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Induction of Neural Lineages from Mesoderm and Endoderm by Defined Transcription Factors

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Programmed Cells from Basic Neuroscience to Therapy

Part of the book series: Research and Perspectives in Neurosciences ((NEUROSCIENCE,volume 20))

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Abstract

A major interest in developmental biology is the lineage plasticity of specialized cells. We recently generated induced neuronal (iN) cells from fibroblasts and hepatocytes by expression of defined pan-neuronal transcription factors. Moreover, we were able to generate induced neural precursor (iNP) cells following a similar transcription factor-based strategy, suggesting that cell fate plasticity is much wider than previously anticipated. Further studies showed that addition of subtype-specific regulators was sufficient to induce characteristic neuronal subtypes such as dopamine and motor neurons. Here, we review the most recent developments of our own research efforts as well as the relevant findings in the field as they pertain to direct induction of neural lineages. The derivation of neuronal cells from patient fibroblasts holds great promise to uncover human neurological disease mechanisms and to provide a donor source for autologous therapeutic transplantation. Similar to induced pluripotent stem (iPS) cells, much has yet to be learned about iN cells before clinical translation can be realized.

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References

  • Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA, Ding S (2011) Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 9:113–118

    Article  PubMed  CAS  Google Scholar 

  • Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, Gage FH (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473:221–225

    Article  PubMed  CAS  Google Scholar 

  • Caiazzo M, Dell’Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova TD, Menegon A, Roncaglia P, Colciago G, Russo G, Carninci P, Pezzoli G, Gainetdinov RR, Gustincich S, Dityatev A, Broccoli V (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476:224–227

    Article  PubMed  CAS  Google Scholar 

  • Efe JA, Hilcove S, Kim J, Zhou H, Ouyang K, Wang G, Chen J, Ding S (2011) Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nature Cell Biol 13:215–222

    Article  PubMed  CAS  Google Scholar 

  • Gaspard N, Bouschet T, Hourez R, Dimidschstein J, Naeije G, van den Ameele J, Espuny-Camacho I, Herpoel A, Passante L, Schiffmann SN, Gaillard A, Vanderhaeghen P (2008) An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature 455:351–357

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Gurdon JB (2006) From nuclear transfer to nuclear reprogramming: the reversal of cell differentiation. Annu Rev Cell Dev Biol 22:1–22

    Article  PubMed  CAS  Google Scholar 

  • Han DW, Tapia N, Hermann A, Hemmer K, Hoing S, Arauzo-Bravo MJ, Zaehres H, Wu G, Frank S, Moritz S, Greber B, Yang JH, Lee HT, Schwamborn JC, Storch A, Schöler HR (2012) Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell 10:465–472

    Article  PubMed  CAS  Google Scholar 

  • Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, Okita K, Yamanaka S (2009) Suppression of induced pluripotent stem cell generation by the p53–p21 pathway. Nature 460:1132–1135

    Article  PubMed  CAS  Google Scholar 

  • 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 fibroblasts by defined factors. Nature 475:386–389

    Article  PubMed  CAS  Google Scholar 

  • Ieda M, Fu JD, 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

    Article  PubMed  CAS  Google Scholar 

  • Jaenisch R, Young R (2008) Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132:567–582

    Article  PubMed  CAS  Google Scholar 

  • Johnson MA, Weick JP, Pearce RA, Zhang SC (2007) Functional neural development from human embryonic stem cells: accelerated synaptic activity via astrocyte coculture. J Neurosci 27:3069–3077

    Article  PubMed  CAS  Google Scholar 

  • Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, Wahl GM, Izpisua Belmonte JC (2009) Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460:1140–1144

    Article  PubMed  CAS  Google Scholar 

  • Kim J, Efe JA, Zhu S, Talantova M, Yuan X, Wang S, Lipton SA, Zhang K, Ding S (2011a) Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci USA 108:7838–7843

    Article  PubMed  CAS  Google Scholar 

  • Kim J, Su SC, Wang H, Cheng AW, Cassady JP, Lodato MA, Lengner CJ, Chung CY, Dawlaty MM, Tsai LH, Jaenisch R (2011b) Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell 9:413–419

    Article  PubMed  CAS  Google Scholar 

  • Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, Yang L, Beal MF, Surmeier DJ, Kordower JH, Tabar V, Studer L (2011) Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 480:547–551

    PubMed  CAS  Google Scholar 

  • Lee SK, Lee B, Ruiz EC, Pfaff SL (2005) Olig2 and Ngn2 function in opposition to modulate gene expression in motor neuron progenitor cells. Genes Devel 19:282–294

    Article  PubMed  CAS  Google Scholar 

  • Li H, Collado M, Villasante A, Strati K, Ortega S, Canamero M, Blasco MA, Serrano M (2009) The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460:1136–1139

