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Transdifferentiation: a cell and molecular reprogramming process

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Abstract

Evidence has emerged recently indicating that differentiation is not entirely a one-way process, and that it is possible to convert one cell type to another, both in vitro and in vivo. This phenomenon is called transdifferentiation, and is generally defined as the stable switch of one cell type to another. Transdifferentiation plays critical roles during development and in regeneration pathways in nature. Although this phenomenon occurs rarely in nature, recent studies have been focused on transdifferentiation and the reprogramming ability of cells to produce specific cells with new phenotypes for use in cell therapy and regenerative medicine. Thus, understanding the principles and the mechanism of this process is important for producing desired cell types. Here some well-documented examples of transdifferentiation, and their significance in development and regeneration are reviewed. In addition, transdifferentiation pathways are considered and their potential molecular mechanisms, especially the role of master switch genes, are considered. Finally, the significance of transdifferentiation in regenerative medicine is discussed.

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References

  • Adams M, Prentice ED, Oki GS (1996) Ethical considerations in informed consent for potential future use of human tissue samples. IRB 18:6–7

    PubMed  Google Scholar 

  • Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H (1998) Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 12:1763–1768

    PubMed  CAS  Google Scholar 

  • Ali AA, Ali MM, Dai D, Sohal GS (1999) Ventrally emigrating neural tube cells differentiate into vascular smooth muscle cells. Gen Pharmacol 33:401–405

    PubMed  CAS  Google Scholar 

  • Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A (2003) Fusion of bone marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968–973

    PubMed  CAS  Google Scholar 

  • Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS (2005) Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans 33:1526–1530

    PubMed  CAS  Google Scholar 

  • Auerbach O, Stout AP, Hammond EC, Garfinkel L (1961) Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N Engl J Med 265:253–267

    PubMed  CAS  Google Scholar 

  • Azuma N, Tadokoro K, Asaka A, Yamada M, Yamaguchi Y, Handa H, Matsushima S, Watanabe T, Kida Y, Ogura T, Torii M, Shimamura K, Nakafuku M (2005) Transdifferentiation of the retinal pigment epithelia to the neural retina by transfer of the Pax6 transcriptional factor. Hum Mol Genet 14:1059–1068

    PubMed  CAS  Google Scholar 

  • Ballas N, Mandel G (2005) The many faces of REST oversee epigenetic programming of neuronal genes. Curr Opin Neurobiol 15:500–506

    PubMed  CAS  Google Scholar 

  • Batts SA, Raphael Y (2007) Transdifferentiation and its applicability for inner ear therapy. Hearing Res 227:41–47

    CAS  Google Scholar 

  • Bird AP, Wolffe AP (1999) Methylation-induced repression — belts, braces, and chromatin. Cell 99:451–454

    PubMed  CAS  Google Scholar 

  • Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL (1999) Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 283:534–537

    PubMed  CAS  Google Scholar 

  • Bonner-Weir S, Inada A, Yatoh S, Li WC, Aye T, Toschi E, Sharma A (2008) Transdifferentiation of pancreatic ductal cells to endocrine β-cells. Biochem Soc Trans 36:353–356

    PubMed  CAS  Google Scholar 

  • Bracken AP, Helin K (2009) Polycomb group proteins: navigators of lineage pathways led astray in cancer. Cancer 9:773–784

    PubMed  CAS  Google Scholar 

  • Brockes JP, Kumar A (2002) Plasticity and reprogramming of differentiated cells in amphibian regeneration. Nat Rev Mol Cell Biol 3:566–574

    PubMed  CAS  Google Scholar 

  • Broelsch CE, Andrea F, Giuliano T, Massimo M (2003) Living donor liver transplantation in adults. Eur J Gastroen Hepat 15:3–6

    Google Scholar 

  • Burke ZD, Shen CN, Ralphs KL, Tosh D (2006) Characterization of liver function in transdifferentiated hepatocytes. J Cell Physiol 206:147–159

    PubMed  CAS  Google Scholar 

  • Chang SJ, Weng SL, Hsieh JY, Wang TY, Chang MD, Wang HW (2011) MicroRNA-34a modulates genes involved in cellular motility and oxidative phosphorylation in neural precursors derived from human umbilical cord mesenchymal stem cells. BMC Med Genomics 4:65

    PubMed  CAS  Google Scholar 

  • Chow RL, Altmann CR, Lang RA, Hemmati-Brivanlou A (1999) Pax6 induces ectopic eye in a vertebrate. Development 126:4213–4222

    PubMed  CAS  Google Scholar 

  • Cobaleda C, Jochum W, Busslinger M (2007) Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 449:473–477

