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
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
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
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
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
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
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
Ballas N, Mandel G (2005) The many faces of REST oversee epigenetic programming of neuronal genes. Curr Opin Neurobiol 15:500–506
Batts SA, Raphael Y (2007) Transdifferentiation and its applicability for inner ear therapy. Hearing Res 227:41–47
Bird AP, Wolffe AP (1999) Methylation-induced repression — belts, braces, and chromatin. Cell 99:451–454
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
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
Bracken AP, Helin K (2009) Polycomb group proteins: navigators of lineage pathways led astray in cancer. Cancer 9:773–784
Brockes JP, Kumar A (2002) Plasticity and reprogramming of differentiated cells in amphibian regeneration. Nat Rev Mol Cell Biol 3:566–574
Broelsch CE, Andrea F, Giuliano T, Massimo M (2003) Living donor liver transplantation in adults. Eur J Gastroen Hepat 15:3–6
Burke ZD, Shen CN, Ralphs KL, Tosh D (2006) Characterization of liver function in transdifferentiated hepatocytes. J Cell Physiol 206:147–159
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
Chow RL, Altmann CR, Lang RA, Hemmati-Brivanlou A (1999) Pax6 induces ectopic eye in a vertebrate. Development 126:4213–4222
Cobaleda C, Jochum W, Busslinger M (2007) Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 449:473–477
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
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
Davis RL, Weintraub H, Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:987–1000
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
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
Dolmatov IY (1999) Regeneration in echinoderms. Russ J Mar Biol 25:225–233
Eberhard D, Tosh D (2008) Transdifferentiation and metaplasia as a paradigm for understanding development and disease. Cell Mol Life Sci 65:33–40
Echeverri K, Tanaka EM (2003) Ectoderm to mesoderm lineage switching during axolotl tail regeneration. Science 298:1993–1996
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
Eguchi G (1988) Cellular and molecular background of Wolffian lens regeneration in regulatory mechanisms in developmental process. Cell Differ Dev 25:147–158
Eguchi G (1995) Introduction: transdifferentiation. Semin Cell Biol 6:105–108
Eguchi G, Kodama R (1993) Transdifferentiation. Curr Opin Cell Biol 5:1023–1028
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
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
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
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
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
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
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
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
Garcia-Arraras JE, Greenberg MJ (2001) Visceral regeneration in holothurians. Microsc Res Tech 55:438–451
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
Gehring WJ (1996) The master control gene for morphogenesis and evolution of the eye. Genes Cells 1:11–15
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
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
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
Graf T, Enver T (2009) Forcing cells to change lineages. Nature 462:587–594
Haberal M, Moray G, Bilgin N (1999) The benefits of cadaver-organ transplantation. Transplant Proc 31:3377–3378
Halder G, Callaerts P, Gehring WJ (1995) Induction of ectopic eye by targeted expression of the eyeless gene in Drosophila. Science 267:1788–1792
Horb ME, Shen CN, Tosh D, Slack JMW (2003) Experimental conversion of liver to pancreas. Curr Biol 13:105–115
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
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
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
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
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
Jarriault S, Schwab Y, Greenwald I (2008) A Caenorhabditis elegans model for epithelial–neuronal transdifferentiation. Proc Natl Acad Sci USA 105:3790–3795
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
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
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
Jonsson J, Carlsson L, Edlund T, Edlund H (1994) Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371:606–609
Kablar B, Tajbakhsh S, Rudnicki MA (2000) Transdifferentiation of esophageal smooth to skeletal muscle is myogenic bHLH factor-dependent. Development 127:1627–1639
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
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
Kaye HR, Reiswig HM (1991) Sexual reproduction in four caribbean commercial sponges. III. Larval behavior, settlement and metamorphosis. Invertebr Reprod Dev 19:25–35
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
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
Knoblich JA (1997) Mechanisms of asymmetric cell division during animal development. Curr Opin Cell Biol 9:833–841
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
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
Kondo T (2006) Epigenetic alchemy for cell fate conversion. Curr Opin Gen Dev 16:502–507
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
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
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
Li WC, Horb ME, Tosh D, Slack JMW (2005a) In vitro transdifferentiation of hepatoma cells into functional pancreatic cells. Mech Dev 122:835–847
Li WC, Yu WY, Quinlan JM, Burke ZD, Tosh D (2005b) The molecular basis of transdifferentiation. J Cell Mol Med 9:569–582
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
Liu Y, Rao MS (2003) Transdifferentiation—fact or artifact. J Cell Biochem 88:29–40
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
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
Maccarty WC, Caylor HD (1922) Metaplasia in ovarian dermoids and cystadenomas: report of three cases. Ann Surg 76:238–245
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
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
Mashanov VS, Dolmatov IY, Heinzeller T (2005) Transdifferentiation in holothurian gut regeneration. Biol Bull 209:184–193
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
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
Mitashov VI (2005) Genetic mechanisms of cell transdifferentiation. Russ J Dev Biol 36:240–246
