Semin Reprod Med 2013; 31(01): 082-094
DOI: 10.1055/s-0032-1331802
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Dedifferentiation, Transdifferentiation, and Reprogramming: Future Directions in Regenerative Medicine

Cristina Eguizabal
1   Center for Regenerative Medicine in Barcelona
,
Nuria Montserrat
1   Center for Regenerative Medicine in Barcelona
,
Anna Veiga
1   Center for Regenerative Medicine in Barcelona
2   Reproductive Medicine Service, Institut Universitari Dexeus, Barcelona, Spain
,
Juan Carlos Izpisua Belmonte
1   Center for Regenerative Medicine in Barcelona
3   Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California
› Author Affiliations
Further Information

Publication History

Publication Date:
17 January 2013 (online)

Abstract

The main goal of regenerative medicine is to replace damaged tissue. To do this it is necessary to understand in detail the whole regeneration process including differentiated cells that can be converted into progenitor cells (dedifferentiation), cells that can switch into another cell type (transdifferentiation), and somatic cells that can be induced to become pluripotent cells (reprogramming). By studying the regenerative processes in both nonmammal and mammal models, natural or artificial processes could underscore the molecular and cellular mechanisms behind these phenomena and be used to create future regenerative strategies for humans.

 
  • References

  • 1 Waddington CH. The Strategy of the Genes. London, UK: Allen & Unwin; 1957
  • 2 Hochedlinger K, Plath K. Epigenetic reprogramming and induced pluripotency. Development 2009; 136 (4) 509-523
  • 3 Steeves TA, Sussex IM. Patterns in Plant Development. Cambridge, UK: Cambridge University Press; 1989
  • 4 Sugimoto K, Gordon SP, Meyerowitz EM. Regeneration in plants and animals: dedifferentiation, transdifferentiation, or just differentiation?. Trends Cell Biol 2011; 21 (4) 212-218
  • 5 Atta R, Laurens L, Boucheron-Dubuisson E , et al. Pluripotency of Arabidopsis xylem pericycle underlies shoot regeneration from root and hypocotyl explants grown in vitro. Plant J 2009; 57 (4) 626-644
  • 6 Knopf F, Hammond C, Chekuru A , et al. Bone regenerates via dedifferentiation of osteoblasts in the zebrafish fin. Dev Cell 2011; 20 (5) 713-724
  • 7 Nakashima K, Zhou X, Kunkel G , et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 2002; 108 (1) 17-29
  • 8 Komori T, Yagi H, Nomura S , et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997; 89 (5) 755-764
  • 9 Gavaia PJ, Simes DC, Ortiz-Delgado JB , et al. Osteocalcin and matrix Gla protein in zebrafish (Danio rerio) and Senegal sole (Solea senegalensis): comparative gene and protein expression during larval development through adulthood. Gene Expr Patterns 2006; 6 (6) 637-652
  • 10 Jopling C, Sleep E, Raya M, Martí M, Raya A, Izpisúa Belmonte JC. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 2010; 464 (7288) 606-609
  • 11 Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science 2002; 298 (5601) 2188-2190
  • 12 Raya A, Koth CM, Büscher D , et al. Activation of Notch signaling pathway precedes heart regeneration in zebrafish. Proc Natl Acad Sci U S A 2003; 100 (Suppl. 01) 11889-11895
  • 13 Jopling C, Boue S, Izpisua Belmonte JC. Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat Rev Mol Cell Biol 2011; 12 (2) 79-89
  • 14 Kikuchi K, Holdway JE, Werdich AA , et al. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature 2010; 464 (7288) 601-605
  • 15 Kragl M, Knapp D, Nacu E , et al. Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature 2009; 460 (7251) 60-65
  • 16 Echeverri K, Clarke JD, Tanaka EM. In vivo imaging indicates muscle fiber dedifferentiation is a major contributor to the regenerating tail blastema. Dev Biol 2001; 236 (1) 151-164
