Transitions between epithelial and mesenchymal states during cell fate conversions

Abstract

Cell fate conversion is considered as the changing of one type of cells to another type including somatic cell reprogramming (de-differentiation), differentiation, and trans-differentiation. Epithelial and mesenchymal cells are two major types of cells and the transitions between these two cell states as epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) have been observed during multiple cell fate conversions including embryonic development, tumor progression and somatic cell reprogramming. In addition, MET and sequential EMT-MET during the generation of induced pluripotent stem cells (iPSC) from fibroblasts have been reported recently. Such observation is consistent with multiple rounds of sequential EMT-MET during embryonic development which could be considered as a reversed process of reprogramming at least partially. Therefore in current review, we briefly discussed the potential roles played by EMT, MET, or even sequential EMT-MET during different kinds of cell fate conversions. We also provided some preliminary hypotheses on the mechanisms that connect cell state transitions and cell fate conversions based on results collected from cell cycle, epigenetic regulation, and stemness acquisition.

Keywords

EMT / MET / cell states / cell fate conversion / iPSC generation / trans-differentiation / differentiation

References

[1] Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, Vassena R, Bilic J, Pekarik V, Tiscornia G (2008) Efflcient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol26: 1276-1284

[2] Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B, Solari A, Bobisse S, Rondina MB, Guzzardo V (2009) A Mutant-p53/Smad complex opposes p63 to empower TGFbetainduced metastasis. Cell137: 87-98

[3] Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF(2003) Prospective identiflcation of tumorigenic breast cancer cells. Proc Natl Acad Sci USA100: 3983-3988

[4] Bou Kheir T, Lund AH(2010) Epigenetic dynamics across the cell cycle. Essays Biochem48: 107-120

[5] Brambrink T, Foreman R, Welstead GG, Lengner CJ, Wernig M, Suh H, Jaenisch R(2008) Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell2: 151-159

[6] Brown SE, Fraga MF, Weaver IC, Berdasco M, Szyf M(2007) Variations in DNA methylation patterns during the cell cycle of HeLa cells. Epigenetics2: 54-65

[7] Buganim Y, Faddah DA, Cheng AW, Itskovich E, Markoulaki S, Ganz K, Klemm SL, van Oudenaarden A, Jaenisch R(2012) Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell150: 1209-1222

[8] Chaffer CL, Thompson EW, Williams ED(2007) Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs185: 7-19

[9] Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW, Yu WH, Rehman SK, Hsu JL, Lee HH (2011) p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol13: 317-323

[10] Chen J, Liu J, Han Q, Qin D, Xu J, Chen Y, Yang J, Song H, Yang D, Peng M (2010a) Towards an optimized culture medium for the generation of mouse induced pluripotent stem cells. J Biol Chem285: 31066-31072

[11] Chen T, Yuan D, Wei B, Jiang J, Kang J, Ling K, Gu Y, Li J, Xiao L, Pei G(2010b) E-cadherin-mediated cell-cell contact is critical for induced pluripotent stem cell generation. Stem Cells28: 1315-1325

[12] Chen J, Liu J, Chen Y, Yang J, Chen J, Liu H, Zhao X, Mo K, Song H, Guo L (2011) Rational optimization of reprogramming culture conditions for the generation of induced pluripotent stem cells with ultra-high efflciency and fast kinetics. Cell Res21: 884-894

[13] Chen J, Liu H, Liu J, Qi J, Wei B, Yang J, Liang H, Chen Y, Chen J, Wu Y (2012) H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nature Genet45: 34-42

[14] Chen J, Guo L, Zhang L, Wu H, Yang J, Liu H, Wang X, Hu X, Gu T, Zhou Z (2013) Vitamin C modulates TET1 function during somatic cell reprogramming. Nature Genet45: 1504-1509

[15] Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ, Chang HT, Chen YS, Lin TW, Hsu HS (2010) Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelialmesenchymal transdifferentiation. Cancer Res70: 10433-10444

[16] Cordenonsi M, Dupont S, Maretto S, Insinga A, Imbriano C, Piccolo S(2003) Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads. Cell113: 301-314

[17] Dalerba P, Cho RW, Clarke MF(2007) Cancer stem cells: models and concepts. Ann Rev Med58: 267-284

