Mechanisms underlying the formation of induced pluripotent stem cells

Overview

Danwei Huangfu, Federico González

Published Online: Sep 18 2015

DOI: 10.1002/wdev.206

Full article on Wiley Online Library: HTML PDF

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Human pluripotent stem cells (hPSCs) offer unique opportunities for studying human biology, modeling diseases, and therapeutic applications. The simplest approach so far to generate human PSC lines is through reprogramming of somatic cells from an individual by defined factors, referred to simply as reprogramming. Reprogramming circumvents the ethical controversies associated with human embryonic stem cells (hESCs) and nuclear transfer hESCs (nt‐hESCs), and the resulting induced pluripotent stem cells (hiPSCs) retain the same basic genetic makeup as the somatic cell used for reprogramming. Since the first report of iPSCs by Takahashi and Yamanaka (Cell 2006, 126:663–676), the molecular mechanisms of reprogramming have been extensively investigated. A better mechanistic understanding of reprogramming is fundamental not only to iPSC biology and improving the quality of iPSCs for therapeutic use, but also to our understanding of the molecular basis of cell identity, pluripotency, and plasticity. Here, we summarize the genetic, epigenetic, and cellular events during reprogramming, and the roles of various factors identified thus far in the reprogramming process. WIREs Dev Biol 2016, 5:39–65. doi: 10.1002/wdev.206 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Methods and Principles Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease

Sources of pluripotent stem cells. Culture‐derived pluripotent stem cells (PSCs) are generated from different in vivo cell types. (a) Embryonal carcinoma cells (ECCs), derived from germline tumors (teratocarcinomas); (b) embryonic stem cells (ESCs), derived from the inner cell mass (ICM) of preimplantation mouse and human embryos at mouse embryonic day 3.5 (mE3.5) or human embryonic day 5.5 (hE5.5); (c) epiblast stem cells (EpiSCs) and region‐selective pluripotent stem cells (rsPSCs), obtained from early postimplantation mouse embryos at mE5.5–7.5; (d) embryonic germ cells (EGCs) retrieved from mouse and human primordial germ cells (PGCs), respectively, at mE8.5–12.5 or between weeks 3 and 5 of human development (hW3‐5); and (e) germline‐derived PSCs (GSCs), derived from spermatogonial stem cells of mouse neonatal and adult testes. In each of the above columns, the cell of origin of the different pluripotent stem cell lines is labeled in blue. Alternatively, exposing the nuclei of somatic cells to exogenous reprogramming factors can induce PSCs. (f) Nuclear transfer embryonic stem cells (ntESC) are obtained by reprogramming somatic nuclei (pink) with factors contained in an enucleated oocyte (blue), and cultured to the blastocyst stage to derive ntESCs from the ICM; (g) through a similar approach, fusion between a somatic cell (pink) and a PSC (blue) gives rise to cell‐fusion‐derived tetraploid (4N) hybrid ESC (cfESC) lines; (h) alternatively, overexpression of the reprogramming transcription factors, Oct4 (O), Sox2 (S), Klf4 (K), and cMyc (M) in a somatic cell (pink) using viral delivery (blue) allows generating induced pluripotent stem cells (iPSC); and (i) F‐class cells are generated through high and constitutive expression of OSKM in a somatic cell (pink) using an inducible integrated transgene (blue). F‐class cells share molecular and phenotypic features with iPSCs and ESCs.

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Phases of reprogramming. (a) Kinetics of pluripotency‐marker appearance and definition of the reprogramming phases. Alkaline phosphatase and stage‐specific embryonic antigen 1 (SSEA1) positive cells appear around days 2 and 3, respectively, after OSKM (Oct4, Sox2, Klf4, and c‐Myc) transduction, coinciding with the downregulation of the mesenchymal marker Thy1. GFP expressed from the endogenous Oct4 or Nanog loci is detected later, around days 9 and 10, respectively. The virally transduced factors need to be expressed for approximately 12 days to generate stable, transgene‐independent induced pluripotent stem cells (iPSCs). (b) A schematic drawing illustrating the kinetics and the magnitude of the molecular changes observed during reprogramming. Permissive reprogramming cells (positive y‐axis) show a biphasic pattern of protein, mRNA, and microRNA (miRNA) expression changes following the kinetics of individual histone modifications. Bivalent domains are generated gradually after an initial burst and DNA methylation changes occur predominantly at the end of reprogramming. Refractory cells (negative y‐axis) undergo a similar wave of expression changes during the initiation phase but remain relatively stable afterward. Forced expression of OKSM in refractory cells can rescue their ability to form iPSCs. (Adapted with permission from Ref . Copyright 2012 Cell Press [Elsevier])

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Models of reprogramming. Two types of models have been proposed to describe reprogramming: deterministic and stochastic. (a–c) Deterministic models predict that somatic donor cells give rise to induced pluripotent stem cells (iPSCs) with a fixed latency (green arrows of same length). (d–f) Stochastic models predict that somatic donor cells give rise to iPSCs with variable latencies (green arrows of different lengths). In both models, either all (a and d) or only a subset of elite cells (brown) (b, c, e, and f) is permissive to reprogramming and elite cells can be present in the donor population before reprogramming (predetermined) (b and e) or induced upon viral delivery (red dots) (c and f). The latency (green arrows) reflects the absolute time or the number of cell divisions required to produce an iPSC from the donor population.

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References

Wu, J, Okamura, D, Li, M, Suzuki, K, Luo, C, Ma, L, He, Y, Li, Z, Benner, C, Tamura, I, et al. An alternative pluripotent state confers interspecies chimaeric competency. Nature 2015, 521:316–321.
Surani, MA. Cellular reprogramming in pursuit of immortality. Cell Stem Cell 2012, 11:748–750.
Gaspar‐Maia, A, Alajem, A, Meshorer, E, Ramalho‐Santos, M. Open chromatin in pluripotency and reprogramming. Nat Rev Mol Cell Biol 2011, 12:36–47.
Evans, MJ, Kaufman, MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981, 292:154–156.
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, 78:7634–7638.
Thomson, JA, Itskovitz‐Eldor, J, Shapiro, SS, Waknitz, MA, Swiergiel, JJ, Marshall, VS, Jones, JM. Embryonic stem cell lines derived from human blastocysts. Science 1998, 282:1145–1147.
Wakayama, T, Tabar, V, Rodriguez, I, Perry, AC, Studer, L, Mombaerts, P. Differentiation of embryonic stem cell lines generated from adult somatic cells by nuclear transfer. Science 2001, 292:740–743.
Tachibana, M, Amato, P, Sparman, M, Gutierrez, NM, Tippner‐Hedges, R, Ma, H, Kang, E, Fulati, A, Lee, HS, Sritanaudomchai, H, et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 2013, 153:1228–1238.
Yamada, M, Johannesson, B, Sagi, I, Burnett, LC, Kort, DH, Prosser, RW, Paull, D, Nestor, MW, Freeby, M, Greenberg, E, et al. Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells. Nature 2014, 510:533–536.
Yamanaka, S, Blau, HM. Nuclear reprogramming to a pluripotent state by three approaches. Nature 2010, 465:704–712.
Takahashi, K, Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126:663–676.
Lowry, WE, Richter, L, Yachechko, R, Pyle, AD, Tchieu, J, Sridharan, R, Clark, AT, Plath, K. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci USA 2008, 105:2883–2888.