  • 17 Hay ED. Microscopic observations on muscle dedifferentiation in regenerating Amblystoma limbs. Dev Biol 1959; 1: 555-585
  • 18 Hay ED, Fischman DA. Origin of the blastema in regenerating limbs of the newt Triturus viridescens. An autoradiographic study using tritiated thymidine to follow cell proliferation and migration. Dev Biol 1961; 3: 26-59
  • 19 Odelberg SJ, Kollhoff A, Keating MT. Dedifferentiation of mammalian myotubes induced by msx1. Cell 2000; 103 (7) 1099-1109
  • 20 Harvey K, Tapon N. The Salvador-Warts-Hippo pathway—an emerging tumour-suppressor network. Nat Rev Cancer 2007; 7 (3) 182-191
  • 21 Nicolay BN, Bayarmagnai B, Moon NS, Benevolenskaya EV, Frolov MV. Combined inactivation of pRB and hippo pathways induces dedifferentiation in the Drosophila retina. PLoS Genet 2010; 6 (4) e1000918
  • 22 Chen ZL, Yu WM, Strickland S. Peripheral regeneration. Annu Rev Neurosci 2007; 30: 209-233
  • 23 Mirsky R, Woodhoo A, Parkinson DB, Arthur-Farraj P, Bhaskaran A, Jessen KR. Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation. J Peripher Nerv Syst 2008; 13 (2) 122-135
  • 24 Woodhoo A, Alonso MB, Droggiti A , et al. Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat Neurosci 2009; 12 (7) 839-847
  • 25 McGann CJ, Odelberg SJ, Keating MT. Mammalian myotube dedifferentiation induced by newt regeneration extract. Proc Natl Acad Sci U S A 2001; 98 (24) 13699-13704
  • 26 Suzuki K, Mitsutake N, Saenko V , et al. Dedifferentiation of human primary thyrocytes into multilineage progenitor cells without gene introduction. PLoS ONE 2011; 6 (4) e19354
  • 27 Sun X, Fu X, Han W, Zhao Y, Liu H, Sheng Z. Dedifferentiation of human terminally differentiating keratinocytes into their precursor cells induced by basic fibroblast growth factor. Biol Pharm Bull 2011; 34 (7) 1037-1045
  • 28 Hanley SC, Assouline-Thomas B, Makhlin J, Rosenberg L. Epidermal growth factor induces adult human islet cell dedifferentiation. J Endocrinol 2011; 211 (3) 231-239
  • 29 Shen JF, Sugawara A, Yamashita J, Ogura H, Sato S. Dedifferentiated fat cells: an alternative source of adult multipotent cells from the adipose tissues. Int J Oral Sci 2011; 3 (3) 117-124
  • 30 Bicknell KA, Coxon CH, Brooks G. Can the cardiomyocyte cell cycle be reprogrammed?. J Mol Cell Cardiol 2007; 42 (4) 706-721
  • 31 Lee J, Hong F, Kwon S , et al. Activation of p38 MAPK induces cell cycle arrest via inhibition of Raf/ERK pathway during muscle differentiation. Biochem Biophys Res Commun 2002; 298 (5) 765-771
  • 32 Engel FB, Schebesta M, Duong MT , et al. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev 2005; 19 (10) 1175-1187
  • 33 Rumyantsev PP. Interrelations of the proliferation and differentiation processes during cardiac myogenesis and regeneration. Int Rev Cytol 1977; 51: 186-273
  • 34 Gassmann M, Casagranda F, Orioli D , et al. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 1995; 378 (6555) 390-394
  • 35 Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 1995; 378 (6555) 394-398
  • 36 Meyer D, Birchmeier C. Multiple essential functions of neuregulin in development. Nature 1995; 378 (6555) 386-390
  • 37 Okada TS. Transdifferentiation: Flexibility in Cell Differentiation. Oxford, UK: Clarendon Press; 1991
  • 38 Tsonis PA, Madhavan M, Tancous EE, Del Rio-Tsonis K. A newt's eye view of lens regeneration. Int J Dev Biol 2004; 48 (8–9) 975-980
  • 39 Thitoff AR, Call MK, Del Rio-Tsonis K, Tsonis PA. Unique expression patterns of the retinoblastoma (Rb) gene in intact and lens regeneration-undergoing newt eyes. Anat Rec A Discov Mol Cell Evol Biol 2003; 271 (1) 185-188
  • 40 Day RC, Beck CW. Transdifferentiation from cornea to lens in Xenopus laevis depends on BMP signalling and involves upregulation of Wnt signalling. BMC Dev Biol 2011; 11: 54