    PubMed  CAS  Google Scholar 

  • Costa RH, Kalinichenko VV, Lim L (2001) Transcription factors in mouse lung development and function. Am J Physiol Lung Cell Mol Physiol 280:L823–L838

    PubMed  CAS  Google Scholar 

  • Crosio C, Heitz E, Allis CD, Borrelli E, Sassone-Corsi P (2003) Chromatin remodelling and neuronal response: multiple signalling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons. J Cell Sci 116:4905–4914

    PubMed  CAS  Google Scholar 

  • Davis RL, Weintraub H, Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:987–1000

    PubMed  CAS  Google Scholar 

  • Del Rio-Tsonis K, Washabaugh CH, Tsonis PA (1995) Expression of Pax-6 during urodele eye development and lens regeneration. Proc Natl Acad Sci USA 92:5092–5096

    PubMed  Google Scholar 

  • Deutsch G, Jung J, Zheng M, Lóra J, Zaret KS (2001) A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development 128:871–881

    PubMed  CAS  Google Scholar 

  • Dolmatov IY (1999) Regeneration in echinoderms. Russ J Mar Biol 25:225–233

    Google Scholar 

  • Eberhard D, Tosh D (2008) Transdifferentiation and metaplasia as a paradigm for understanding development and disease. Cell Mol Life Sci 65:33–40

    PubMed  CAS  Google Scholar 

  • Echeverri K, Tanaka EM (2003) Ectoderm to mesoderm lineage switching during axolotl tail regeneration. Science 298:1993–1996

    Google Scholar 

  • Edalatmanesh MA, Matin MM, Neshati Z, Bahrami AR, Kheirabadi M (2010) Systemic transplantation of mesenchymal stem cells can reduce cognitive and motor deficits in rats with unilateral lesions of the neostriatum. Neurol Res 32:166–172

    PubMed  Google Scholar 

  • Eguchi G (1988) Cellular and molecular background of Wolffian lens regeneration in regulatory mechanisms in developmental process. Cell Differ Dev 25:147–158

    PubMed  CAS  Google Scholar 

  • Eguchi G (1995) Introduction: transdifferentiation. Semin Cell Biol 6:105–108

    Google Scholar 

  • Eguchi G, Kodama R (1993) Transdifferentiation. Curr Opin Cell Biol 5:1023–1028

    PubMed  CAS  Google Scholar 

  • Eguchi G, Okada TS (1973) Differentiation of lens tissue from the progeny of chick retinal pigment cultured in vitro: a demonstration of a switch of cell types in clonal cell culture. Proc Natl Acad Sci USA 70:1495–1499

    PubMed  CAS  Google Scholar 

  • Eguchi G, Abe SI, Watanabe K (1974) Differentiation of lens-like structures from newt iris epithelial cells in vitro. Proc Natl Acad Sci USA 71:5052–5056

    PubMed  CAS  Google Scholar 

  • Enver T, Soneji S, Joshi C, Brown J, Iborra F, Orntoft T, Thykjaer T, Maltby E, Smith K, Abu Dawud R, Jones M, Matin M, Gokhale P, Draper J, Andrews PW (2005) Cellular differentiation hierarchies in normal and culture adapted human embryonic stem cells. Hum Mol Genet 14:3129–3140

    PubMed  CAS  Google Scholar 

  • Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    PubMed  CAS  Google Scholar 

  • Filoni S, Bernardini S, Cannata SM, D’Alessio A (2003) Lens regeneration in larval Xenopus Laevis: experimental analysis of the regenerative capacity during development. Dev Biol 187:13–24

    Google Scholar 

  • Flecknoe S, Harding R, Maritz G, Hooper SB (2000) Increased lung expansion alters the proportions of type I and type II alveolar epithelial cells in fetal sheep. Am J Physiol Lung Cell Mol Physiol 278:L1180–L1185

    PubMed  CAS  Google Scholar 

  • Foster CD, Varghese LS, Skalina RB, Gonzales LW, Guttentag SH (2007) In vitro transdifferentiation of human fetal type II cells toward a type I–like cell. Ped Res 61:404–409

    Google Scholar 

  • Galle S, Yanze N, Seipel K (2005) The homeobox gene Msx in development and transdifferentiation of jellyfish striated muscle. Int J Dev Biol 49:961–967

    PubMed  CAS  Google Scholar 

  • Garcia-Arraras JE, Greenberg MJ (2001) Visceral regeneration in holothurians. Microsc Res Tech 55:438–451

    PubMed  CAS  Google Scholar 

  • Gargioli C, Giambra V, Santoni S, Bernardini S, Frezza D, Filoni S, Cannata SM (2008) The lens-regenerating competence in the outer cornea and epidermis of larval Xenopus laevis is related to pax6 expression. J Anat 212:612–620