Park, IH, Zhao, R, West, JA, Yabuuchi, A, Huo, H, Ince, TA, Lerou, PH, Lensch, MW, Daley, GQ. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 2008, 451:141–146.
Takahashi, K, Tanabe, K, Ohnuki, M, Narita, M, Ichisaka, T, Tomoda, K, Yamanaka, S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007, 131:861–872.
Yu, J, Vodyanik, MA, Smuga‐Otto, K, Antosiewicz‐Bourget, J, Frane, JL, Tian, S, Nie, J, Jonsdottir, GA, Ruotti, V, Stewart, R, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007, 318:1917–1920.
Meissner, A, Wernig, M, Jaenisch, R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol 2007, 25:1177–1181.
Varas, F, Stadtfeld, M, de Andres‐Aguayo, L, Maherali, N, di Tullio, A, Pantano, L, Notredame, C, Hochedlinger, K, Graf, T. Fibroblast‐derived induced pluripotent stem cells show no common retroviral vector insertions. Stem Cells 2009, 27:300–306.
Wernig, M, Lengner, CJ, Hanna, J, Lodato, MA, Steine, E, Foreman, R, Staerk, J, Markoulaki, S, Jaenisch, R. A drug‐inducible transgenic system for direct reprogramming of multiple somatic cell types. Nat Biotechnol 2008, 26:916–924.
Carey, BW, Markoulaki, S, Beard, C, Hanna, J, Jaenisch, R. Single‐gene transgenic mouse strains for reprogramming adult somatic cells. Nat Methods 2010, 7:56–59.
Stadtfeld, M, Maherali, N, Borkent, M, Hochedlinger, K. A reprogrammable mouse strain from gene‐targeted embryonic stem cells. Nat Methods 2010, 7:53–55.
Eminli, S, Foudi, A, Stadtfeld, M, Maherali, N, Ahfeldt, T, Mostoslavsky, G, Hock, H, Hochedlinger, K. Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nat Genet 2009, 41:968–976.
Hanna, J, Saha, K, Pando, B, van Zon, J, Lengner, CJ, Creyghton, MP, van Oudenaarden, A, Jaenisch, R. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 2009, 462:595–601.
Guo, S, Zi, X, Schulz, VP, Cheng, J, Zhong, M, Koochaki, SH, Megyola, CM, Pan, X, Heydari, K, Weissman, SM, et al. Nonstochastic reprogramming from a privileged somatic cell state. Cell 2014, 156:649–662.
Rais, Y, Zviran, A, Geula, S, Gafni, O, Chomsky, E, Viukov, S, Mansour, AA, Caspi, I, Krupalnik, V, Zerbib, M, et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature 2013, 502:65–70.
dos Santos, RL, Tosti, L, Radzisheuskaya, A, Caballero, IM, Kaji, K, Hendrich, B, Silva, JC. MBD3/NuRD facilitates induction of pluripotency in a context‐dependent manner. Cell Stem Cell 2014, 15:102–110.
Jaenisch, R, Young, R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 2008, 132:567–582.
Brambrink, T, Foreman, R, Welstead, GG, Lengner, CJ, Wernig, M, Suh, H, Jaenisch, R. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell 2008, 2:151–159.
Stadtfeld, M, Maherali, N, Breault, DT, Hochedlinger, K. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell 2008, 2:230–240.
Samavarchi‐Tehrani, P, Golipour, A, David, L, Sung, HK, Beyer, TA, Datti, A, Woltjen, K, Nagy, A, Wrana, JL. Functional genomics reveals a BMP‐driven mesenchymal‐to‐epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 2010, 7:64–77.
Polo, JM, Anderssen, E, Walsh, RM, Schwarz, BA, Nefzger, CM, Lim, SM, Borkent, M, Apostolou, E, Alaei, S, Cloutier, J, et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 2012, 151:1617–1632.
Hansson, J, Rafiee, MR, Reiland, S, Polo, JM, Gehring, J, Okawa, S, Huber, W, Hochedlinger, K, Krijgsveld, J. Highly coordinated proteome dynamics during reprogramming of somatic cells to pluripotency. Cell Rep 2012, 2:1579–1592.
Buganim, Y, Faddah, DA, Cheng, AW, Itskovich, E, Markoulaki, S, Ganz, K, Klemm, SL, van Oudenaarden, A, Jaenisch, R. Single‐cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell 2012, 150:1209–1222.
Li, R, Liang, J, Ni, S, Zhou, T, Qing, X, Li, H, He, W, Chen, J, Li, F, Zhuang, Q, et al. A mesenchymal‐to‐epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 2010, 7:51–63.
Araki, R, Jincho, Y, Hoki, Y, Nakamura, M, Tamura, C, Ando, S, Kasama, Y, Abe, M. Conversion of ancestral fibroblasts to induced pluripotent stem cells. Stem Cells 2010, 28:213–220.
Megyola, CM, Gao, Y, Teixeira, AM, Cheng, J, Heydari, K, Cheng, EC, Nottoli, T, Krause, DS, Lu, J, Guo, S. Dynamic migration and cell‐cell interactions of early reprogramming revealed by high‐resolution time‐lapse imaging. Stem Cells 2013, 31:895–905.
Smith, ZD, Nachman, I, Regev, A, Meissner, A. Dynamic single‐cell imaging of direct reprogramming reveals an early specifying event. Nat Biotechnol 2010, 28:521–526.
Khalil, AM, Guttman, M, Huarte, M, Garber, M, Raj, A, Rivea Morales, D, Thomas, K, Presser, A, Bernstein, BE, van Oudenaarden, A, et al. Many human large intergenic noncoding RNAs associate with chromatin‐modifying complexes and affect gene expression. Proc Natl Acad Sci USA 2009, 106:11667–11672.
Guttman, M, Donaghey, J, Carey, BW, Garber, M, Grenier, JK, Munson, G, Young, G, Lucas, AB, Ach, R, Bruhn, L, et al. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 2011, 477:295–300.
Mikkelsen, TS, Hanna, J, Zhang, X, Ku, M, Wernig, M, Schorderet, P, Bernstein, BE, Jaenisch, R, Lander, ES, Meissner, A. Dissecting direct reprogramming through integrative genomic analysis. Nature 2008, 454:49–55.
Sridharan, R, Tchieu, J, Mason, MJ, Yachechko, R, Kuoy, E, Horvath, S, Zhou, Q, Plath, K. Role of the murine reprogramming factors in the induction of pluripotency. Cell 2009, 136:364–377.
Hussein, SM, Puri, MC, Tonge, PD, Benevento, M, Corso, AJ, Clancy, JL, Mosbergen, R, Li, M, Lee, DS, Cloonan, N, et al. Genome‐wide characterization of the routes to pluripotency. Nature 2014, 516:198–206.
Lujan, E, Zunder, ER, Ng, YH, Goronzy, IN, Nolan, GP, Wernig, M. Early reprogramming regulators identified by prospective isolation and mass cytometry. Nature 2015, 521:352–356.
Golipour, A, David, L, Liu, Y, Jayakumaran, G, Hirsch, CL, Trcka, D, Wrana, JL. A late transition in somatic cell reprogramming requires regulators distinct from the pluripotency network. Cell Stem Cell 2012, 11:769–782.