  • 41 Schmid V. The potential for transdifferentiation and regeneration of isolated striated muscle of medusae in vitro. Cell Differ 1988; 22 (3) 173-182
  • 42 Galle S, Yanze N, Seipel K. The homeobox gene Msx in development and transdifferentiation of jellyfish striated muscle. Int J Dev Biol 2005; 49 (8) 961-967
  • 43 Patapoutian A, Wold BJ, Wagner RA. Evidence for developmentally programmed transdifferentiation in mouse esophageal muscle. Science 1995; 270 (5243) 1818-1821
  • 44 Wells JM, Melton DA. Vertebrate endoderm development. Annu Rev Cell Dev Biol 1999; 15: 393-410
  • 45 Deutsch G, Jung J, Zheng M, Lóra J, Zaret KS. A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development 2001; 128 (6) 871-881
  • 46 Yang L, Li S, Hatch H , et al. In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci U S A 2002; 99 (12) 8078-8083
  • 47 Meivar-Levy I, Sapir T, Gefen-Halevi S , et al. Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/enhancer-binding protein beta. Hepatology 2007; 46 (3) 898-905
  • 48 Gradwohl G, Dierich A, LeMeur M, Guillemot F. Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A 2000; 97 (4) 1607-1611
  • 49 Bernardo AS, Hay CW, Docherty K. Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic beta cell. Mol Cell Endocrinol 2008; 294 (1–2) 1-9
  • 50 Kataoka K, Han SI, Shioda S, Hirai M, Nishizawa M, Handa H. MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene. J Biol Chem 2002; 277 (51) 49903-49910
  • 51 Thorel F, Népote V, Avril I , et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 2010; 464 (7292) 1149-1154
  • 52 Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell 2004; 117 (5) 663-676
  • 53 Rodriguez-Ubreva J, Ciudad L, Gomez-Cabrero D , et al. Pre-B cell to macrophage transdifferentiation without significant promoter DNA methylation changes. Nucleic Acids Res 2012; 40 (5) 1954-1968
  • 54 Kim J, Efe JA, Zhu S , et al. Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci U S A 2011; 108 (19) 7838-7843
  • 55 Loy B, Apostolova G, Dorn R, McGuire VA, Arthur JS, Dechant G. p38α and p38β mitogen-activated protein kinases determine cholinergic transdifferentiation of sympathetic neurons. J Neurosci 2011; 31 (34) 12059-12067
  • 56 Ieda M, Fu JD, Delgado-Olguin P , et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 2010; 142 (3) 375-386
  • 57 Numasawa Y, Kimura T, Miyoshi S , et al. Treatment of human mesenchymal stem cells with angiotensin receptor blocker improved efficiency of cardiomyogenic transdifferentiation and improved cardiac function via angiogenesis. Stem Cells 2011; 29 (9) 1405-1414
  • 58 Szabo E, Rampalli S, Risueño RM , et al. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 2010; 468 (7323) 521-526
  • 59 Hochedlinger K, Jaenisch R. Nuclear reprogramming and pluripotency. Nature 2006; 441 (7097) 1061-1067
  • 60 Tanaka M, Kihara M, Meczekalski B, King GJ, Adashi EY. H1oo: a pre-embryonic H1 linker histone in search of a function. Mol Cell Endocrinol 2003; 202 (1-2) 5-9
  • 61 Govin J, Escoffier E, Rousseaux S , et al. Pericentric heterochromatin reprogramming by new histone variants during mouse spermiogenesis. J Cell Biol 2007; 176 (3) 283-294
  • 62 Wu F, Caron C, De Robertis C, Khochbin S, Rousseaux S. Testis-specific histone variants H2AL1/2 rapidly disappear from paternal heterochromatin after fertilization. J Reprod Dev 2008; 54 (6) 413-417
  • 63 Arney KL, Bao S, Bannister AJ, Kouzarides T, Surani MA. Histone methylation defines epigenetic asymmetry in the mouse zygote. Int J Dev Biol 2002; 46 (3) 317-320
  • 64 Santos AP, Abranches R, Stoger E, Beven A, Viegas W, Shaw PJ. The architecture of interphase chromosomes and gene positioning are altered by changes in DNA methylation and histone acetylation. J Cell Sci 2002; 115 (Pt 23) 4597-4605