    PubMed  CAS  Google Scholar 

  • Gehring WJ (1996) The master control gene for morphogenesis and evolution of the eye. Genes Cells 1:11–15

    PubMed  CAS  Google Scholar 

  • Gettings M, Serman F, Rousset R, Bagnerini P, Almeida L, Noselli S (2010) JNK signalling controls remodelling of the segment boundary through cell reprogramming during drosophila morphogenesis. PLoS Biol 8:e1000390

    PubMed  Google Scholar 

  • Ghosh Z, Huang M, Hu S, Wilson KD, Dey D, Wu JC (2011) Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells. Cancer Res 71:5030–5039

    PubMed  CAS  Google Scholar 

  • Gradwohl G, Dierich A, LeMeur M, Guillemot F (2000) Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA 97:1607–1611

    PubMed  CAS  Google Scholar 

  • Graf T, Enver T (2009) Forcing cells to change lineages. Nature 462:587–594

    PubMed  CAS  Google Scholar 

  • Haberal M, Moray G, Bilgin N (1999) The benefits of cadaver-organ transplantation. Transplant Proc 31:3377–3378

    PubMed  CAS  Google Scholar 

  • Halder G, Callaerts P, Gehring WJ (1995) Induction of ectopic eye by targeted expression of the eyeless gene in Drosophila. Science 267:1788–1792

    PubMed  CAS  Google Scholar 

  • Horb ME, Shen CN, Tosh D, Slack JMW (2003) Experimental conversion of liver to pancreas. Curr Biol 13:105–115

    PubMed  CAS  Google Scholar 

  • Hu E, Tontonoz P, Spiegelman BM (1995) Transdifferentiation of myoblasts by the adipogenic transcription factors PPARγ and C/EBPα. Proc Natl Acad Sci USA 92:9856–9860

    PubMed  CAS  Google Scholar 

  • Ieda M, Fu J-D, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, Srivastava D (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142:375–386

    PubMed  CAS  Google Scholar 

  • Imai J, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Uno K, Hasegawa Y, Gao J, Ishihara H, Sasano H, Mizuguchi H, Asano T, Oka Y (2005) Constitutively active PDX1 induced efficient insulin production in adult murine liver. Biochem Biophys Res Commun 326:402–409

    PubMed  CAS  Google Scholar 

  • Ishibashi M, Ang SL, Shiota K, Nakanishi S, Kageyama R, Guillemot F (1995) Targeted disruption of mammalian hairy and enhancer of split homolog-1 (HES-1) leads to up regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev 9:3136–3148

    PubMed  CAS  Google Scholar 

  • Iwakiri R, Kobayashi K, Okinami S, Kobayashi H (2005) Suppression of Mitf by small interfering RNA induces dedifferentiation of chick embryonic retinal pigment epithelium. Exp Eye Res 81:15–21

    PubMed  CAS  Google Scholar 

  • Jarriault S, Schwab Y, Greenwald I (2008) A Caenorhabditis elegans model for epithelial–neuronal transdifferentiation. Proc Natl Acad Sci USA 105:3790–3795

    PubMed  CAS  Google Scholar 

  • Jenny M, Uhl C, Roche C, Duluc I, Guillermin V, Guillemot F, Jensen J, Kedinger M, Gradwohl G (2002) Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J 21:6338–6347

    PubMed  CAS  Google Scholar 

  • Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, Kageyama R, Guillemot F, Serup P, Madsen OD (2000) Control of endodermal endocrine development by Hes-1. Nat Genet 24:36–44

    PubMed  CAS  Google Scholar 

  • Jiang X, Xu R, Yang Z, Jin P, Xu Q, Li G, Wang W, Liao K, Liu X, Ke Y, Zhang S, Du M, Zou Y, Cai Y, Zeng Y (2008) Experimental study on trace marking and oncogenicity of neural stem cells derive from bone marrow. Cell Mol Neurobiol 28:689–711

    PubMed  Google Scholar 

  • Jonsson J, Carlsson L, Edlund T, Edlund H (1994) Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371:606–609

    PubMed  CAS  Google Scholar 

  • Kablar B, Tajbakhsh S, Rudnicki MA (2000) Transdifferentiation of esophageal smooth to skeletal muscle is myogenic bHLH factor-dependent. Development 127:1627–1639

    PubMed  CAS  Google Scholar 

  • Kaneto H, Nakatani Y, Miyatsuka T, Matsuoka TA, Matsuhisa M, Hori M, Yamasaki Y (2005) PDX1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. Diabetes 54:1009–1022

    PubMed  CAS  Google Scholar 

  • Kawaguchi Y, Cooper B, Gannon M, Ray M, MacDonald RJ, Wright CV (2002) The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet 32:128–134