Mathieu, J, Zhou, W, Xing, Y, Sperber, H, Ferreccio, A, Agoston, Z, Kuppusamy, KT, Moon, RT, Ruohola‐Baker, H. Hypoxia‐inducible factors have distinct and stage‐specific roles during reprogramming of human cells to pluripotency. Cell Stem Cell 2014, 14:592–605.
Buganim, Y, Markoulaki, S, van Wietmarschen, N, Hoke, H, Wu, T, Ganz, K, Akhtar‐Zaidi, B, He, Y, Abraham, BJ, Porubsky, D, et al. The developmental potential of iPSCs is greatly influenced by reprogramming factor selection. Cell Stem Cell 2014, 15:295–309.
David, L, Polo, JM. Phases of reprogramming. Stem Cell Res 2014, 12:754–761.
Marion, RM, Strati, K, Li, H, Murga, M, Blanco, R, Ortega, S, Fernandez‐Capetillo, O, Serrano, M, Blasco, MA. A p53‐mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 2009, 460:1149–1153.
Buganim, Y, Faddah, DA, Jaenisch, R. Mechanisms and models of somatic cell reprogramming. Nat Rev Genet 2013, 14:427–439.
Bernstein, BE, Meissner, A, Lander, ES. The mammalian epigenome. Cell 2007, 128:669–681.
Liang, G, Zhang, Y. Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective. Cell Res 2013, 23:49–69.
Schmidt, R, Plath, K. The roles of the reprogramming factors Oct4, Sox2 and Klf4 in resetting the somatic cell epigenome during induced pluripotent stem cell generation. Genome Biol 2012, 13:251.
Koche, RP, Smith, ZD, Adli, M, Gu, H, Ku, M, Gnirke, A, Bernstein, BE, Meissner, A. Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell 2011, 8:96–105.
Soufi, A, Donahue, G, Zaret, KS. Facilitators and impediments of the pluripotency reprogramming factors` initial engagement with the genome. Cell 2012, 151:994–1004.
Blackledge, NP, Zhou, JC, Tolstorukov, MY, Farcas, AM, Park, PJ, Klose, RJ. CpG islands recruit a histone H3 lysine 36 demethylase. Mol Cell 2010, 38:179–190.
Liang, G, He, J, Zhang, Y. Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nat Cell Biol 2012, 14:457–466.
Wang, T, Chen, K, Zeng, X, Yang, J, Wu, Y, Shi, X, Qin, B, Zeng, L, Esteban, MA, Pan, G, et al. The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin‐C‐dependent manner. Cell Stem Cell 2011, 9:575–587.
Nguyen, AT, Zhang, Y. The diverse functions of Dot1 and H3K79 methylation. Genes Dev 2011, 25:1345–1358.
Chen, J, Liu, H, Liu, J, Qi, J, Wei, B, Yang, J, Liang, H, Chen, Y, Chen, J, Wu, Y, et al. H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat Genet 2013, 45:34–42.
Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev 2002, 16:6–21.
Berdasco, M, Esteller, M. DNA methylation in stem cell renewal and multipotency. Stem Cell Res Ther 2011, 2:42.
Pasque, V, Tchieu, J, Karnik, R, Uyeda, M, Sadhu Dimashkie, A, Case, D, Papp, B, Bonora, G, Patel, S, Ho, R, et al. X chromosome reactivation dynamics reveal stages of reprogramming to pluripotency. Cell 2014, 159:1681–1697.
Kim, JS, Choi, HW, Arauzo‐Bravo, MJ, Scholer, HR, Do, JT. Reactivation of the inactive X chromosome and post‐transcriptional reprogramming of Xist in iPSCs. J Cell Sci 2015, 128:81–87.
Kim, KY, Hysolli, E, Tanaka, Y, Wang, B, Jung, YW, Pan, X, Weissman, SM, Park, IH. X Chromosome of female cells shows dynamic changes in status during human somatic cell reprogramming. Stem Cell Reports 2014, 2:896–909.
O`Malley, J, Skylaki, S, Iwabuchi, KA, Chantzoura, E, Ruetz, T, Johnsson, A, Tomlinson, SR, Linnarsson, S, Kaji, K. High‐resolution analysis with novel cell‐surface markers identifies routes to iPS cells. Nature 2013, 499:88–91.
Takahashi, K, Tanabe, K, Ohnuki, M, Narita, M, Sasaki, A, Yamamoto, M, Nakamura, M, Sutou, K, Osafune, K, Yamanaka, S. Induction of pluripotency in human somatic cells via a transient state resembling primitive streak‐like mesendoderm. Nat Commun 2014, 5:3678.
Han, DW, Greber, B, Wu, G, Tapia, N, Arauzo‐Bravo, MJ, Ko, K, Bernemann, C, Stehling, M, Scholer, HR. Direct reprogramming of fibroblasts into epiblast stem cells. Nat Cell Biol 2011, 13:66–71.
Kim, J, Efe, JA, Zhu, S, Talantova, M, Yuan, X, Wang, S, Lipton, SA, Zhang, K, Ding, S. Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci USA 2011, 108:7838–7843.
Margariti, A, Winkler, B, Karamariti, E, Zampetaki, A, Tsai, TN, Baban, D, Ragoussis, J, Huang, Y, Han, JD, Zeng, L, et al. Direct reprogramming of fibroblasts into endothelial cells capable of angiogenesis and reendothelialization in tissue‐engineered vessels. Proc Natl Acad Sci USA 2012, 109:13793–13798.
Efe, JA, Hilcove, S, Kim, J, Zhou, H, Ouyang, K, Wang, G, Chen, J, Ding, S. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol 2011, 13:215–222.
Bar‐Nur, O, Verheul, C, Sommer, AG, Brumbaugh, J, Schwarz, BA, Lipchina, I, Huebner, AJ, Mostoslavsky, G, Hochedlinger, K. Lineage conversion induced by pluripotency factors involves transient passage through an iPSC stage. Nat Biotechnol 2015, 33:761–768.
Maza, I, Caspi, I, Zviran, A, Chomsky, E, Rais, Y, Viukov, S, Geula, S, Buenrostro, JD, Weinberger, L, Krupalnik, V, et al. Transient acquisition of pluripotency during somatic cell transdifferentiation with iPSC reprogramming factors. Nat Biotechnol 2015, 33:769–774.
Tonge, PD, Corso, AJ, Monetti, C, Hussein, SM, Puri, MC, Michael, IP, Li, M, Lee, DS, Mar, JC, Cloonan, N, et al. Divergent reprogramming routes lead to alternative stem‐cell states. Nature 2014, 516:192–197.
Benevento, M, Tonge, PD, Puri, MC, Hussein, SM, Cloonan, N, Wood, DL, Grimmond, SM, Nagy, A, Munoz, J, Heck, AJ. Proteome adaptation in cell reprogramming proceeds via distinct transcriptional networks. Nat Commun 2014, 5:5613.
Clancy, JL, Patel, HR, Hussein, SM, Tonge, PD, Cloonan, N, Corso, AJ, Li, M, Lee, DS, Shin, JY, Wong, JJ, et al. Small RNA changes en route to distinct cellular states of induced pluripotency. Nat Commun 2014, 5:5522.
Lee, DS, Shin, JY, Tonge, PD, Puri, MC, Lee, S, Park, H, Lee, WC, Hussein, SM, Bleazard, T, Yun, JY, et al. An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator. Nat Commun 2014, 5:5619.
