A.C., Flynn, R.A., McCuine, S., Burge, C.B., Sharp, P.A., and Young, R.A. (2010). c-Myc regulates transcriptional pause release. Cell 141, 432-445 .10.1016/j.cell.2010.03.030
[140] Rashid, S.T., Corbineau, S., Hannan, N., Marciniak, S.J., Miranda, E., Alexander, G., Huang-Doran, I., Griffin, J., Ahrlund-Richter, L., Skepper, J., . (2010). Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest 120, 3127-3136 .10.1172/JCI43122
[141] Raya, A., Rodríguez-Pizà, I., Guenechea, G., Vassena, R., Navarro, S., Barrero, M.J., Consiglio, A., Castellà, M., Río, P., Sleep, E., . (2009). Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460, 53-59 .10.1038/nature08129
[142] Redmer, T., Diecke, S., Grigoryan, T., Quiroga-Negreira, A., Birchmeier, W., and Besser, D. (2011). E-cadherin is crucial for embryonic stem cell pluripotency and can replace OCT4 during somatic cell reprogramming. EMBO Rep 12, 720-726 .10.1038/embor.2011.88
[143] Rodda, D.J., Chew, J.L., Lim, L.H., Loh, Y.H., Wang, B., Ng, H.H., and Robson, P. (2005). Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem 280, 24731-24737 .10.1074/jbc.M502573200
[144] Roode, M., Blair, K., Snell, P., Elder, K., Marchant, S., Smith, A., and Nichols, J. (2012). Human hypoblast formation is not dependent on FGF signalling. Dev Biol 361, 358-363 .10.1016/j.ydbio.2011.10.030
[145] Roux, W. (1888). Beitrage zur Entwicklungsmechanik des Embryo. Virchows Arch Pathol Anat Physiol Klin Med 144, 113-153 .
[146] Rowland, B.D., Bernards, R., and Peeper, D.S. (2005). The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat Cell Biol 7, 1074-1082 .10.1038/ncb1314
[147] Samavarchi-Tehrani, P., Golipour, A., David, L., Sung, H.K., Beyer, T.A., Datti, A., Woltjen, K., Nagy, A., and Wrana, J.L. (2010). Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7, 64-77 .10.1016/j.stem.2010.04.015
[148] Shi, Y., Do, J.T., Desponts, C., Hahm, H.S., Sch?ler, H.R., and Ding, S. (2008). A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2, 525-528 .10.1016/j.stem.2008.05.011
[149] Shi, Y., Kirwan, P., Smith, J., Maclean, G., Orkin, S.H., and Livesey, F.J. (2012). A human stem cell model of early Alzheimer's disease pathology in Down Syndrome. Sci Transl Med 4, 124ra29.
[150] Silva, J., Chambers, I., Pollard, S., and Smith, A. (2006). Nanog promotes transfer of pluripotency after cell fusion. Nature 441, 997-1001 .10.1038/nature04914
[151] Silva, J., Nichols, J., Theunissen, T.W., Guo, G., van Oosten, A.L., Barrandon, O., Wray, J., Yamanaka, S., Chambers, I., and Smith, A. (2009). Nanog is the gateway to the pluripotent ground state. Cell 138, 722-737 .10.1016/j.cell.2009.07.039
[152] Sommer, C.A., Stadtfeld, M., Murphy, G.J., Hochedlinger, K., Kotton, D.N., and Mostoslavsky, G. (2009). Induced pluripotent stem cell generation using a single lentiviral stem cell cassette. Stem Cells 27, 543-549 .10.1634/stemcells.2008-1075
[153] Spemann, H. (1928). Die Entwicklung seitlicher und dorso-ventraler Keimhalften bei verzogerter Kernversogung. Z Wiss Zool 132, 105-134 .