    PubMed  CAS  Google Scholar 

  • Kaye HR, Reiswig HM (1991) Sexual reproduction in four caribbean commercial sponges. III. Larval behavior, settlement and metamorphosis. Invertebr Reprod Dev 19:25–35

    Google Scholar 

  • Kim J, Efe JA, Zhu S, Talantova M, Yuan X, Wang S, Lipton SA, Zhang K, Ding S (2010) Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci USA 108:7838–7843

    Google Scholar 

  • Kitzmann M, Carnac G, Vandromme M, Primig M, Lamb NJ, Fernandez A (1998) The muscle regulatory factors MyoD and myf-5 undergo distinct cell cycle-specific expression in muscle cells. J Cell Biol 142:1447–1459

    PubMed  CAS  Google Scholar 

  • Knoblich JA (1997) Mechanisms of asymmetric cell division during animal development. Curr Opin Cell Biol 9:833–841

    PubMed  CAS  Google Scholar 

  • Kohyama J, Abe H, Shimazaki T, Koizumi A, Nakashima K, Gojo S, Taga T, Okano H, Hata J, Umezawa A (2001) Brain from bone: efficient “meta-differentiation” of marrow stroma-derived mature osteoblasts to neurons with noggin or a demethylating agent. Differentiation 68:235–244

    PubMed  CAS  Google Scholar 

  • Koizumi M, Doi R, Toyoda E, Tulachan SS, Kami K, Mori T, Ito D, Kawaguchi Y, Fujimoto K, Gittes GK, Imamura M (2004) Hepatic regeneration and enforced PDX1 expression accelerate transdifferentiation in liver. Surgery 136:449–457

    PubMed  Google Scholar 

  • Kondo T (2006) Epigenetic alchemy for cell fate conversion. Curr Opin Gen Dev 16:502–507

    CAS  Google Scholar 

  • Kotton DN, Ma BY, Cardoso WV, Sanderson EA, Summer RS, Williams MC, Fine A (2001) Bone marrow derived cells as progenitors of lung alveolar epithelium. Development 128:5181–5188

    PubMed  CAS  Google Scholar 

  • Kragl M, Knapp D, Nacu E, Khattak S, Maden M, Epperlein HH, Tanaka EM (2009) Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature 460:60–65

    PubMed  CAS  Google Scholar 

  • Lee N, Maurange C, Ringrose L, Paro R (2005) Suppression of polycomb group proteins by JNK signalling induces transdetermination in Drosophila imaginal discs. Nature 438:234–237

    PubMed  CAS  Google Scholar 

  • Li WC, Horb ME, Tosh D, Slack JMW (2005a) In vitro transdifferentiation of hepatoma cells into functional pancreatic cells. Mech Dev 122:835–847

    PubMed  CAS  Google Scholar 

  • Li WC, Yu WY, Quinlan JM, Burke ZD, Tosh D (2005b) The molecular basis of transdifferentiation. J Cell Mol Med 9:569–582

    PubMed  CAS  Google Scholar 

  • Lin JW, Biankin AV, Horb ME, Ghosh B, Prasad NB, Yee NS, Pack MA, Leach SD (2004) Differential requirement for ptf1a in endocrine and exocrine lineages of developing zebrafish pancreas. Dev Biol 270:474–486

    PubMed  CAS  Google Scholar 

  • Liu Y, Rao MS (2003) Transdifferentiation—fact or artifact. J Cell Biochem 88:29–40

    PubMed  CAS  Google Scholar 

  • Liu S, Wang Y, Wang L, Wang N, Li Y, Li H (2010) Transdifferentiation of fibroblasts into adipocyte-like cells by chicken adipogenic transcription factors. Comp Biochem Physiol A Mol Integr Physiol 156:502–508

    PubMed  Google Scholar 

  • Liu Z, Lu CL, Cui LP, Hu YL, Yu Q, Jiang Y, Ma T, Jiao DK, Wang D, Jia CY (2011) MicroRNA-146a modulates TGF-β1-induced phenotypic differentiation in human dermal fibroblasts by targeting SMAD4. Arch Dermatol Res Oct 4 [Epub ahead of print]

  • Lunyak VV, Prefontaine GG, Rosenfeld MG (2004) REST and peace for the neuronal-specific transcriptional program. Ann N Y Acad Sci 1014:110–120

    PubMed  CAS  Google Scholar 

  • Maccarty WC, Caylor HD (1922) Metaplasia in ovarian dermoids and cystadenomas: report of three cases. Ann Surg 76:238–245

    PubMed  CAS  Google Scholar 

  • Mann J, Chu DCK, Maxwell A, Oakley F, Zhu NL, Tsukamoto H, Mann DA (2010) MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138:705–714