Wu, J, Izpisua Belmonte, JC. Stem cells: a designer`s guide to pluripotency. Nature 2014, 516:172–173.
Nakagawa, M, Koyanagi, M, Tanabe, K, Takahashi, K, Ichisaka, T, Aoi, T, Okita, K, Mochiduki, Y, Takizawa, N, Yamanaka, S. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 2008, 26:101–106.
Wernig, M, Meissner, A, Cassady, JP, Jaenisch, R. c‐Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2008, 2:10–12.
Meyer, N, Penn, LZ. Reflecting on 25 years with MYC. Nat Rev Cancer 2008, 8:976–990.
Chen, X, Xu, H, Yuan, P, Fang, F, Huss, M, Vega, VB, Wong, E, Orlov, YL, Zhang, W, Jiang, J, et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 2008, 133:1106–1117.
Kim, J, Chu, J, Shen, X, Wang, J, Orkin, SH. An extended transcriptional network for pluripotency of embryonic stem cells. Cell 2008, 132:1049–1061.
Maekawa, M, Yamaguchi, K, Nakamura, T, Shibukawa, R, Kodanaka, I, Ichisaka, T, Kawamura, Y, Mochizuki, H, Goshima, N, Yamanaka, S. Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1. Nature 2011, 474:225–229.
Anokye‐Danso, F, Trivedi, CM, Juhr, D, Gupta, M, Cui, Z, Tian, Y, Zhang, Y, Yang, W, Gruber, PJ, Epstein, JA, et al. Highly efficient miRNA‐mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 2011, 8:376–388.
Liao, B, Bao, X, Liu, L, Feng, S, Zovoilis, A, Liu, W, Xue, Y, Cai, J, Guo, X, Qin, B, et al. MicroRNA cluster 302–367 enhances somatic cell reprogramming by accelerating a mesenchymal‐to‐epithelial transition. J Biol Chem 2011, 286:17359–17364.
Subramanyam, D, Lamouille, S, Judson, RL, Liu, JY, Bucay, N, Derynck, R, Blelloch, R. Multiple targets of miR‐302 and miR‐372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol 2011, 29:443–448.
Kagey, MH, Newman, JJ, Bilodeau, S, Zhan, Y, Orlando, DA, van Berkum, NL, Ebmeier, CC, Goossens, J, Rahl, PB, Levine, SS, et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 2010, 467:430–435.
Lin, C, Garruss, AS, Luo, Z, Guo, F, Shilatifard, A. The RNA Pol II elongation factor Ell3 marks enhancers in ES cells and primes future gene activation. Cell 2013, 152:144–156.
Nie, Z, Hu, G, Wei, G, Cui, K, Yamane, A, Resch, W, Wang, R, Green, DR, Tessarollo, L, Casellas, R, et al. c‐Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 2012, 151:68–79.
Lin, CY, Loven, J, Rahl, PB, Paranal, RM, Burge, CB, Bradner, JE, Lee, TI, Young, RA. Transcriptional amplification in tumor cells with elevated c‐Myc. Cell 2012, 151:56–67.
Pan, G, Thomson, JA. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res 2007, 17:42–49.
Silva, J, Nichols, J, Theunissen, TW, Guo, G, van Oosten, AL, Barrandon, O, Wray, J, Yamanaka, S, Chambers, I, Smith, A. Nanog is the gateway to the pluripotent ground state. Cell 2009, 138:722–737.
Viswanathan, SR, Daley, GQ. Lin28: a microRNA regulator with a macro role. Cell 2010, 140:445–449.
Shyh‐Chang, N, Daley, GQ. Lin28: primal regulator of growth and metabolism in stem cells. Cell Stem Cell 2013, 12:395–406.
Kumar, MS, Lu, J, Mercer, KL, Golub, TR, Jacks, T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 2007, 39:673–677.
Lim, CY, Tam, WL, Zhang, J, Ang, HS, Jia, H, Lipovich, L, Ng, HH, Wei, CL, Sung, WK, Robson, P, et al. Sall4 regulates distinct transcription circuitries in different blastocyst‐derived stem cell lineages. Cell Stem Cell 2008, 3:543–554.
Yang, J, Chai, L, Fowles, TC, Alipio, Z, Xu, D, Fink, LM, Ward, DC, Ma, Y. Genome‐wide analysis reveals Sall4 to be a major regulator of pluripotency in murine‐embryonic stem cells. Proc Natl Acad Sci USA 2008, 105:19756–19761.
Wu, Q, Chen, X, Zhang, J, Loh, YH, Low, TY, Zhang, W, Zhang, W, Sze, SK, Lim, B, Ng, HH. Sall4 interacts with Nanog and co‐occupies Nanog genomic sites in embryonic stem cells. J Biol Chem 2006, 281:24090–24094.
Zhang, J, Tam, WL, Tong, GQ, Wu, Q, Chan, HY, Soh, BS, Lou, Y, Yang, J, Ma, Y, Chai, L, et al. Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 2006, 8:1114–1123.
Tsubooka, N, Ichisaka, T, Okita, K, Takahashi, K, Nakagawa, M, Yamanaka, S. Roles of Sall4 in the generation of pluripotent stem cells from blastocysts and fibroblasts. Genes Cells 2009, 14:683–694.
Ivanova, N, Dobrin, R, Lu, R, Kotenko, I, Levorse, J, DeCoste, C, Schafer, X, Lun, Y, Lemischka, IR. Dissecting self‐renewal in stem cells with RNA interference. Nature 2006, 442:533–538.
Loh, YH, Wu, Q, Chew, JL, Vega, VB, Zhang, W, Chen, X, Bourque, G, George, J, Leong, B, Liu, J, et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 2006, 38:431–440.
Feng, B, Jiang, J, Kraus, P, Ng, JH, Heng, JC, Chan, YS, Yaw, LP, Zhang, W, Loh, YH, Han, J, et al. Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Cell Biol 2009, 11:197–203.
Young, RA. Control of the embryonic stem cell state. Cell 2011, 144:940–954.
Loh, KM, Lim, B. A precarious balance: pluripotency factors as lineage specifiers. Cell Stem Cell 2011, 8:363–369.
Shu, J, Wu, C, Wu, Y, Li, Z, Shao, S, Zhao, W, Tang, X, Yang, H, Shen, L, Zuo, X, et al. Induction of pluripotency in mouse somatic cells with lineage specifiers. Cell 2013, 153:963–975.
Montserrat, N, Nivet, E, Sancho‐Martinez, I, Hishida, T, Kumar, S, Miquel, L, Cortina, C, Hishida, Y, Xia, Y, Esteban, CR, et al. Reprogramming of human fibroblasts to pluripotency with lineage specifiers. Cell Stem Cell 2013, 13:341–350.
Ben‐David, U, Nissenbaum, J, Benvenisty, N. New balance in pluripotency: reprogramming with lineage specifiers. Cell 2013, 153:939–940.
Aloia, L, Di Stefano, B, Di Croce, L. Polycomb complexes in stem cells and embryonic development. Development 2013, 140:2525–2534.
Onder, TT, Kara, N, Cherry, A, Sinha, AU, Zhu, N, Bernt, KM, Cahan, P, Marcarci, BO, Unternaehrer, J, Gupta, PB, et al. Chromatin‐modifying enzymes as modulators of reprogramming. Nature 2012, 483:598–602.