[18] D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE(2005) Efflcient differentiation of human embryonic stem cells to deflnitive endoderm. Nat Biotechnol23: 1534-1541

[19] Dupont S, Zacchigna L, Adorno M, Soligo S, Volpin D, Piccolo S, Cordenonsi M(2004) Convergence of p53 and TGF-beta signaling networks. Cancer Lett213: 129-138

[20] Eastham AM, Spencer H, Soncin F, Ritson S, Merry CL, Stern PL, Ward CM(2007) Epithelial-mesenchymal transition events during human embryonic stem cell differentiation. Cancer Res67: 11254-11262

[21] Efe JA, Hilcove S, Kim J, Zhou H, Ouyang K, Wang G, Chen J, Ding S(2011) Conversion of mouse flbroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol13: 215-222

[22] Esteban MA, Pei D(2012) Vitamin C improves the quality of somatic cell reprogramming. Nature Genet44: 366-367

[23] Esteban MA, 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 Chem284: 17634-17640

[24] Esteban MA, 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 Cell6: 71-79

[25] Folmes CD, Nelson TJ, Martinez-Fernandez A, Arrell DK, Lindor JZ, Dzeja PP, Ikeda Y, Perez-Terzic C, Terzic A(2011) Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metabol14: 264-271

[26] Franco DL, Mainez J, Vega S, Sancho P, Murillo MM, de Frutos CA, Del Castillo G, Lopez-Blau C, Fabregat I, Nieto MA(2010) Snail1 suppresses TGF-beta-induced apoptosis and is sufflcient to trigger EMT in hepatocytes. J Cell Sci123: 3467-3477

[27] Freire-de-Lima L, Gelfenbeyn K, Ding Y, Mandel U, Clausen H, Handa K, Hakomori SI(2011) Involvement of O-glycosylation deflning oncofetal flbronectin in epithelial-mesenchymal transition process. Proc Natl Acad Sci USA108: 17690-17695

[28] Fu J, Qin L, He T, Qin J, Hong J, Wong J, Liao L, Xu J(2011) The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis. Cell Res21: 275-289

[29] Fujiwara T, Mukhopadhyay T, Cai DW, Morris DK, Roth JA, Grimm EA(1994) Retroviral-mediated transduction of p53 gene increases TGF-beta expression in a human glioblastoma cell line. Int J Cancer J Int du Cancer56: 834-839

[30] Gao Y, Chen J, Li K, Wu T, Huang B, Liu W, Kou X, Zhang Y, Huang H, Jiang Y (2013) Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell12: 453-469

[31] Grabel L(2012) Prospects for pluripotent stem cell therapies: into the clinic and back to the bench. J Cell Biochem113: 381-387

[32] Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA(2007) A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res13: 7003-7011

[33] Gurdon JB(1962a) Adult frogs derived from the nuclei of single somatic cells. Dev Biol4: 256-273

[34] Gurdon JB(1962b) The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exper Morphol10: 622-640

[35] Hanna J, Saha K, Pando B, van Zon J, Lengner CJ, Creyghton MP, van Oudenaarden A, Jaenisch R(2009) Direct cell reprogramming is a stochastic process amenable to acceleration. Nature462: 595-601

[36] Hayashida T, Jinno H, Kitagawa Y, Kitajima M(2011) Cooperation of cancer stem cell properties and epithelial-mesenchymal transition in the establishment of breast cancer metastasis. J Oncol2011: 591427

[37] Horie M, Ito A, Kiyohara T, Kawabe Y, Kamihira M(2010) E-cadherin gene-engineered feeder systems for supporting undifferentiated growth of mouse embryonic stem cells. J Biosci Bioeng110: 582-587

[38] Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K (2013) Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science341: 651-654

[39] Huang P, He Z, Ji S, Sun H, Xiang D, Liu C, Hu Y, Wang X, Hui L(2011) Induction of functional hepatocyte-like cells from mouse flbroblasts by deflned factors. Nature475: 386-389

[40] Hugo HJ, Pereira L, Suryadinata R, Drabsch Y, Gonda TJ, Gunasinghe NP, Pinto C, Soo ET, van Denderen B, Hill P (2013) Direct repression of MYB by ZEB1 suppresses proliferation and epithelial gene expression during epithelial-tomesenchymal transition of breast cancer cells. Breast Cancer Res15: R113