    PubMed  CAS  Google Scholar 

  • Marek CJ, Cameron GA, Elrick LJ, Hawksworth GM, Wright MC (2003) Generation of hepatocytes expressing functional cytochromes P450 from a pancreatic progenitor line in vitro. Biochem J 370:763–769

    PubMed  CAS  Google Scholar 

  • Mashanov VS, Dolmatov IY, Heinzeller T (2005) Transdifferentiation in holothurian gut regeneration. Biol Bull 209:184–193

    PubMed  Google Scholar 

  • Maves L, Schubiger G (2003) Transdetermination in Drosophila imaginal discs: a model for understanding pluripotency and selector gene maintenance. Curr Opin Genet Dev 13:472–479

    PubMed  CAS  Google Scholar 

  • Means AL, Meszoely IM, Suzuki K, Miyamoto Y, Rustgi AK, Coffey RJ, Wright CVE, Stoffers DA, Leach SD (2005) Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132:3767–3776

    PubMed  CAS  Google Scholar 

  • Mitashov VI (2005) Genetic mechanisms of cell transdifferentiation. Russ J Dev Biol 36:240–246

    Google Scholar 

  • Mochii M, Mazaki Y, Mizuno N, Hayashi H, Eguchi G (1998) Role of Mitf in differentiation and transdifferentiation of chicken pigmented epithelial cell. Dev Biol 193:47–62

    PubMed  CAS  Google Scholar 

  • Nelson TJ, Behfar A, Terzic A (2008) Stem cells: biologics for regeneration. Clin Pharmacol Ther 84:620–623

    PubMed  CAS  Google Scholar 

  • Neshati Z, Matin MM, Bahrami AR, Moghimi A (2010) Differentiation of mesenchymal stem cells to insulin-producing cells and their impact on type 1 diabetic rats. J Physiol Biochem 66:181–187

    PubMed  CAS  Google Scholar 

  • Nishikawa S, Goldstein RA, Nierras CR (2008) The promise of human induced pluripotent stem cells for research and therapy. Nat Rev Mol Cell Biol 9:725–729

    PubMed  CAS  Google Scholar 

  • Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BL, Wright CV (1996) PDX1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122:983–995

    PubMed  CAS  Google Scholar 

  • Okada TS (1986) Transdifferentiation in animal cells: fact or artifact? Develop Growth Differ 28:213–221

    Google Scholar 

  • Okada TS (1991) Retinal pigmented epithelial cells transdifferentiate into lens,transdifferentiation: flexibility in cell differentiation. Clarendon Press, Oxford, pp 118–125

    Google Scholar 

  • Okura H, Komoda H, Fumimoto Y, Lee CM, Nishida T, Sawa Y, Matsuyama A (2009) Transdifferentiation of human adipose tissue-derived stromal cells into insulin-producing clusters. J Artif Organs 12:123–130

    PubMed  CAS  Google Scholar 

  • Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Science 313:1922–1927

    PubMed  CAS  Google Scholar 

  • Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 98:10344–10349

    PubMed  CAS  Google Scholar 

  • Park K-S, Wells JM, Zorn AM, Wert SE, Laubach VE, Fernandez LG, Whitsett JA (2006) Transdifferentiation of ciliated cells during repair of the respiratory epithelium. Am J Respir Cell Mol Biol 34:151–157

    PubMed  CAS  Google Scholar 

  • Parker MH, Seale P, Rudnicki MA (2003) Looking back to the embryo: defining transcriptional networks in adult myogenesis. Nat Rev Genet 4:497–507

    PubMed  CAS  Google Scholar 

  • Patapoutian A, Wold BJ, Wagner RA (1995) Evidence for developmentally programmed transdifferentiation in mouse esophageal muscle. Science 270:1818–1821

    PubMed  CAS  Google Scholar 

  • Piraino S, Boero F, Aeschbach B, Schmid V (1996) Reversing the life cycle: medusae transforming into polyps and cell transdifferentiation in turritopsis nutricula (Cnidaria, Hydrozoa). Biol Bull 190:302–312

    Google Scholar 

  • Rawlins EL, Hogan BL (2006) Epithelial stem cells of the lung: privileged few or opportunities for many? Development 133:2455–2465

    PubMed  CAS  Google Scholar 

  • Red-Horse K, Ueno H, Weissman IL, Krasnow MA (2010) Coronary arteries form by developmental reprogramming of venous cells. Nature 464:549–553

    PubMed  CAS  Google Scholar 

  • Richard JP, Zuryn S, Fischer N, Pavet V, Vaucamps N, Jarriault S (2011) Direct in vivo cellular reprogramming involves transition through discrete, non-pluripotent steps. Development 138:1483–1492