  • 65 Torres-Padilla ME, Bannister AJ, Hurd PJ, Kouzarides T, Zernicka-Goetz M. Dynamic distribution of the replacement histone variant H3.3 in the mouse oocyte and preimplantation embryos. Int J Dev Biol 2006; 50 (5) 455-461
  • 66 van der Heijden GW, Dieker JW, Derijck AA , et al. Asymmetry in histone H3 variants and lysine methylation between paternal and maternal chromatin of the early mouse zygote. Mech Dev 2005; 122 (9) 1008-1022
  • 67 Mayer W, Niveleau A, Walter J, Fundele R, Haaf T. Demethylation of the zygotic paternal genome. Nature 2000; 403 (6769) 501-502
  • 68 Oswald J, Engemann S, Lane N , et al. Active demethylation of the paternal genome in the mouse zygote. Curr Biol 2000; 10 (8) 475-478
  • 69 Hajkova P, Ancelin K, Waldmann T , et al. Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 2008; 452 (7189) 877-881
  • 70 Hajkova P. Epigenetic reprogramming–taking a lesson from the embryo. Curr Opin Cell Biol 2010; 22 (3) 342-350
  • 71 Okamoto I, Otte AP, Allis CD, Reinberg D, Heard E. Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 2004; 303 (5658) 644-649
  • 72 Mak W, Nesterova TB, de Napoles M , et al. Reactivation of the paternal X chromosome in early mouse embryos. Science 2004; 303 (5658) 666-669
  • 73 Kurimoto K, Yamaji M, Seki Y, Saitou M. Specification of the germ cell lineage in mice: a process orchestrated by the PR-domain proteins, Blimp1 and Prdm14. Cell Cycle 2008; 7 (22) 3514-3518
  • 74 de Napoles M, Nesterova T, Brockdorff N. Early loss of Xist RNA expression and inactive X chromosome associated chromatin modification in developing primordial germ cells. PLoS ONE 2007; 2 (9) e860
  • 75 Chuva de Sousa Lopes SM, Hayashi K, Shovlin TC, Mifsud W, Surani MA, McLaren A. X chromosome activity in mouse XX primordial germ cells. PLoS Genet 2008; 4 (2) e30
  • 76 Ancelin K, Lange UC, Hajkova P , et al. Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells. Nat Cell Biol 2006; 8 (6) 623-630
  • 77 Hajkova P, Jeffries SJ, Lee C , et al. Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway. Science 2010; 329 (5987) 78-82
  • 78 Briggs R, King TJ. Transplantation of living nuclei from blastula cells into enucleated frogs' eggs. Proc Natl Acad Sci U S A 1952; 38 (5) 455-463
  • 79 Briggs R, King TJ. Nuclear transplantation studies on the early gastrula (Rana pipiens). I. Nuclei of presumptive endoderm. Dev Biol 1960; 2: 252-270
  • 80 Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol 1962; 10: 622-640
  • 81 Gurdon JB, Uehlinger V. “Fertile” intestine nuclei. Nature 1966; 210 (5042) 1240-1241
  • 82 Wilmut I, Beaujean N, de Sousa PA , et al. Somatic cell nuclear transfer. Nature 2002; 419 (6907) 583-586
  • 83 Eggan K, Baldwin K, Tackett M , et al. Mice cloned from olfactory sensory neurons. Nature 2004; 428 (6978) 44-49
  • 84 Cibelli JB, Stice SL, Golueke PJ , et al. Cloned transgenic calves produced from nonquiescent fetal fibroblasts. Science 1998; 280 (5367) 1256-1258
  • 85 Baguisi A, Behboodi E, Melican DT , et al. Production of goats by somatic cell nuclear transfer. Nat Biotechnol 1999; 17 (5) 456-461
  • 86 Keefer CL, Baldassarre H, Keyston R , et al. Generation of dwarf goat (Capra hircus) clones following nuclear transfer with transfected and nontransfected fetal fibroblasts and in vitro-matured oocytes. Biol Reprod 2001; 64 (3) 849-856
  • 87 Wakayama T, Perry AC, Zuccotti M, Johnson KR, Yanagimachi R. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 1998; 394 (6691) 369-374
  • 88 Betthauser J, Forsberg E, Augenstein M , et al. Production of cloned pigs from in vitro systems. Nat Biotechnol 2000; 18 (10) 1055-1059