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
Nelson TJ, Behfar A, Terzic A (2008) Stem cells: biologics for regeneration. Clin Pharmacol Ther 84:620–623
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
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
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
Okada TS (1986) Transdifferentiation in animal cells: fact or artifact? Develop Growth Differ 28:213–221
Okada TS (1991) Retinal pigmented epithelial cells transdifferentiate into lens,transdifferentiation: flexibility in cell differentiation. Clarendon Press, Oxford, pp 118–125
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
Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Science 313:1922–1927
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
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
Parker MH, Seale P, Rudnicki MA (2003) Looking back to the embryo: defining transcriptional networks in adult myogenesis. Nat Rev Genet 4:497–507
Patapoutian A, Wold BJ, Wagner RA (1995) Evidence for developmentally programmed transdifferentiation in mouse esophageal muscle. Science 270:1818–1821
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
Rawlins EL, Hogan BL (2006) Epithelial stem cells of the lung: privileged few or opportunities for many? Development 133:2455–2465
Red-Horse K, Ueno H, Weissman IL, Krasnow MA (2010) Coronary arteries form by developmental reprogramming of venous cells. Nature 464:549–553
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
Rishniw M, Xin HB, Deng KY, Kotlikoff MI (2003) Skeletal myogenesis in the mouse esophagus does not occur through transdifferentiation. Genesis 36:81–82
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
Robertson KD, Jones PA (2000) DNA methylation: past, present, and future directions. Carcinogenesis 21:461–467
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
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
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
Schmid V, Reber-Muller S (1995) Transdifferentiation of isolated striated muscle of jellyfish in vitro: the initiation process. Semin Cell Biol 6:109–116
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
Schoenherr CJ, Anderson DJ (1995) Silencing is golden: negative regulation in the control of neuronal gene transcription. Curr Opin Neurobiol 5:566–571
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
Selman K, Kafatos FC (1974) Transdifferentiation in the labial gland of silk moths: is DNA required for cellular metamorphosis? Cell Differ 3:81–94
Shen CN, Slack JM, Tosh D (2000) Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol 2:879–887
Shen CN, Burke ZD, Tosh D (2004) Transdifferentiation, metaplasia and tissue regeneration. Organogenesis 1:36–44
Simon JA, Kingston RE (2009) Mechanisms of polycomb gene silencing: knowns and unknowns. Mol Cell Biol 10:697–708
Slack JMW (1986) Epithelial metaplasia and the second anatomy. Lancet 2:268–271
Slack JMW, Tosh D (2001) Transdifferentiation and metaplasia — switching cell types. Curr Opin Genet Dev 11:581–586
Soltanian S, Matin MM (2011) Cancer stem cells and cancer therapy. Tumor Biol 32:425–440
Sommer L, Rao M (2002) Neural stem cells and regulation of cell number. Prog Neurobiol 66:1–18
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
Sprecher SG, Desplan C (2008) Switch of rhodopsin expression in terminally differentiated Drosophila sensory neurons. Nature 454:533–537
Srivastava D (2006) Making or breaking the heart: from lineage determination to morphogenesis. Cell 126:1037–1048
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
Surani MA (2001) Reprogramming of genome function through epigenetic inheritance. Nature 414:122–128
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
Tada T, Tada M (2001) Toti-/pluripotential stem cells and epigenetic modifications. Cell Struct Funct 26:149–160
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676
Takeuchi JK, Bruneau BG (2009) Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459:708–712
Tang G (2005) siRNA and miRNA: an insight into RISCs. Trends Biochem Sci 30:106–114
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
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
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
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
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
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
Thowfeequ S, Myatt EJ, Tosh D (2007) Transdifferentiation in developmental biology, disease, and in therapy. Dev Dyn 236:3208–3217
Tosh D, Slack JMW (2002) How cells change their phenotype. Nat Rev Mol Cell Biol 3:187–194
Tosh D, Shen CN, Slack JWM (2002) Differentiated properties of hepatocytes induced from pancreatic cells. Hepatology 36:534–543
Tsonis PA, Del Rio-Tsonis K (2004) Lens and retina regeneration: transdifferentiation, stem cells and clinical applications. Exp Eye Res 78:161–172
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
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
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
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
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
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
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
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
Wells JM, Melton DA (1999) Vertebrate endoderm development. Annu Rev Cell Dev Biol 15:393–410
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
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
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
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
Wright ME, Tsai M-J, Aebersold R (2003) Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells. Mol Endocrin 17:1726–1737
Wu J, Grunstein M (2000) 25 Years after the nucleosome model: chromatin modifications. Trends Biochem Sci 25:619–623
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
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
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
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
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
Zaret KS (2008) Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation. Nat Rev Genet 9:329–340
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
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
Zhao T, Zhang Z-N, Rong Z, Xu Y (2011) Immunogenicity of induced pluripotent stem cells. Nature 474:212–215
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
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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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DOI: https://doi.org/10.1007/s00441-012-1403-y