    PubMed  CAS  Google Scholar 

  • Rishniw M, Xin HB, Deng KY, Kotlikoff MI (2003) Skeletal myogenesis in the mouse esophagus does not occur through transdifferentiation. Genesis 36:81–82

    PubMed  Google Scholar 

  • Roberson DW, Alosi JA, Cotanche DA (2004) Direct transdifferentiation gives rise to the earliest new hair cells in regenerating avian auditory epithelium. J Neurosci Res 78:461–471

    PubMed  CAS  Google Scholar 

  • Robertson KD, Jones PA (2000) DNA methylation: past, present, and future directions. Carcinogenesis 21:461–467

    PubMed  CAS  Google Scholar 

  • Roh J, Cho E, Seong I, Limb J, Lee S, Han S, Kim J (2006) Down regulation of Sox10 with specific small interfering RNA promotes transdifferentiation of Schwannoma cells into myofibroblasts. Differentiation 74:542–551

    PubMed  CAS  Google Scholar 

  • Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, Spiegelman BM (2002) C/EBPα induces adipogenesis through PPARγ: a unified pathway. Genes Dev 16:22–26

    PubMed  CAS  Google Scholar 

  • Sasai Y, Kageyama R, Tagawa Y, Shigemoto R, Nakanishi S (1992) Two mammalian helix–loop–helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev 6:2620–2634

    PubMed  CAS  Google Scholar 

  • Schmid V, Reber-Muller S (1995) Transdifferentiation of isolated striated muscle of jellyfish in vitro: the initiation process. Semin Cell Biol 6:109–116

    PubMed  CAS  Google Scholar 

  • Schmittwolf C, Kirchhof N, Jauch A, Durr M, Harder F, Zenke M, Muller AM (2005) In vivo haematopoietic activity is induced in neurosphere cells by chromatin-modifying agents. EMBO J 24:554–566

    PubMed  CAS  Google Scholar 

  • Schoenherr CJ, Anderson DJ (1995) Silencing is golden: negative regulation in the control of neuronal gene transcription. Curr Opin Neurobiol 5:566–571

    PubMed  CAS  Google Scholar 

  • Schwitzgebel VM, Scheel DW, Conners JR, Kalamaras J, Lee JE, Anderson DJ, Sussel L, Johnson JD, German MS (2000) Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 127:3533–3542

    PubMed  CAS  Google Scholar 

  • Selman K, Kafatos FC (1974) Transdifferentiation in the labial gland of silk moths: is DNA required for cellular metamorphosis? Cell Differ 3:81–94

    PubMed  CAS  Google Scholar 

  • Shen CN, Slack JM, Tosh D (2000) Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol 2:879–887

    PubMed  CAS  Google Scholar 

  • Shen CN, Burke ZD, Tosh D (2004) Transdifferentiation, metaplasia and tissue regeneration. Organogenesis 1:36–44

    PubMed  CAS  Google Scholar 

  • Simon JA, Kingston RE (2009) Mechanisms of polycomb gene silencing: knowns and unknowns. Mol Cell Biol 10:697–708

    CAS  Google Scholar 

  • Slack JMW (1986) Epithelial metaplasia and the second anatomy. Lancet 2:268–271

    PubMed  CAS  Google Scholar 

  • Slack JMW, Tosh D (2001) Transdifferentiation and metaplasia — switching cell types. Curr Opin Genet Dev 11:581–586

    PubMed  CAS  Google Scholar 

  • Soltanian S, Matin MM (2011) Cancer stem cells and cancer therapy. Tumor Biol 32:425–440

    Google Scholar 

  • Sommer L, Rao M (2002) Neural stem cells and regulation of cell number. Prog Neurobiol 66:1–18

    PubMed  CAS  Google Scholar 

  • Sommer L, Ma Q, Anderson DJ (1996) Neurogenins, a novel family of atonal-related bHLH transcription factors, are putative mammalian neuronal determination genes that reveal progenitor cell heterogeneity in the developing CNS and PNS. Mol Cell Neurosci 8:221–241

    PubMed  CAS  Google Scholar 

  • Sprecher SG, Desplan C (2008) Switch of rhodopsin expression in terminally differentiated Drosophila sensory neurons. Nature 454:533–537

    PubMed  CAS  Google Scholar 

  • Srivastava D (2006) Making or breaking the heart: from lineage determination to morphogenesis. Cell 126:1037–1048

    PubMed  CAS  Google Scholar 

  • Sumazaki R, Shiojiri N, Isoyama S, Masu M, Keino-Masu K, Osawa M, Nakauchi H, Kageyama R, Matsui A (2004) Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nat Genet 36:83–87