[41] Ichida JK, Blanchard J, Lam K, Son EY, Chung JE, Egli D, Loh KM, Carter AC, Di Giorgio FP, Koszka K (2009) A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell5: 491-503

[42] Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, Srivastava D(2010) Direct reprogramming of flbroblasts into functional cardiomyocytes by deflned factors. Cell142: 375-386

[43] Kannan K, Amariglio N, Rechavi G, Givol D(2000) Proflle of gene expression regulated by induced p53: connection to the TGFbeta family. FEBS Lett470: 77-82

[44] Karpowicz P, Willaime-Morawek S, Balenci L, DeVeale B, Inoue T, van der Kooy D (2009) E-Cadherin regulates neural stem cell self-renewal. J Neurosci29: 3885-3896

[45] Kashyap V, Rezende NC, Scotland KB, Shaffer SM, Persson JL, Gudas LJ, Mongan NP(2009) Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Devel18: 1093-1108

[46] Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Arauzo- Bravo MJ, Ruau D, Han DW, Zenke M (2008) Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature454: 646-650

[47] Kim J, Efe JA, Zhu S, Talantova M, Yuan X, Wang S, Lipton SA, Zhang K, Ding S(2011a) Direct reprogramming of mouse flbroblasts to neural progenitors. Proc Natl Acad Sci USA108: 7838-7843

[48] Kim T, Veronese A, Pichiorri F, Lee TJ, Jeon YJ, Volinia S, Pineau P, Marchio A, Palatini J, Suh SS (2011b) p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J Exper Med208: 875-883

[49] Koche RP, Smith ZD, Adli M, Gu H, Ku M, Gnirke A, Bernstein BE, Meissner A(2011) Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell8: 96-105

[50] Lamouille S, Connolly E, Smyth JW, Akhurst RJ, Derynck R(2012) TGF-beta-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci125: 1259-1273

[51] 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 flbroblasts. Cell Stem Cell7: 51-63

[52] Li B, Zheng YW, Sano Y, Taniguchi H(2011) Evidence for mesenchymal-epithelial transition associated with mouse hepatic stem cell differentiation. PloS one6: e17092

[53] Li L, Bennett SA, Wang L(2012) Role of E-cadherin and other cell adhesion molecules in survival and differentiation of human pluripotent stem cells. Cell Adhesion Migr6: 59-70

[54] Li X, Xu Y, Chen Y, Chen S, Jia X, Sun T, Liu Y, Li X, Xiang R, Li N(2013) SOX2 promotes tumor metastasis by stimulating epithelial-to-mesenchymal transition via regulation of WNT/beta-catenin signal network. Cancer Lett336: 379-389

[55] Liao J, Cui C, Chen S, Ren J, Chen J, Gao Y, Li H, Jia N, Cheng L, iao H (2009) Generation of induced pluripotent stem cell lines from adult rat cells. Cell Stem Cell4: 11-15

[56] Lin Y, Wu Y, Li J, Dong C, Ye X, Chi YI, Evers BM, Zhou BP(2010) The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-speciflc demethylase 1. EMBO J29: 1803-1816

[57] Lin SL, Chang DC, Lin CH, Ying SY, Leu D, Wu DT(2011) Regulation of somatic cell reprogramming through inducible mir-302 expression. Nucleic Acids Res39: 1054-1065

[58] Litvinov SV, Balzar M, Winter MJ, Bakker HA, Briaire-de Bruijn IH, Prins F, Fleuren GJ, Warnaar SO(1997) Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins. J Cell Biol139: 1337-1348

[59] 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 flbroblasts. Cell Stem Cell3: 587-590

[60] Liu YN, Abou-Kheir W, Yin JJ, Fang L, Hynes P, Casey O, Hu D, Wan Y, Seng V, Sheppard-Tillman H (2012) Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor beta-initiated prostate cancer epithelial-mesenchymal transition. Mol Cell Biol32: 941-953

[61] Liu X, Sun H, Qi J, Wang L, He S, Liu J, Feng C, Chen C, Li W, Guo Y (2013a) Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT-MET mechanism for optimal reprogramming. Nat Cell Biol15: 829-838