Rao, RA, Dhele, N, Cheemadan, S, Ketkar, A, Jayandharan, GR, Palakodeti, D, Rampalli, S. Ezh2 mediated H3K27me3 activity facilitates somatic transition during human pluripotent reprogramming. Sci Rep 2015, 5:8229.
Ringrose, L, Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 2004, 38:413–443.
Ang, YS, Tsai, SY, Lee, DF, Monk, J, Su, J, Ratnakumar, K, Ding, J, Ge, Y, Darr, H, Chang, B, et al. Wdr5 mediates self‐renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell 2011, 145:183–197.
Mansour, AA, Gafni, O, Weinberger, L, Zviran, A, Ayyash, M, Rais, Y, Krupalnik, V, Zerbib, M, Amann‐Zalcenstein, D, Maza, I, et al. The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature 2012, 488:409–413.
Sridharan, R, Gonzales‐Cope, M, Chronis, C, Bonora, G, McKee, R, Huang, C, Patel, S, Lopez, D, Mishra, N, Pellegrini, M, et al. Proteomic and genomic approaches reveal critical functions of H3K9 methylation and heterochromatin protein‐1γ in reprogramming to pluripotency. Nat Cell Biol 2013, 15:872–882.
Banaszynski, LA, Allis, CD, Lewis, PW. Histone variants in metazoan development. Dev Cell 2010, 19:662–674.
González, F, Georgieva, D, Vanoli, F, Shi, ZD, Stadtfeld, M, Ludwig, T, Jasin, M, Huangfu, D. Homologous recombination DNA repair genes play a critical role in reprogramming to a pluripotent state. Cell Rep 2013, 3:651–660.
Muller, LU, Milsom, MD, Harris, CE, Vyas, R, Brumme, KM, Parmar, K, Moreau, LA, Schambach, A, Park, IH, London, WB, et al. Overcoming reprogramming resistance of Fanconi anemia cells. Blood 2012, 119:5449–5457.
Navarro, S, Moleiro, V, Molina‐Estevez, FJ, Lozano, ML, Chinchon, R, Almarza, E, Quintana‐Bustamante, O, Mostoslavsky, G, Maetzig, T, Galla, M, et al. Generation of iPSCs from genetically corrected Brca2 hypomorphic cells: implications in cell reprogramming and stem cell therapy. Stem Cells 2014, 32:436–446.
Wu, T, Liu, Y, Wen, D, Tseng, Z, Tahmasian, M, Zhong, M, Rafii, S, Stadtfeld, M, Hochedlinger, K, Xiao, A. Histone variant H2A.X deposition pattern serves as a functional epigenetic mark for distinguishing the developmental potentials of iPSCs. Cell Stem Cell 2014, 15:281–294.
Buschbeck, M, Di Croce, L. Approaching the molecular and physiological function of macroH2A variants. Epigenetics 2010, 5:118–123.
Pasque, V, Radzisheuskaya, A, Gillich, A, Halley‐Stott, RP, Panamarova, M, Zernicka‐Goetz, M, Surani, MA, Silva, JC. Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency. J Cell Sci 2012, 125:6094–6104.
Gaspar‐Maia, A, Qadeer, ZA, Hasson, D, Ratnakumar, K, Leu, NA, Leroy, G, Liu, S, Costanzi, C, Valle‐Garcia, D, Schaniel, C, et al. MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency. Nat Commun 2013, 4:1565.
Barrero, MJ, Sese, B, Kuebler, B, Bilic, J, Boue, S, Marti, M, Izpisua Belmonte, JC. Macrohistone variants preserve cell identity by preventing the gain of H3K4me2 during reprogramming to pluripotency. Cell Rep 2013, 3:1005–1011.
Shinagawa, T, Takagi, T, Tsukamoto, D, Tomaru, C, Huynh, LM, Sivaraman, P, Kumarevel, T, Inoue, K, Nakato, R, Katou, Y, et al. Histone variants enriched in oocytes enhance reprogramming to induced pluripotent stem cells. Cell Stem Cell 2014, 14:217–227.
Gonzalez‐Munoz, E, Arboleda‐Estudillo, Y, Otu, HH, Cibelli, JB. Cell reprogramming. Histone chaperone ASF1A is required for maintenance of pluripotency and cellular reprogramming. Science 2014, 345:822–825.
Ho, L, Crabtree, GR. Chromatin remodelling during development. Nature 2010, 463:474–484.
Singhal, N, Graumann, J, Wu, G, Arauzo‐Bravo, MJ, Han, DW, Greber, B, Gentile, L, Mann, M, Scholer, HR. Chromatin‐remodeling components of the BAF complex facilitate reprogramming. Cell 2010, 141:943–955.
Gaspar‐Maia, A, Alajem, A, Polesso, F, Sridharan, R, Mason, MJ, Heidersbach, A, Ramalho‐Santos, J, McManus, MT, Plath, K, Meshorer, E, et al. Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature 2009, 460:863–868.
Wang, L, Du, Y, Ward, JM, Shimbo, T, Lackford, B, Zheng, X, Miao, YL, Zhou, B, Han, L, Fargo, DC, et al. INO80 facilitates pluripotency gene activation in embryonic stem cell self‐renewal, reprogramming, and blastocyst development. Cell Stem Cell 2014, 14:575–591.
Luo, M, Ling, T, Xie, W, Sun, H, Zhou, Y, Zhu, Q, Shen, M, Zong, L, Lyu, G, Zhao, Y, et al. NuRD blocks reprogramming of mouse somatic cells into pluripotent stem cells. Stem Cells 2013, 31:1278–1286.
Apostolou, E, Hochedlinger, K. Chromatin dynamics during cellular reprogramming. Nature 2013, 502:462–471.
Apostolou, E, Ferrari, F, Walsh, RM, Bar‐Nur, O, Stadtfeld, M, Cheloufi, S, Stuart, HT, Polo, JM, Ohsumi, TK, Borowsky, ML, et al. Genome‐wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming. Cell Stem Cell 2013, 12:699–712.
Wei, Z, Gao, F, Kim, S, Yang, H, Lyu, J, An, W, Wang, K, Lu, W. Klf4 organizes long‐range chromosomal interactions with the oct4 locus in reprogramming and pluripotency. Cell Stem Cell 2013, 13:36–47.
Zhang, H, Jiao, W, Sun, L, Fan, J, Chen, M, Wang, H, Xu, X, Shen, A, Li, T, Niu, B, et al. Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming. Cell Stem Cell 2013, 13:30–35.
Smith, ZD, Meissner, A. DNA methylation: roles in mammalian development. Nat Rev Genet 2013, 14:204–220.
Pawlak, M, Jaenisch, R. De novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells to a pluripotent state. Genes Dev 2011, 25:1035–1040.
Kohli, RM, Zhang, Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 2013, 502:472–479.
Wang, T, Wu, H, Li, Y, Szulwach, KE, Lin, L, Li, X, Chen, IP, Goldlust, IS, Chamberlain, SJ, Dodd, A, et al. Subtelomeric hotspots of aberrant 5‐hydroxymethylcytosine‐mediated epigenetic modifications during reprogramming to pluripotency. Nat Cell Biol 2013, 15:700–711.
Gao, Y, Chen, J, Li, K, Wu, T, Huang, B, Liu, W, Kou, X, Zhang, Y, Huang, H, Jiang, Y, et al. Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell 2013, 12:453–469.