[154] Spits, C., Mateizel, I., Geens, M., Mertzanidou, A., Staessen, C., Vandeskelde, Y., Van der Elst, J., Liebaers, I., and Sermon, K. (2008). Recurrent chromosomal abnormalities in human embryonic stem cells. Nat Biotechnol 26, 1361-1363 .10.1038/nbt.1510
[155] Sridharan, R., Tchieu, J., Mason, M.J., Yachechko, R., Kuoy, E., Horvath, S., Zhou, Q., and Plath, K. (2009). Role of the murine reprogramming factors in the induction of pluripotency. Cell 136, 364-377 .10.1016/j.cell.2009.01.001
[156] Stadtfeld, M., Apostolou, E., Akutsu, H., Fukuda, A., Follett, P., Natesan, S., Kono, T., Shioda, T., and Hochedlinger, K. (2010). Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465, 175-181 .10.1038/nature09017
[157] Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., and Hochedlinger, K. (2008). Induced pluripotent stem cells generated without viral integration. Science 322, 945-949 .10.1126/science.1162494
[158] Stojkovic, M., Stojkovic, P., Leary, C., Hall, V.J., Armstrong, L., Herbert, M., Nesbitt, M., Lako, M., and Murdoch, A. (2005). Derivation of a human blastocyst after heterologous nuclear transfer to donated oocytes. Reprod Biomed Online 11, 226-231 .10.1016/S1472-6483(10)60962-5
[159] Subramanyam, D., Lamouille, S., Judson, R.L., Liu, J.Y., Bucay, N., Derynck, R., and Blelloch, R. (2011). Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol 29, 443-448 .10.1038/nbt.1862
[160] Szabo, E., Rampalli, S., Risue?o, R.M., Schnerch, A., Mitchell, R., Fiebig-Comyn, A., Levadoux-Martin, M., and Bhatia, M. (2010). Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468, 521-526 .10.1038/nature09591
[161] Tada, M., Takahama, Y., Abe, K., Nakatsuji, N., and Tada, T. (2001). Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr Biol 11, 1553-1558 .10.1016/S0960-9822(01)00459-6
[162] Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872 .10.1016/j.cell.2007.11.019
[163] Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676 .10.1016/j.cell.2006.07.024
[164] Taranger, C.K., Noer, A., S?rensen, A.L., H?kelien, A.M., Boquest, A.C., and Collas, P. (2005). Induction of dedifferentiation, genomewide transcriptional programming, and epigenetic reprogramming by extracts of carcinoma and embryonic stem cells. Mol Biol Cell 16, 5719-5735 .10.1091/mbc.E05-06-0572
[165] Teranishi, T., Tanaka, M., Kimoto, S., Ono, Y., Miyakoshi, K., Kono, T., and Yoshimura, Y. (2004). Rapid replacement of somatic linker histones with the oocyte-specific linker histone H1foo in nuclear transfer. Dev Biol 266, 76-86 .10.1016/j.ydbio.2003.10.004
[166] Tesar, P.J., Chenoweth, J.G., Brook, F.A., Davies, T.J., Evans, E.P., Mack, D.L., Gardner, R.L., and McKay, R.D. (2007). New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448, 196-199 .10.1038/nature05972
[167] Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S., and Jones, J.M. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282, 1145-1147 .10.1126/science.282.5391.1145
[168] Thorel, F., Népote, V., Avril, I., Kohno, K., Desgraz, R., Chera, S., and Herrera, P.L. (2010). Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464, 1149-1154 .10.1038/nature08894
[169] Tomioka, M., Nishimoto, M., Miyagi, S., Katayanagi, T., Fukui, N., Niwa, H., Muramatsu, M., and Okuda, A. (2002). Identification of Sox-2 regulatory region which is under the control of Oct-3/4-Sox-2 complex. Nucleic Acids Res 30, 3202-3213 .10.1093/nar/gkf435
[170] Tontonoz, P., Hu, E., and Spiegelman, B.M. (1994). Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79, 1147-1156 .10.1016/0092-8674(94)90006-X
[171] Tsai, S.Y., Clavel, C., Kim, S., Ang, Y.S., Grisanti, L., Lee, D.F., Kelley, K., and Rendl, M. (2010). Oct4 and klf4 reprogram dermal papilla cells into induced pluripotent stem cells. Stem Cells 28, 221-228 .
[172] Tsonis, P.A., and Del Rio-Tsonis, K. (2004). Lens and retina regeneration: transdifferentiation, stem cells and clinical applications. Exp Eye Res 78, 161-172 .10.1016/j.exer.2003.10.022
[173] Urbach, A., Bar-Nur, O., Daley, G.Q., and Benvenisty, N. (2010). Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 6, 407-411 .10.1016/j.stem.2010.04.005
[174] Utikal, J., Polo, J.M., Stadtfeld, M., Maherali, N., Kulalert, W., Walsh, R.M., Khalil, A., Rheinwald, J.G., and Hochedlinger, K. (2009). Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460, 1145-1148 .10.1038/nature08285
[175] Vierbuchen, T., Ostermeier, A., Pang, Z.P., Kokubu, Y., Südhof, T.C., and Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035-1041 .10.1038/nature08797
[176] von Baer, K.E. (1828). über Entwickelungsgeschichte der Thier. Beobachtung und Reflexion (K?nigsberg, Bei den Gebrüdern Borntr?ger).