[62] Liu Y, Mukhopadhyay P, Pisano MM, Lu X, Huang L, Lu Q, Dean DC(2013b) Repression of Zeb1 and hypoxia cause sequential mesenchymal-to-epithelial transition and induction of aid, Oct4, and Dnmt1, leading to immortalization and multipotential reprogramming of flbroblasts in spheres. Stem Cells31: 1350-1362

[63] Maeda M, Johnson KR, Wheelock MJ(2005) Cadherin switching: essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition. J Cell Sci118: 873-887

[64] Maekawa M, Yamaguchi K, Nakamura T, Shibukawa R, Kodanaka I, Ichisaka T, Kawamura Y, Mochizuki H, Goshima N, Yamanaka S(2011) Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1. Nature474: 225-229

[65] Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M (2008) The epithelialmesenchymal transition generates cells with properties of stem cells. Cell133: 704-715

[66] Mansour AA, Gafni O, Weinberger L, Zviran A, Ayyash M, Rais Y, Krupalnik V, Zerbib M, Amann-Zalcenstein D, Maza I (2012) The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature488: 409-413

[67] Marie-Egyptienne DT, Lohse I, Hill RP(2013) Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: potential role of hypoxia. Cancer Lett341: 63-72

[68] Massague J(2008) TGFbeta in Cancer. Cell134: 215-230

[69] McPherson JM(1996) p53/TGF-beta/cancer: an intriguing connection. Cytokine Growth Factor Rev7: 295

[70] Miura M, Miura Y, Padilla-Nash HM, Molinolo AA, Fu B, Patel V, Seo BM, Sonoyama W, Zheng JJ, Baker CC (2006) Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation. Stem Cells24: 1095-1103

[71] Muller LU, Daley GQ, Williams DA(2009) Upping the ante: recent advances in direct reprogramming. Mol Ther17: 947-953

[72] Nakajima Y, Yamagishi T, Hokari S, Nakamura H(2000) Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP). Anat Rec258: 119-127

[73] Nakaya Y, Sheng G(2008) Epithelial to mesenchymal transition during gastrulation: an embryological view. Devel Growth Differ50: 755-766

[74] Neganova I, Lako M(2008) G1 to S phase cell cycle transition in somatic and embryonic stem cells. J Anat213: 30-44

[75] Ni A, Wu MJ, Nakanishi Y, Chavala SH(2013) Facile and efflcient reprogramming of ciliary body epithelial cells into induced pluripotent stem cells. Stem cells and development22: 2543-2550

[76] Nieto MA(2011) The ins and outs of the epithelial to mesenchymal transition in health and disease. Ann Rev Cell Devel Biol27: 347-376

[77] Nishikawa S, Goldstein RA, Nierras CR(2008) The promise of human induced pluripotent stem cells for research and therapy. Nat Rev Mol Cell Biol9: 725-729

[78] Ocana OH, Nieto MA(2008) A new regulatory loop in cancer-cell invasion. EMBO Rep9: 521-522

[79] Pan GJ, Chang ZY, Scholer HR, Pei D(2002) Stem cell pluripotency and transcription factor Oct4. Cell Res12: 321-329

[80] Pan G, Li J, Zhou Y, Zheng H, Pei D(2006) A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal. FASEB J20: 1730-1732

[81] Panman L, Galli A, Lagarde N, Michos O, Soete G, Zuniga A, Zeller R(2006) Differential regulation of gene expression in the digit forming area of the mouse limb bud by SHH and gremlin 1/FGFmediated epithelial-mesenchymal signalling. Development133: 3419-3428

[82] Papp B, Plath K(2012) Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape. Cell Res21: 486-501

[83] Park SM, Gaur AB, Lengyel E, Peter ME(2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev22: 894-907

[84] Peinado H, Olmeda D, Cano A(2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nature Rev Cancer7: 415-428

[85] Polyak K, Weinberg RA(2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature Rev Cancer9: 265-273

[86] Probst AV, Dunleavy E, Almouzni G(2009) Epigenetic inheritance during the cell cycle. Nat Rev Mol Cell Biol10: 192-206