Chen, J, Guo, L, Zhang, L, Wu, H, Yang, J, Liu, H, Wang, X, Hu, X, Gu, T, Zhou, Z, et al. Vitamin C modulates TET1 function during somatic cell reprogramming. Nat Genet 2013, 45:1504–1509.
Costa, Y, Ding, J, Theunissen, TW, Faiola, F, Hore, TA, Shliaha, PV, Fidalgo, M, Saunders, A, Lawrence, M, Dietmann, S, et al. NANOG‐dependent function of TET1 and TET2 in establishment of pluripotency. Nature 2013, 495:370–374.
Doege, CA, Inoue, K, Yamashita, T, Rhee, DB, Travis, S, Fujita, R, Guarnieri, P, Bhagat, G, Vanti, WB, Shih, A, et al. Early‐stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 2012, 488:652–655.
Hu, X, Zhang, L, Mao, SQ, Li, Z, Chen, J, Zhang, RR, Wu, HP, Gao, J, Guo, F, Liu, W, et al. Tet and TDG mediate DNA demethylation essential for mesenchymal‐to‐epithelial transition in somatic cell reprogramming. Cell Stem Cell 2014, 14:512–522.
Weber, FA, Bartolomei, G, Hottiger, MO, Cinelli, P. Artd1/Parp1 regulates reprogramming by transcriptional regulation of Fgf4 via Sox2 ADP‐ribosylation. Stem Cells 2013, 31:2364–2373.
Gao, F, Kwon, SW, Zhao, Y, Jin, Y. PARP1 poly(ADP‐ribosyl)ates Sox2 to control Sox2 protein levels and FGF4 expression during embryonic stem cell differentiation. J Biol Chem 2009, 284:22263–22273.
Wu, SC, Zhang, Y. Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol 2010, 11:607–620.
Bhutani, N, Brady, JJ, Damian, M, Sacco, A, Corbel, SY, Blau, HM. Reprogramming towards pluripotency requires AID‐dependent DNA demethylation. Nature 2010, 463:1042–1047.
Foshay, KM, Looney, TJ, Chari, S, Mao, FF, Lee, JH, Zhang, L, Fernandes, CJ, Baker, SW, Clift, KL, Gaetz, J, et al. Embryonic stem cells induce pluripotency in somatic cell fusion through biphasic reprogramming. Mol Cell 2012, 46:159–170.
Bhutani, N, Decker, MN, Brady, JJ, Bussat, RT, Burns, DM, Corbel, SY, Blau, HM. A critical role for AID in the initiation of reprogramming to induced pluripotent stem cells. FASEB J 2013, 27:1107–1113.
Kumar, R, DiMenna, L, Schrode, N, Liu, TC, Franck, P, Munoz‐Descalzo, S, Hadjantonakis, AK, Zarrin, AA, Chaudhuri, J, Elemento, O, et al. AID stabilizes stem‐cell phenotype by removing epigenetic memory of pluripotency genes. Nature 2013, 500:89–92.
Habib, O, Habib, G, Do, JT, Moon, SH, Chung, HM. Activation‐induced deaminase‐coupled DNA demethylation is not crucial for the generation of induced pluripotent stem cells. Stem Cells Dev 2014, 23:209–218.
Shimamoto, R, Amano, N, Ichisaka, T, Watanabe, A, Yamanaka, S, Okita, K. Generation and characterization of induced pluripotent stem cells from Aid‐deficient mice. PLoS One 2014, 9:e94735.
Li, Z, Yang, CS, Nakashima, K, Rana, TM. Small RNA‐mediated regulation of iPS cell generation. EMBO J 2011, 30:823–834.
Yang, CS, Li, Z, Rana, TM. microRNAs modulate iPS cell generation. RNA 2011, 17:1451–1460.
Melton, C, Judson, RL, Blelloch, R. Opposing microRNA families regulate self‐renewal in mouse embryonic stem cells. Nature 2010, 463:621–626.
Choi, YJ, Lin, CP, Ho, JJ, He, X, Okada, N, Bu, P, Zhong, Y, Kim, SY, Bennett, MJ, Chen, C, et al. miR‐34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol 2011, 13:1353–1360.
Yang, CS, Rana, TM. Learning the molecular mechanisms of the reprogramming factors: let`s start from microRNAs. Mol Biosyst 2013, 9:10–17.
Unternaehrer, JJ, Zhao, R, Kim, K, Cesana, M, Powers, JT, Ratanasirintrawoot, S, Onder, T, Shibue, T, Weinberg, RA, Daley, GQ. The epithelial‐mesenchymal transition factor SNAIL paradoxically enhances reprogramming. Stem Cell Reports 2014, 3:691–698.
Gingold, JA, Fidalgo, M, Guallar, D, Lau, Z, Sun, Z, Zhou, H, Faiola, F, Huang, X, Lee, DF, Waghray, A, et al. A genome‐wide RNAi screen identifies opposing functions of Snai1 and Snai2 on the Nanog dependency in reprogramming. Mol Cell 2014, 56:140–152.
Pfaff, N, Fiedler, J, Holzmann, A, Schambach, A, Moritz, T, Cantz, T, Thum, T. miRNA screening reveals a new miRNA family stimulating iPS cell generation via regulation of Meox2. EMBO Rep 2011, 12:1153–1159.
Guo, X, Liu, Q, Wang, G, Zhu, S, Gao, L, Hong, W, Chen, Y, Wu, M, Liu, H, Jiang, C, et al. microRNA‐29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming. Cell Res 2013, 23:142–156.
Li, Z, Dang, J, Chang, KY, Rana, TM. MicroRNA‐mediated regulation of extracellular matrix formation modulates somatic cell reprogramming. RNA 2014, 20:1900–1915.
Wang, Y, Baskerville, S, Shenoy, A, Babiarz, JE, Baehner, L, Blelloch, R. Embryonic stem cell‐specific microRNAs regulate the G1‐S transition and promote rapid proliferation. Nat Genet 2008, 40:1478–1483.
Judson, RL, Babiarz, JE, Venere, M, Blelloch, R. Embryonic stem cell‐specific microRNAs promote induced pluripotency. Nat Biotechnol 2009, 27:459–461.
Card, DA, Hebbar, PB, Li, L, Trotter, KW, Komatsu, Y, Mishina, Y, Archer, TK. Oct4/Sox2‐regulated miR‐302 targets cyclin D1 in human embryonic stem cells. Mol Cell Biol 2008, 28:6426–6438.
Huangfu, D, Maehr, R, Guo, W, Eijkelenboom, A, Snitow, M, Chen, AE, Melton, DA. Induction of pluripotent stem cells by defined factors is greatly improved by small‐molecule compounds. Nat Biotechnol 2008, 26:795–797.
Ng, SY, Johnson, R, Stanton, LW. Human long non‐coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors. EMBO J 2012, 31:522–533.
Flynn, RA, Chang, HY. Long noncoding RNAs in cell‐fate programming and reprogramming. Cell Stem Cell 2014, 14:752–761.
Loewer, S, Cabili, MN, Guttman, M, Loh, YH, Thomas, K, Park, IH, Garber, M, Curran, M, Onder, T, Agarwal, S, et al. Large intergenic non‐coding RNA‐RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet 2010, 42:1113–1117.