    PubMed  CAS  Google Scholar 

  • Surani MA (2001) Reprogramming of genome function through epigenetic inheritance. Nature 414:122–128

    PubMed  CAS  Google Scholar 

  • Szabo E, Rampalli S, Risueño RM, Schnerch A, Mitchell R, Fiebig-Comyn A, Levadoux-Martin M, Bhatia M (2010) Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468:521–526

    PubMed  CAS  Google Scholar 

  • Tada T, Tada M (2001) Toti-/pluripotential stem cells and epigenetic modifications. Cell Struct Funct 26:149–160

    PubMed  CAS  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    PubMed  CAS  Google Scholar 

  • Takeuchi JK, Bruneau BG (2009) Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459:708–712

    PubMed  CAS  Google Scholar 

  • Tang G (2005) siRNA and miRNA: an insight into RISCs. Trends Biochem Sci 30:106–114

    PubMed  CAS  Google Scholar 

  • Tang DQ, Cao LZ, Chou W, Shun L, Farag C, Atkinson MA, Li SW, Chang LJ, Yang LJ (2006a) Role of Pax4 in Pdx1-VP16-mediated liver-to-endocrine pancreas transdifferentiation. Lab Invest 86:829–841

    PubMed  CAS  Google Scholar 

  • Tang DQ, Lu S, Sun YP, Rodrigues E, Chou W, Yang C, Cao LZ, Chang LJ, Yang LJ (2006b) Reprogramming liver stem WB cells into functional insulin-producing cells by persistent expression of Pdx1- and Pdx1-VP16 mediated by lentiviral vectors. Lab Invest 86:83–93

    PubMed  CAS  Google Scholar 

  • Tateishi K, He J, Taranova O, Liang G, D’Alessio AC, Zhang Y (2008) Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Bio Chem 283:31601–31607

    CAS  Google Scholar 

  • Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545

    PubMed  CAS  Google Scholar 

  • Theise ND, Badve S, Saxena R, Henegariu O, Sell S, Crawford JM, Krause DS (2000a) Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 31:235–240

    PubMed  CAS  Google Scholar 

  • Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, Henegariu O, Krause DS (2000b) Liver from bone marrow in humans. Hepatology 32:11–16

    PubMed  CAS  Google Scholar 

  • Thowfeequ S, Myatt EJ, Tosh D (2007) Transdifferentiation in developmental biology, disease, and in therapy. Dev Dyn 236:3208–3217

    PubMed  CAS  Google Scholar 

  • Tosh D, Slack JMW (2002) How cells change their phenotype. Nat Rev Mol Cell Biol 3:187–194

    PubMed  CAS  Google Scholar 

  • Tosh D, Shen CN, Slack JWM (2002) Differentiated properties of hepatocytes induced from pancreatic cells. Hepatology 36:534–543

    PubMed  CAS  Google Scholar 

  • Tsonis PA, Del Rio-Tsonis K (2004) Lens and retina regeneration: transdifferentiation, stem cells and clinical applications. Exp Eye Res 78:161–172

    PubMed  CAS  Google Scholar 

  • Tsonis PA, Madhavan M, Tancous EE, Del Rio-Tsonis K (2004) A newt’s eye view of lens regeneration. Int J Dev Biol 48:975–980

    PubMed  Google Scholar 

  • Tsonis PA, Call MK, Grogg MW, Sartor MA, Taylor RR, Forge A, Fyffe R, Goldenberg R, Cowper-Sal-lari R, Tomlinson CR (2007) microRNAs and regeneration: let-7 members as potential regulators of dedifferentiation in lens and inner ear hair cell regeneration of the adult newt. Biochem Biophys Res Commun 362:940–945

    PubMed  CAS  Google Scholar 

  • Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463:1035–1041

    PubMed  CAS  Google Scholar 

  • Wallace K, Marek CJ, Hoppler S, Wright MC (2010) Glucocorticoid-dependent transdifferentiation of pancreatic progenitor cells into hepatocytes is dependent on transient suppression of WNT signalling. J Cell Science 123:2103–2110

    PubMed  CAS  Google Scholar 

  • Wang RY, Shen CN, Lin MH, Tosh D, Shih C (2005) Hepatocyte-like cells transdifferentiated from a pancreatic origin can support replication of hepatitis B virus. J Virol 79:13116–13128

    PubMed  CAS  Google Scholar 

  • Wang Y, Bhaskaran M, Zhang H, Gou Y, Chintagari NR, Liu L (2009) MicroRNA-375 Regulates alveolar epithelial cell transdifferentiation through the Wnt/β-catenin pathway. FASEB J 23:997–6