[87] Qiao B, Gopalan V, Chen Z, Smith RA, Tao Q, Lam AK(2012) Epithelial-mesenchymal transition and mesenchymal-epithelial transition are essential for the acquisition of stem cell properties in hTERT-immortalised oral epithelial cells. Biol Cell104: 476-489

[88] Redmer T, Diecke S, Grigoryan T, Quiroga-Negreira A, Birchmeier W, Besser D(2011) E-cadherin is crucial for embryonic stem cell pluripotency and can replace OCT4 during somatic cell reprogramming. EMBO Rep12: 720-726

[89] Robertson KD, Keyomarsi K, Gonzales FA, Velicescu M, Jones PA(2000) Differential mRNA expression of the human DNA methyltransferases (DNMTs) 1, 3a and 3b during the G(0)/G(1) to S phase transition in normal and tumor cells. Nucleic Acids Res28: 2108-2113

[90] Roschke AV, Glebov OK, Lababidi S, Gehlhaus KS, Weinstein JN, Kirsch IR(2008) Chromosomal instability is associated with higher expression of genes implicated in epithelial-mesenchymal transition, cancer invasiveness, and metastasis and with lower expression of genes involved in cell cycle checkpoints, DNA repair, and chromatin maintenance. Neoplasia10: 1222-1230

[91] Ruiz S, Panopoulos AD, Herrerias A, Bissig KD, Lutz M, Berggren WT, Verma IM, Izpisua Belmonte JC (2010) A high proliferation rate is required for cell reprogramming and maintenance of human embryonic stem cell identity. Curr Biol21: 45-52

[92] Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A, Woltjen K, Nagy A, Wrana JL(2010) Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell7: 64-77

[93] Sheng C, Zheng Q, Wu J, Xu Z, Sang L, Wang L, Guo C, Zhu W, Tong M, Liu L (2012a). Generation of dopaminergic neurons directly from mouse flbroblasts and flbroblast-derived neural progenitors. Cell Res

[94] Sheng C, Zheng Q, Wu J, Xu Z, Wang L, Li W, Zhang H, Zhao XY, Liu L, Wang Z (2012b) Direct reprogramming of Sertoli cells into multipotent neural stem cells by deflned factors. Cell Res22: 208-218

[95] Subramanyam D, Lamouille S, Judson RL, Liu JY, Bucay N, Derynck R, Blelloch R(2011) Multiple targets of miR-302 and miR-372 promote reprogramming of human flbroblasts to induced pluripotent stem cells. Nat Biotechnol29: 443-448

[96] Szabo E, Rampalli S, Risueno RM, Schnerch A, Mitchell R, Fiebig-Comyn A, Levadoux-Martin M, Bhatia M(2010) Direct conversion of human flbroblasts to multilineage blood progenitors. Nature468: 521-526

[97] Takahashi K, Yamanaka S(2006) Induction of pluripotent stem cells from mouse embryonic and adult flbroblast cultures by deflned factors. Cell126: 663-676

[98] Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S(2007) Induction of pluripotent stem cells from adult human flbroblasts by deflned factors. Cell131: 861-872

[99] Tan ZJ, Peng Y, Song HL, Zheng JJ, Yu X(2010) N-cadherindependent neuron-neuron interaction is required for the maintenance of activity-induced dendrite growth. Proc Natl Acad Sci USA107: 9873-9878

[100] Termen S, Tan EJ, Heldin CH, Moustakas A(2013) p53 regulates epithelial-mesenchymal transition induced by transforming growth factor beta. J Cell Physiol228: 801-813

[101] Thiery JP(2002) Epithelial-mesenchymal transitions in tumour progression. Nature Rev Cancer2: 442-454

[102] Thiery JP, Acloque H, Huang RY, Nieto MA(2009) Epithelialmesenchymal transitions in development and disease. Cell139: 871-890

[103] Tian X, Liu Z, Niu B, Zhang J, Tan TK, Lee SR, Zhao Y, Harris DC, Zheng G(2011) E-cadherin/beta-catenin complex and the epithelial barrier. J Biomed Biotechnol2011: 567305

[104] Ullmann U, In’t Veld P, Gilles C, Sermon K, De Rycke M, Van de Velde H, Van Steirteghem A, Liebaers I(2007) Epithelialmesenchymal transition process in human embryonic stem cells cultured in feeder-free conditions. Molecular Human Rep13: 21-32