Kim, DH, Marinov, GK, Pepke, S, Singer, ZS, He, P, Williams, B, Schroth, GP, Elowitz, MB, Wold, BJ. Single‐cell transcriptome analysis reveals dynamic changes in lncRNA expression during reprogramming. Cell Stem Cell 2015, 16:88–101.
Dreesen, O, Brivanlou, AH. Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev 2007, 3:7–17.
Ying, QL, Wray, J, Nichols, J, Batlle‐Morera, L, Doble, B, Woodgett, J, Cohen, P, Smith, A. The ground state of embryonic stem cell self‐renewal. Nature 2008, 453:519–523.
Shi, Y, Do, JT, Desponts, C, Hahm, HS, Scholer, HR, Ding, S. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2008, 2:525–528.
Marson, A, Foreman, R, Chevalier, B, Bilodeau, S, Kahn, M, Young, RA, Jaenisch, R. Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell 2008, 3:132–135.
Li, W, Zhou, H, Abujarour, R, Zhu, S, Young Joo, J, Lin, T, Hao, E, Scholer, HR, Hayek, A, Ding, S. Generation of human‐induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells 2009, 27:2992–3000.
Cole, MF, Johnstone, SE, Newman, JJ, Kagey, MH, Young, RA. Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev 2008, 22:746–755.
Marucci, L, Pedone, E, Di Vicino, U, Sanuy‐Escribano, B, Isalan, M, Cosma, MP. β‐Catenin fluctuates in mouse ESCs and is essential for Nanog‐mediated reprogramming of somatic cells to pluripotency. Cell Rep 2014, 8:1686–1696.
Silva, J, Barrandon, O, Nichols, J, Kawaguchi, J, Theunissen, TW, Smith, A. Promotion of reprogramming to ground state pluripotency by signal inhibition. PLoS Biol 2008, 6:e253.
Yang, J, van Oosten, AL, Theunissen, TW, Guo, G, Silva, JC, Smith, A. Stat3 activation is limiting for reprogramming to ground state pluripotency. Cell Stem Cell 2010, 7:319–328.
Chan, YS, Goke, J, Ng, JH, Lu, X, Gonzales, KA, Tan, CP, Tng, WQ, Hong, ZZ, Lim, YS, Ng, HH. Induction of a human pluripotent state with distinct regulatory circuitry that resembles preimplantation epiblast. Cell Stem Cell 2013, 13:663–675.
Gafni, O, Weinberger, L, Mansour, AA, Manor, YS, Chomsky, E, Ben‐Yosef, D, Kalma, Y, Viukov, S, Maza, I, Zviran, A, et al. Derivation of novel human ground state naive pluripotent stem cells. Nature 2013, 504:282–286.
Hanna, J, Cheng, AW, Saha, K, Kim, J, Lengner, CJ, Soldner, F, Cassady, JP, Muffat, J, Carey, BW, Jaenisch, R. Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc Natl Acad Sci USA 2010, 107:9222–9227.
Takashima, Y, Guo, G, Loos, R, Nichols, J, Ficz, G, Krueger, F, Oxley, D, Santos, F, Clarke, J, Mansfield, W, et al. Resetting transcription factor control circuitry toward ground‐state pluripotency in human. Cell 2014, 158:1254–1269.
Theunissen, TW, Powell, BE, Wang, H, Mitalipova, M, Faddah, DA, Reddy, J, Fan, ZP, Maetzel, D, Ganz, K, Shi, L, et al. Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell 2014, 15:471–487.
Ware, CB, Nelson, AM, Mecham, B, Hesson, J, Zhou, W, Jonlin, EC, Jimenez‐Caliani, AJ, Deng, X, Cavanaugh, C, Cook, S, et al. Derivation of naive human embryonic stem cells. Proc Natl Acad Sci USA 2014, 111:4484–4489.
Wang, Y, Adjaye, J. A cyclic AMP analog, 8‐Br‐cAMP, enhances the induction of pluripotency in human fibroblast cells. Stem Cell Rev 2011, 7:331–341.
Liao, J, Marumoto, T, Yamaguchi, S, Okano, S, Takeda, N, Sakamoto, C, Kawano, H, Nii, T, Miyamato, S, Nagai, Y, et al. Inhibition of PTEN tumor suppressor promotes the generation of induced pluripotent stem cells. Mol Ther 2013, 21:1242–1250.
Lian, I, Kim, J, Okazawa, H, Zhao, J, Zhao, B, Yu, J, Chinnaiyan, A, Israel, MA, Goldstein, LS, Abujarour, R, et al. The role of YAP transcription coactivator in regulating stem cell self‐renewal and differentiation. Genes Dev 2010, 24:1106–1118.
Staerk, J, Lyssiotis, CA, Medeiro, LA, Bollong, M, Foreman, RK, Zhu, S, Garcia, M, Gao, Q, Bouchez, LC, Lairson, LL, et al. Pan‐Src family kinase inhibitors replace Sox2 during the direct reprogramming of somatic cells. Angew Chem Int Ed Engl 2011, 50:5734–5736.
Ichida, JK, Tcw, J, Williams, LA, Carter, AC, Shi, Y, Moura, MT, Ziller, M, Singh, S, Amabile, G, Bock, C, et al. Notch inhibition allows oncogene‐independent generation of iPS cells. Nat Chem Biol 2014, 10:632–639.
Maherali, N, Hochedlinger, K. Tgfβ signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Curr Biol 2009, 19:1718–1723.
Ichida, JK, Blanchard, J, Lam, K, Son, EY, Chung, JE, Egli, D, Loh, KM, Carter, AC, Di Giorgio, FP, Koszka, K, et al. A small‐molecule inhibitor of tgf‐β signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell 2009, 5:491–503.
Zhang, Y, Li, W, Laurent, T, Ding, S. Small molecules, big roles—the chemical manipulation of stem cell fate and somatic cell reprogramming. J Cell Sci 2012, 125:5609–5620.
Hou, P, Li, Y, Zhang, X, Liu, C, Guan, J, Li, H, Zhao, T, Ye, J, Yang, W, Liu, K, et al. Pluripotent stem cells induced from mouse somatic cells by small‐molecule compounds. Science 2013, 341:651–654.
Vidal, SE, Amlani, B, Chen, T, Tsirigos, A, Stadtfeld, M. Combinatorial modulation of signaling pathways reveals cell‐type‐specific requirements for highly efficient and synchronous iPSC reprogramming. Stem Cell Reports 2014, 3:574–584.
Ho, R, Papp, B, Hoffman, JA, Merrill, BJ, Plath, K. Stage‐specific regulation of reprogramming to induced pluripotent stem cells by Wnt signaling and T cell factor proteins. Cell Rep 2013, 3:2113–2126.
Michael, D, Oren, M. The p53‐Mdm2 module and the ubiquitin system. Semin Cancer Biol 2003, 13:49–58.
Spike, BT, Wahl, GM. p53, stem cells, and reprogramming: tumor suppression beyond guarding the genome. Genes Cancer 2011, 2:404–419.
Hong, H, Takahashi, K, Ichisaka, T, Aoi, T, Kanagawa, O, Nakagawa, M, Okita, K, Yamanaka, S. Suppression of induced pluripotent stem cell generation by the p53‐p21 pathway. Nature 2009, 460:1132–1135.