  • 89 Polejaeva IA, Chen SH, Vaught TD , et al. Cloned pigs produced by nuclear transfer from adult somatic cells. Nature 2000; 407 (6800) 86-90
  • 90 De Sousa PA, Dobrinsky JR, Zhu J , et al. Somatic cell nuclear transfer in the pig: control of pronuclear formation and integration with improved methods for activation and maintenance of pregnancy. Biol Reprod 2002; 66 (3) 642-650
  • 91 Hochedlinger K, Jaenisch R. Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature 2002; 415 (6875) 1035-1038
  • 92 Meirelles FV, Bordignon V, Watanabe Y , et al. Complete replacement of the mitochondrial genotype in a Bos indicus calf reconstructed by nuclear transfer to a Bos taurus oocyte. Genetics 2001; 158 (1) 351-356
  • 93 Hwang W, Kim K, Jin Y , et al. Interspecies somatic cell nuclear transfer for the production of endangered Korean tiger. Theriogenology 2001; 55: 271
  • 94 Hammer CJ, Tyler HD, Loskutoff NM , et al. Compromised development of calves (Bos gaurus) derived from in vitro-generated embryos and transferred interspecifically into domestic cattle (Bos taurus). Theriogenology 2001; 55 (7) 1447-1455
  • 95 Markoulaki S, Meissner A, Jaenisch R. Somatic cell nuclear transfer and derivation of embryonic stem cells in the mouse. Methods 2008; 45 (2) 101-114
  • 96 Huang Y, Tang X, Xie W , et al. Histone deacetylase inhibitor significantly improved the cloning efficiency of porcine somatic cell nuclear transfer embryos. Cell Reprogram 2011; 13 (6) 513-520
  • 97 Tian J, Song J, Li H , et al. Effect of donor cell type on nuclear remodelling in rabbit somatic cell nuclear transfer embryos. Reprod Domest Anim 2012; 47 (4) 544-552
  • 98 Byrne JA, Pedersen DA, Clepper LL , et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature 2007; 450 (7169) 497-502
  • 99 Kato Y, Tsunoda Y. Role of the donor nuclei in cloning efficiency: can the ooplasm reprogram any nucleus?. Int J Dev Biol 2010; 54 (11–12) 1623-1629
  • 100 Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. Viable offspring derived from fetal and adult mammalian cells. Nature 1997; 385 (6619) 810-813
  • 101 Campbell KH, McWhir J, Ritchie WA, Wilmut I. Sheep cloned by nuclear transfer from a cultured cell line. Nature 1996; 380 (6569) 64-66
  • 102 Kato Y, Tani T, Tsunoda Y. Cloning of calves from various somatic cell types of male and female adult, newborn and fetal cows. J Reprod Fertil 2000; 120 (2) 231-237
  • 103 Kato Y, Imabayashi H, Mori T , et al. Nuclear transfer of adult bone marrow mesenchymal stem cells: developmental totipotency of tissue-specific stem cells from an adult mammal. Biol Reprod 2004; 70 (2) 415-418
  • 104 Sung LY, Gao S, Shen H , et al. Differentiated cells are more efficient than adult stem cells for cloning by somatic cell nuclear transfer. Nat Genet 2006; 38 (11) 1323-1328
  • 105 Yamanaka S, Blau HM. Nuclear reprogramming to a pluripotent state by three approaches. Nature 2010; 465 (7299) 704-712
  • 106 Blau HM, Chiu CP, Webster C. Cytoplasmic activation of human nuclear genes in stable heterocaryons. Cell 1983; 32 (4) 1171-1180
  • 107 Harris H, Watkins JF, Ford CE, Schoefl GI. Artificial heterokaryons of animal cells from different species. J Cell Sci 1966; 1 (1) 1-30
  • 108 Wright WE. Induction of muscle genes in neural cells. J Cell Biol 1984; 98 (2) 427-435
  • 109 Baron MH, Maniatis T. Rapid reprogramming of globin gene expression in transient heterokaryons. Cell 1986; 46 (4) 591-602
  • 110 Spear BT, Tilghman SM. Role of alpha-fetoprotein regulatory elements in transcriptional activation in transient heterokaryons. Mol Cell Biol 1990; 10 (10) 5047-5054
  • 111 Chiu CP, Blau HM. Reprogramming cell differentiation in the absence of DNA synthesis. Cell 1984; 37 (3) 879-887