    Google Scholar 

  • Watanabe Y, Kameoka S, Gopalakrishnan V, Aldape KD, Pan ZZ, Lang FF, Majumder S (2004) Conversion of myoblasts to physiologically active neuronal phenotype. Genes Dev 18:889–900

    PubMed  CAS  Google Scholar 

  • Weintraub H, Tapscott SJ, Davis RL, Thayer MJ, Adam MA, Lassar AB, Miller AD (1989) Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proc Natl Acad Sci USA 86:5434–5438

    PubMed  CAS  Google Scholar 

  • Wells JM, Melton DA (1999) Vertebrate endoderm development. Annu Rev Cell Dev Biol 15:393–410

    PubMed  CAS  Google Scholar 

  • Westmacott A, Burke ZD, Oliver G, Slack JM, Tosh D (2006) C/EBPα and C/EBPβ are markers of early liver development. Int J Dev Biol 50:653–657

    PubMed  CAS  Google Scholar 

  • White PM, Doetzlhofer A, Lee YS, Groves AK, Segil N (2006) Mammalian cochlear supporting cells can divide and transdifferentiate into hair cells. Nature 441:984–987

    PubMed  CAS  Google Scholar 

  • Wolfe-Coote S, Louw J, Woodroof C, Du Toit DF (1996) The nonhuman primate endocrine pancreas: development, regeneration potential and metaplasia. Cell Biol Int 20:95–101

    PubMed  CAS  Google Scholar 

  • Woodbury D, Reynolds K, Black IB (2002) Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J Neurosci Res 69:908–917

    PubMed  CAS  Google Scholar 

  • Wright ME, Tsai M-J, Aebersold R (2003) Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells. Mol Endocrin 17:1726–1737

    CAS  Google Scholar 

  • Wu J, Grunstein M (2000) 25 Years after the nucleosome model: chromatin modifications. Trends Biochem Sci 25:619–623

    PubMed  CAS  Google Scholar 

  • Yañez R, Lamana ML, García-Castro J, Colmenero I, Ramírez M, Bueren JA (2006) Adipose tissue-derived mesenchymal stem cells (AD-MSCS) have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease (GVHD). Stem Cells 24:2582–2591

    PubMed  Google Scholar 

  • Yao Q, Cao S, Li C, Mengesha A, Kong B, Wei M (2011) Micro-RNA-21 regulates TGF-b-induced myofibroblast differentiation by targeting PDCD4 in tumor-stroma interaction. Int J Cancer 128:1783–1792

    PubMed  CAS  Google Scholar 

  • Yechoor V, Liu V, Espiritu C, Paul A, Oka K, Kojima H, Chan L (2009) Neurogenin3 is sufficient for in vivo transdetermination of hepatic progenitor cells into islet-like cells but not transdifferentiation of hepatocytes. Dev Cell 16:358–373

    PubMed  CAS  Google Scholar 

  • Yeh WC, Cao Z, Classon M, McKnight SL (1995) Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev 9:168–181

    PubMed  CAS  Google Scholar 

  • Yoshida S, Kajimoto Y, Yasuda T, Watada H, Fujitani Y, Kosaka H, Gotow T, Miyatsuka T, Umayahara Y, Yamasaki Y, Hori M (2002) PDX1 induces differentiation of intestinal epithelioid IEC-6 into insulin-producing cells. Diabetes 51:2505–2513

    PubMed  CAS  Google Scholar 

  • Zaret KS (2008) Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation. Nat Rev Genet 9:329–340

    PubMed  CAS  Google Scholar 

  • Zhang J, Wilson GF, Soerens AG, Koonce CH, Yu J, Palecek SP, Thomson JA, Kamp TJ (2009) Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 104:e30–e41

    PubMed  CAS  Google Scholar 

  • Zhao R, Watt AJ, Battle MA, Li J, Bondow BJ, Duncan SA (2008) Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in mice. Dev Biol 317:614–619

    PubMed  CAS  Google Scholar 

  • Zhao T, Zhang Z-N, Rong Z, Xu Y (2011) Immunogenicity of induced pluripotent stem cells. Nature 474:212–215

    PubMed  CAS  Google Scholar 

  • Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA (2008) In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature 455:627–633

    PubMed  CAS  Google Scholar 

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  1. Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran, P.O. Box: 9177948974

    Sajjad Sisakhtnezhad & Maryam M. Matin

  2. Cell and Molecular Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran

    Maryam M. Matin

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  1. Sajjad Sisakhtnezhad
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Sisakhtnezhad, S., Matin, M.M. Transdifferentiation: a cell and molecular reprogramming process. Cell Tissue Res 348, 379–396 (2012). https://doi.org/10.1007/s00441-012-1403-y

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