Kawamura, T, Suzuki, J, Wang, YV, Menendez, S, Morera, LB, Raya, A, Wahl, GM, Izpisua Belmonte, JC. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 2009, 460:1140–1144.
Utikal, J, Polo, JM, Stadtfeld, M, Maherali, N, Kulalert, W, Walsh, RM, Khalil, A, Rheinwald, JG, Hochedlinger, K. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 2009, 460:1145–1148.
Banito, A, Rashid, ST, Acosta, JC, Li, S, Pereira, CF, Geti, I, Pinho, S, Silva, JC, Azuara, V, Walsh, M, et al. Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev 2009, 23:2134–2139.
Marion, RM, Strati, K, Li, H, Tejera, A, Schoeftner, S, Ortega, S, Serrano, M, Blasco, MA. Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 2009, 4:141–154.
Kim, WY, Sharpless, NE. The regulation of INK4/ARF in cancer and aging. Cell 2006, 127:265–275.
Li, H, Collado, M, Villasante, A, Strati, K, Ortega, S, Canamero, M, Blasco, MA, Serrano, M. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 2009, 460:1136–1139.
Kareta, MS, Gorges, LL, Hafeez, S, Benayoun, BA, Marro, S, Zmoos, AF, Cecchini, MJ, Spacek, D, Batista, LF, O`Brien, M, et al. Inhibition of pluripotency networks by the rb tumor suppressor restricts reprogramming and tumorigenesis. Cell Stem Cell 2015, 16:39–50.
Fukawatase, Y, Toyoda, M, Okamura, K, Nakamura, K, Nakabayashi, K, Takada, S, Yamazaki‐Inoue, M, Masuda, A, Nasu, M, Hata, K, et al. Ataxia telangiectasia derived iPS cells show preserved x‐ray sensitivity and decreased chromosomal instability. Sci Rep 2014, 4:5421.
Kinoshita, T, Nagamatsu, G, Kosaka, T, Takubo, K, Hotta, A, Ellis, J, Suda, T. Ataxia‐telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells. Biochem Biophys Res Commun 2011, 407:321–326.
Soyombo, AA, Wu, Y, Kolski, L, Rios, JJ, Rakheja, D, Chen, A, Kehler, J, Hampel, H, Coughran, A, Ross, TS. Analysis of induced pluripotent stem cells from a BRCA1 mutant family. Stem Cell Reports 2013, 1:336–349.
Raya, A, Rodriguez‐Piza, I, Guenechea, G, Vassena, R, Navarro, S, Barrero, MJ, Consiglio, A, Castella, M, Rio, P, Sleep, E, et al. Disease‐corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 2009, 460:53–59.
Rio, P, Banos, R, Lombardo, A, Quintana‐Bustamante, O, Alvarez, L, Garate, Z, Genovese, P, Almarza, E, Valeri, A, Diez, B, et al. Targeted gene therapy and cell reprogramming in Fanconi anemia. EMBO Mol Med 2014, 6:835–848.
Yung, SK, Tilgner, K, Ledran, MH, Habibollah, S, Neganova, I, Singhapol, C, Saretzki, G, Stojkovic, M, Armstrong, L, Przyborski, S, et al. Brief report: human pluripotent stem cell models of fanconi anemia deficiency reveal an important role for fanconi anemia proteins in cellular reprogramming and survival of hematopoietic progenitors. Stem Cells 2013, 31:1022–1029.
Liu, GH, Suzuki, K, Li, M, Qu, J, Montserrat, N, Tarantino, C, Gu, Y, Yi, F, Xu, X, Zhang, W, et al. Modelling Fanconi anemia pathogenesis and therapeutics using integration‐free patient‐derived iPSCs. Nat Commun 2014, 5:4330.
Tilgner, K, Neganova, I, Moreno‐Gimeno, I, Al‐Aama, JY, Burks, D, Yung, S, Singhapol, C, Saretzki, G, Evans, J, Gorbunova, V, et al. A human iPSC model of Ligase IV deficiency reveals an important role for NHEJ‐mediated‐DSB repair in the survival and genomic stability of induced pluripotent stem cells and emerging haematopoietic progenitors. Cell Death Differ 2013, 20:1089–1100.
Molina‐Estevez, FJ, Lozano, ML, Navarro, S, Torres, Y, Grabundzija, I, Ivics, Z, Samper, E, Bueren, JA, Guenechea, G. Brief report: impaired cell reprogramming in nonhomologous end joining deficient cells. Stem Cells 2013, 31:1726–1730.
Suva, ML, Riggi, N, Bernstein, BE. Epigenetic reprogramming in cancer. Science 2013, 339:1567–1570.
Mohyeldin, A, Garzon‐Muvdi, T, Quinones‐Hinojosa, A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 2010, 7:150–161.
Yoshida, Y, Takahashi, K, Okita, K, Ichisaka, T, Yamanaka, S. Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 2009, 5:237–241.
Zhu, S, Li, W, Zhou, H, Wei, W, Ambasudhan, R, Lin, T, Kim, J, Zhang, K, Ding, S. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 2010, 7:651–655.
Gustafsson, MV, Zheng, X, Pereira, T, Gradin, K, Jin, S, Lundkvist, J, Ruas, JL, Poellinger, L, Lendahl, U, Bondesson, M. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 2005, 9:617–628.
Covello, KL, Kehler, J, Yu, H, Gordan, JD, Arsham, AM, Hu, CJ, Labosky, PA, Simon, MC, Keith, B. HIF‐2alpha regulates Oct‐4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 2006, 20:557–570.
Esteban, MA, Wang, T, Qin, B, Yang, J, Qin, D, Cai, J, Li, W, Weng, Z, Chen, J, Ni, S, et al. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 2010, 6:71–79.
Stadtfeld, M, Apostolou, E, Ferrari, F, Choi, J, Walsh, RM, Chen, T, Ooi, SS, Kim, SY, Bestor, TH, Shioda, T, et al. Ascorbic acid prevents loss of Dlk1‐Dio3 imprinting and facilitates generation of all‐iPS cell mice from terminally differentiated B cells. Nat Genet 2012, 44:398–405, S391‐392.
González, F, Boue, S, Izpisua Belmonte, JC. Methods for making induced pluripotent stem cells: reprogramming a la carte. Nat Rev Genet 2011, 12:231–242.
Liang, G, Zhang, Y. Genetic and epigenetic variations in iPSCs: potential causes and implications for application. Cell Stem Cell 2013, 13:149–159.
Wu, SM, Hochedlinger, K. Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nat Cell Biol 2011, 13:497–505.
Sullivan, GJ, Bai, Y, Fletcher, J, Wilmut, I. Induced pluripotent stem cells: epigenetic memories and practical implications. Mol Hum Reprod 2010, 16:880–885.
Johannesson, B, Sagi, I, Gore, A, Paull, D, Yamada, M, Golan‐Lev, T, Li, Z, LeDuc, C, Shen, Y, Stern, S, et al. Comparable frequencies of coding mutations and loss of imprinting in human pluripotent cells derived by nuclear transfer and defined factors. Cell Stem Cell 2014, 15:634–642.
Ma, H, Morey, R, O`Neil, RC, He, Y, Daughtry, B, Schultz, MD, Hariharan, M, Nery, JR, Castanon, R, Sabatini, K, et al. Abnormalities in human pluripotent cells due to reprogramming mechanisms. Nature 2014, 511:177–183.

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