    Article  PubMed  CAS  Google Scholar 

  • Lu QR, Sun T, Zhu Z, Ma N, Garcia M, Stiles CD, Rowitch DH (2002) Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109:75–86

    Article  PubMed  CAS  Google Scholar 

  • Lujan E, Chanda S, Ahlenius H, Sudhof TC, Wernig M (2012) Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc Natl Acad Sci USA 109:2527–2532

    Article  PubMed  CAS  Google Scholar 

  • Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR (2010) A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143:527–39

    Article  PubMed  CAS  Google Scholar 

  • Marion RM, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M, Blasco MA (2009) A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460:1149–1153

    Article  PubMed  CAS  Google Scholar 

  • Marro S, Pang ZP, Yang N, Tsai MC, Qu K, Chang HY, Sudhof TC, Wernig M (2011) Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell 9:374–382

    Article  PubMed  CAS  Google Scholar 

  • Massari ME, Murre C (2000) Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol 20:429–440

    Article  PubMed  CAS  Google Scholar 

  • Mizuguchi R, Sugimori M, Takebayashi H, Kosako H, Nagao M, Yoshida S, Nabeshima Y, Shimamura K, Nakafuku M (2001) Combinatorial roles of olig2 and neurogenin2 in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons. Neuron 31:757–771

    Article  PubMed  CAS  Google Scholar 

  • Nguyen HN, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P, Kee K, Schüle B, Dolmetsch RE, Langston W, Palmer TD, Pera RR (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8:267–280

    Article  PubMed  CAS  Google Scholar 

  • Novitch BG, Chen AI, Jessell TM (2001) Coordinate regulation of motor neuron subtype identity and pan-neuronal properties by the bHLH repressor Olig2. Neuron 31:773–789

    Article  PubMed  CAS  Google Scholar 

  • Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Sudhof TC, Wernig M (2011) Induction of human neuronal cells by defined transcription factors. Nature 476:220–223

    PubMed  CAS  Google Scholar 

  • Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Bjorklund A, Lindvall O, Jakobsson J, Parmar M (2011) Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci USA 108:10343–10348

    Article  PubMed  CAS  Google Scholar 

  • Qiang L, Fujita R, Yamashita T, Angulo S, Rhinn H, Rhee D, Doege C, Chau L, Aubry L, Vanti WB, Moreno H, Abeliovich A (2011) Directed conversion of Alzheimer’s disease patient skin fibroblasts into functional neurons. Cell 146:359–371

    Article  PubMed  CAS  Google Scholar 

  • Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA (2006) Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med 12:1259–1268

    Article  PubMed  CAS  Google Scholar 

  • Sekiya S, Suzuki A (2011) Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475:390–393

    Article  PubMed  CAS  Google Scholar 

  • Son EY, Ichida JK, Wainger BJ, Toma JS, Rafuse VF, Woolf CJ, Eggan K (2011) Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9:205–218

    Article  PubMed  CAS  Google Scholar 

  • Szabo E, Rampalli S, Risueno 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

    Article  PubMed  CAS  Google Scholar 

  • Thier M, Worsdorfer P, Lakes YB, Gorris R, Herms S, Opitz T, Seiferling D, Quandel T, Hoffmann P, Nothen MM, Brüstle O, Edenhofer F (2012) Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell 10:473–479

    Article  PubMed  CAS  Google Scholar 

  • Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, Khalil A, Rheinwald JG, Hochedlinger K (2009) Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460:1145–1148

    Article  PubMed  CAS  Google Scholar 

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

    Article  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

    Article  PubMed  CAS  Google Scholar 

  • Wu H, Xu J, Pang ZP, Ge W, Kim KJ, Blanchi B, Chen C, Sudhof TC, Sun YE (2007) Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines. Proc Natl Acad Sci USA 104:13821–13826

    Article  PubMed  CAS  Google Scholar 

  • Yamanaka S (2007) Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1:39–49

    Article  PubMed  CAS  Google Scholar 

  • Yang D, Zhang ZJ, Oldenburg M, Ayala M, Zhang SC (2008) Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in Parkinsonian rats. Stem Cells 26:55–63

    Article  PubMed  CAS  Google Scholar 

  • Yoo AS, Staahl BT, Chen L, Crabtree GR (2009) MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460:642–646

    PubMed  CAS  Google Scholar 

  • Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch RE, Tsien RW, Crabtree GR (2011) MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476:228–231

    Article  PubMed  CAS  Google Scholar 

  • Zhou Q, Melton DA (2008) Extreme makeover: converting one cell into another. Cell Stem Cell 3:382–388

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Marius Wernig .

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Wernig, M. (2013). Induction of Neural Lineages from Mesoderm and Endoderm by Defined Transcription Factors. In: Gage, F., Christen, Y. (eds) Programmed Cells from Basic Neuroscience to Therapy. Research and Perspectives in Neurosciences, vol 20. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-36648-2_3

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