[177] Wang, T., Chen, K., Zeng, X., Yang, J., Wu, Y., Shi, X., Qin, B., Zeng, L., Esteban, M.A., Pan, G., . (2011a). The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell 9, 575-587 .10.1016/j.stem.2011.10.005
[178] Wang, W., Yang, J., Liu, H., Lu, D., Chen, X., Zenonos, Z., Campos, L.S., Rad, R., Guo, G., Zhang, S., . (2011b). Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1. Proc Natl Acad Sci U S A 108, 18283-18288 .10.1073/pnas.1100893108
[179] Warren, L., Manos, P.D., Ahfeldt, T., Loh, Y.H., Li, H., Lau, F., Ebina, W., Mandal, P.K., Smith, Z.D., Meissner, A., . (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7, 618-630 .10.1016/j.stem.2010.08.012
[180] Weintraub, H., Tapscott, S.J., Davis, R.L., Thayer, M.J., Adam, M.A., Lassar, A.B., and Miller, A.D. (1989). Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proc Natl Acad Sci U S A 86, 5434-5438 .10.1073/pnas.86.14.5434
[181] Willadsen, S.M. (1986). Nuclear transplantation in sheep embryos. Nature 320, 63-65 .10.1038/320063a0
[182] Wilmut, I., Schnieke, A.E., McWhir, J., Kind, A.J., and Campbell, K.H. (1997). Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810-813 .10.1038/385810a0
[183] Woltjen, K., Michael, I.P., Mohseni, P., Desai, R., Mileikovsky, M., H?m?l?inen, R., Cowling, R., Wang, W., Liu, P., Gertsenstein, M., . (2009). piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766-770 .10.1038/nature07863
[184] Wu, H., and Zhang, Y. (2011). Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 25, 2436-2452 .10.1101/gad.179184.111
[185] Xie, H., Ye, M., Feng, R., and Graf, T. (2004). Stepwise reprogramming of B cells into macrophages. Cell 117, 663-676 .10.1016/S0092-8674(04)00419-2
[186] Ying, Q.L., Nichols, J., Evans, E.P., and Smith, A.G. (2002). Changing potency by spontaneous fusion. Nature 416, 545-548 .10.1038/nature729
[187] Ying, Q.L., Wray, J., Nichols, J., Batlle-Morera, L., Doble, B., Woodgett, J., Cohen, P., and Smith, A. (2008). The ground state of embryonic stem cell self-renewal. Nature 453, 519-523 .10.1038/nature06968
[188] Yoshida, Y., Takahashi, K., Okita, K., Ichisaka, T., and Yamanaka, S. (2009). Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 5, 237-241 .10.1016/j.stem.2009.08.001
[189] Yu, J., Hu, K., Smuga-Otto, K., Tian, S., and Stewart, R.Slukvin, II, and Thomson, J.A. (2009). Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797-801 .10.1126/science.1172482
[190] Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., . (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science (New York, NY 318, 1917-1920 .
[191] Yusa, K., Rad, R., Takeda, J., and Bradley, A. (2009). Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon. Nat Methods 6, 363-369 .10.1038/nmeth.1323
[192] Yusa, K., Rashid, S.T., Strick-Marchand, H., Varela, I., Liu, P.Q., Paschon, D.E., Miranda, E., Ordó?ez, A., Hannan, N.R., Rouhani, F.J., . (2011). Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478, 391-394 .10.1038/nature10424
[193] Zhang, J., Lian, Q., Zhu, G., Zhou, F., Sui, L., Tan, C., Mutalif, R.A., Navasankari, R., Zhang, Y., Tse, H.F., . (2011). A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8, 31-45 .10.1016/j.stem.2010.12.002
[194] Zhao, T., Zhang, Z.N., Rong, Z., and Xu, Y. (2011). Immunogenicity of induced pluripotent stem cells. Nature 474, 212-215 .
[195] Zhao, Y., Yin, X., Qin, H., Zhu, F., Liu, H., Yang, W., Zhang, Q., Xiang, C., Hou, P., Song, Z., . (2008). Two supporting factors greatly improve the efficiency of human iPSC generation. Cell Stem Cell 3, 475-479 .10.1016/j.stem.2008.10.002
[196] Zhou, H., Wu, S., Joo, J.Y., Zhu, S., Han, D.W., Lin, T., Trauger, S., Bien, G., Yao, S., Zhu, Y., . (2009). Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4, 381-384 .10.1016/j.stem.2009.04.005
[197] Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J., and Melton, D.A. (2008). In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627-632 .10.1038/nature07314