  • 112 Miller SC, Pavlath GK, Blakely BT, Blau HM. Muscle cell components dictate hepatocyte gene expression and the distribution of the Golgi apparatus in heterokaryons. Genes Dev 1988; 2 (3) 330-340
  • 113 Tada M, Tada T, Lefebvre L, Barton SC, Surani MA. Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. EMBO J 1997; 16 (21) 6510-6520
  • 114 Tada M, Takahama Y, Abe K, Nakatsuji N, Tada T. Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr Biol 2001; 11 (19) 1553-1558
  • 115 Cowan CA, Atienza J, Melton DA, Eggan K. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 2005; 309 (5739) 1369-1373
  • 116 Pereira CF, Terranova R, Ryan NK , et al. Heterokaryon-based reprogramming of human B lymphocytes for pluripotency requires Oct4 but not Sox2. PLoS Genet 2008; 4 (9) e1000170
  • 117 Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 2010; 463 (7284) 1042-1047
  • 118 Agarwal S, Daley GQ. AID for reprogramming. Cell Res 2010; 20 (3) 253-255
  • 119 Durcova-Hills G, Tang F, Doody G, Tooze R, Surani MA. Reprogramming primordial germ cells into pluripotent stem cells. PLoS ONE 2008; 3 (10) e3531
  • 120 Durcova-Hills G, Adams IR, Barton SC, Surani MA, McLaren A. The role of exogenous fibroblast growth factor-2 on the reprogramming of primordial germ cells into pluripotent stem cells. Stem Cells 2006; 24 (6) 1441-1449
  • 121 Youngren KK, Coveney D, Peng X , et al. The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature 2005; 435 (7040) 360-364
  • 122 Muller AJ, Teresky AK, Levine AJ. A male germ cell tumor-susceptibility-determining locus, pgct1, identified on murine chromosome 13. Proc Natl Acad Sci U S A 2000; 97 (15) 8421-8426
  • 123 Kimura T, Tomooka M, Yamano N , et al. AKT signaling promotes derivation of embryonic germ cells from primordial germ cells. Development 2008; 135 (5) 869-879
  • 124 Shamblott MJ, Axelman J, Littlefield JW , et al. Human embryonic germ cell derivatives express a broad range of developmentally distinct markers and proliferate extensively in vitro. Proc Natl Acad Sci U S A 2001; 98 (1) 113-118
  • 125 Shamblott MJ, Axelman J, Wang S , et al. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci U S A 1998; 95 (23) 13726-13731
  • 126 Schneuwly S, Klemenz R, Gehring WJ. Redesigning the body plan of Drosophila by ectopic expression of the homoeotic gene Antennapedia. Nature 1987; 325 (6107) 816-818
  • 127 Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 1987; 51 (6) 987-1000
  • 128 Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126 (4) 663-676
  • 129 Welstead GG, Brambrink T, Jaenisch R. Generating iPS cells from MEFS through forced expression of Sox-2, Oct-4, c-Myc, and Klf4. J Vis Exp 2008; (14)
  • 130 Yamanaka S. Pluripotency and nuclear reprogramming. Philos Trans R Soc Lond B Biol Sci 2008; 363 (1500) 2079-2087
  • 131 Hamilton B, Feng Q, Ye M, Welstead GG. Generation of induced pluripotent stem cells by reprogramming mouse embryonic fibroblasts with a four transcription factor, doxycycline inducible lentiviral transduction system. J Vis Exp 2009; (33)
  • 132 Nakagawa M, Koyanagi M, Tanabe K , et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 2008; 26 (1) 101-106
  • 133 Aasen T, Raya A, Barrero MJ , et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 2008; 26 (11) 1276-1284
  • 134 Giorgetti A, Montserrat N, Rodriguez-Piza I, Azqueta C, Veiga A, Izpisúa Belmonte JC. Generation of induced pluripotent stem cells from human cord blood cells with only two factors: Oct4 and Sox2. Nat Protoc 2010; 5 (4) 811-820
  • 135 González F, Boué S, Izpisúa Belmonte JC. Methods for making induced pluripotent stem cells: reprogramming à la carte. Nat Rev Genet 2011; 12 (4) 231-242
  • 136 Tiscornia G, Vivas EL, Izpisúa Belmonte JC. Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nat Med 2011; 17 (12) 1570-1576