[105] van Roy F, Berx G(2008) The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci65: 3756-3788

[106] Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M(2010) Direct conversion of flbroblasts to functional neurons by deflned factors. Nature463: 1035-1041

[107] Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, Liang J, Sun L, Yang X, Shi L (2009) LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell138: 660-672

[108] Wang Z, Li Y, Kong D, Sarkar FH(2010) The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Curr Drug Targets11: 745-751

[109] Wang Q, Xu X, Li J, Liu J, Gu H, Zhang R, Chen J, Kuang Y, Fei J, Jiang C (2011a) Lithium, an anti-psychotic drug, greatly enhances the generation of induced pluripotent stem cells. Cell Res21: 1424-1435

[110] Wang T, Chen K, Zeng X, Yang J, Wu Y, Shi X, Qin B, Zeng L, Esteban MA, Pan G (2011b) The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-Cdependent manner. Cell Stem Cell9: 575-587

[111] Wang L, Wang L, Huang W, Su H, Xue Y, Su Z, Liao B, Wang H, Bao X, Qin D (2012) Generation of integration-free neural progenitor cells from cells in human urine. Nature Methods10: 84-89

[112] Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A (2010) Highly efflcient reprogramming to pluripotency and directed differentiation of human cells with synthetic modifled mRNA. Cell Stem Cell7: 618-630

[113] Watanabe A, Yamada Y, Yamanaka S(2013) Epigenetic regulation in pluripotent stem cells: a key to breaking the epigenetic barrier. Philos Trans Royal Soc London Ser B Biol Sci368: 20120292

[114] White J, Dalton S(2005) Cell cycle control of embryonic stem cells. Stem Cell Rev1: 131-138

[115] Wu J, Issa JP, Herman J, Bassett DE Jr, Nelkin BD, Baylin SB(1993) Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. Proc Natl Acad Sci USA90: 8891-8895

[116] Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, Teng SC, Wu KJ(2011) Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell43: 811-822

[117] Wu ZQ, Li XY, Hu CY, Ford M, Kleer CG, Weiss SJ(2012) Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression. Proc Natl Acad Sci USA109: 16654-16659

[118] Yang Y, Pan X, Lei W, Wang J, Song J(2006) Transforming growth factor-beta1 induces epithelial-to-mesenchymal transition and apoptosis via a cell cycle-dependent mechanism. Oncogene25: 7235-7244

[119] Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science318: 1917-1920

[120] Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA(2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science324: 797-801

[121] Yu L, Liu S, Guo W, Zhang C, Zhang B, Yan H, Wu Z(2014) hTERT promoter activity identifles osteosarcoma cells with increased EMT characteristics. Oncol Lett7: 239-244

[122] Zhang X, Stappenbeck TS, White AC, Lavine KJ, Gordon JI, Ornitz DM(2006) Reciprocal epithelial-mesenchymal FGF signaling is required for cecal development. Development133: 173-180

[123] Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, Hao J, Guo CL, Ma QW, Wang L (2009) iPS cells produce viable mice through tetraploid complementation. Nature461: 86-90

[124] Zhou C, Nitschke AM, Xiong W, Zhang Q, Tang Y, Bloch M, Elliott S, Zhu Y, Bazzone L, Yu D (2008) Proteomic analysis of tumor necrosis factor-alpha resistant human breast cancer cells reveals a MEK5/Erk5-mediated epithelial-mesenchymal transition phenotype. Breast Cancer Res BCR10: R105

[125] Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, Trauger S, Bien G, Yao S, Zhu Y (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell4: 381-384

[126] Zhou T, Benda C, Duzinger S, Huang Y, Li X, Li Y, Guo X, Cao G, Chen S, Hao L (2011) Generation of Induced Pluripotent Stem Cells from Urine. J Am Soc Nephrol22: 1221-1228

[127] Zhou T, Benda C, Dunzinger S, Huang Y, Ho JC, Yang J, Wang Y, Zhang Y, Zhuang Q, Li Y (2012) Generation of human induced pluripotent stem cells from urine samples. Nature Protoc7: 2080-2089

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