Home LiteratureArticle Details
PMID: 23486282 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Leveling Waddington: the emergence of direct programming and the loss of cell fate hierarchies.

Nature reviews. Molecular cell biology ·Vol. 14 ·No. 4 ·2013-04-00 ·Pages 225-36

Ladewig J, Koch P, Brüstle O

Abstract

For decades, Waddington's concept of the 'epigenetic landscape' has served as an educative hierarchical model to illustrate the progressive restriction of cell differentiation potential during normal development. While still being highly valuable in the context of normal development, the Waddington model falls short of accommodating recent breakthroughs in cell programming. The advent of induced pluripotent stem (iPS) cells and advances in direct cell fate conversion (also known as transdifferentiation) suggest that somatic and pluripotent cell fates can be interconverted without transiting through distinct hierarchies. We propose a non-hierarchical 'epigenetic disc' model to explain such cell fate transitions, which provides an alternative landscape for modelling cell programming and reprogramming.

MeSH Terms
Animals Cell Differentiation/genetics Cell Lineage/genetics Cell Transdifferentiation/genetics Cellular Reprogramming/genetics Epigenesis, Genetic Humans Models, Genetic Pluripotent Stem Cells/cytology,metabolism
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Ladewig Julia
Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn, Sigmund Freud Straße 25, 53127 Bonn, Germany.
Koch Philipp
Brüstle Oliver
References (112)
112 references, click to expand
  1. Neurogenin3 is sufficient for transdetermination of hepatic progenitor cells into neo-islets in vivo but not transdifferentiation of hepatocytes.
    Dev Cell. 2009 Mar;16(3):358-73 PMID: 19289082
  2. Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation.
    Nat Rev Genet. 2008 May;9(5):329-40 PMID: 18398419
  3. Capturing pluripotency.
    Cell. 2008 Feb 22;132(4):532-6 PMID: 18295569
  4. Stepwise reprogramming of B cells into macrophages.
    Cell. 2004 May 28;117(5):663-76 PMID: 15163413
  5. Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD.
    Proc Natl Acad Sci U S A. 1989 Jul;86(14):5434-8 PMID: 2748593
  6. Key events of pancreas formation are triggered in gut endoderm by ectopic expression of pancreatic regulatory genes.
    Genes Dev. 2001 Feb 15;15(4):444-54 PMID: 11230152
  7. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling.
    Nat Biotechnol. 2009 Mar;27(3):275-80 PMID: 19252484
  8. Sheep cloned by nuclear transfer from a cultured cell line.
    Nature. 1996 Mar 7;380(6569):64-6 PMID: 8598906
  9. MicroRNA-mediated conversion of human fibroblasts to neurons.
    Nature. 2011 Jul 13;476(7359):228-31 PMID: 21753754
  10. Direct reprogramming of mouse fibroblasts to neural progenitors.
    Proc Natl Acad Sci U S A. 2011 May 10;108(19):7838-43 PMID: 21521790
  11. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts.
    Cell Stem Cell. 2010 Jul 2;7(1):51-63 PMID: 20621050
  12. Mammalian heart renewal by pre-existing cardiomyocytes.
    Nature. 2013 Jan 17;493(7432):433-6 PMID: 23222518
  13. Functional integration of dopaminergic neurons directly converted from mouse fibroblasts.
    Cell Stem Cell. 2011 Nov 4;9(5):413-9 PMID: 22019014
  14. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells.
    Science. 2005 Aug 26;309(5739):1369-73 PMID: 16123299
  15. Neurogenin 2 controls cortical neuron migration through regulation of Rnd2.
    Nature. 2008 Sep 4;455(7209):114-8 PMID: 18690213
  16. Myeloid lineage commitment from the hematopoietic stem cell.
    Immunity. 2007 Jun;26(6):726-40 PMID: 17582345
  17. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia.
    Nat Med. 2000 May;6(5):568-72 PMID: 10802714
  18. Pioneer factors: directing transcriptional regulators within the chromatin environment.
    Trends Genet. 2011 Nov;27(11):465-74 PMID: 21885149
  19. MafA is a dedicated activator of the insulin gene in vivo.
    J Endocrinol. 2008 Aug;198(2):271-9 PMID: 18515495
  20. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells.
    Nat Cell Biol. 2011 May;13(5):541-9 PMID: 21499256
  21. Effect of cell history on response to helix-loop-helix family of myogenic regulators.
    Nature. 1990 Mar 29;344(6265):454-8 PMID: 2157160
  22. PU.1 induces myeloid lineage commitment in multipotent hematopoietic progenitors.
    Genes Dev. 1998 Aug 1;12(15):2403-12 PMID: 9694804
  23. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions.
    Cell Stem Cell. 2011 Aug 5;9(2):113-8 PMID: 21802386
  24. Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork head gene family, in the developing rat brain.
    Neuron. 1992 May;8(5):957-66 PMID: 1350202
  25. Direct conversion of human fibroblasts to multilineage blood progenitors.
    Nature. 2010 Nov 25;468(7323):521-6 PMID: 21057492
  26. Small molecules enable highly efficient neuronal conversion of human fibroblasts.
    Nat Methods. 2012 Jun;9(6):575-8 PMID: 22484851
  27. Potential autoregulation of transcription factor PU.1 by an upstream regulatory element.
    Mol Cell Biol. 2005 Apr;25(7):2832-45 PMID: 15767686
  28. Pioneer factors, genetic competence, and inductive signaling: programming liver and pancreas progenitors from the endoderm.
    Cold Spring Harb Symp Quant Biol. 2008;73:119-26 PMID: 19028990
  29. Translating the histone code.
    Science. 2001 Aug 10;293(5532):1074-80 PMID: 11498575
  30. PU.1 and C/EBPalpha/beta convert fibroblasts into macrophage-like cells.
    Proc Natl Acad Sci U S A. 2008 Apr 22;105(16):6057-62 PMID: 18424555
  31. Glial cells generate neurons: the role of the transcription factor Pax6.
    Nat Neurosci. 2002 Apr;5(4):308-15 PMID: 11896398
  32. Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages.
    Cell Stem Cell. 2007 Oct 11;1(4):416-27 PMID: 18371378
  33. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
    Cell. 2006 Aug 25;126(4):663-76 PMID: 16904174
  34. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming.
    Cell Stem Cell. 2010 Jul 2;7(1):64-77 PMID: 20621051
  35. Transcription factor-mediated lineage switching reveals plasticity in primary committed progenitor cells.
    EMBO J. 2002 Jul 15;21(14):3770-81 PMID: 12110589
  36. The origin and specification of cortical interneurons.
    Nat Rev Neurosci. 2006 Sep;7(9):687-96 PMID: 16883309
  37. Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells.
    Proc Natl Acad Sci U S A. 2005 May 31;102(22):7964-9 PMID: 15899968
  38. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes.
    Circ Res. 2012 May 25;110(11):1465-73 PMID: 22539765
  39. Cellular and molecular control of neurogenesis in the mammalian telencephalon.
    Curr Opin Cell Biol. 2005 Dec;17(6):639-47 PMID: 16226447
  40. Cellular plasticity within the pancreas--lessons learned from development.
    Dev Cell. 2010 Mar 16;18(3):342-56 PMID: 20230744
  41. Expression of achaete-scute homolog 3 in Xenopus embryos converts ectodermal cells to a neural fate.
    Genes Dev. 1994 Jun 15;8(12):1434-47 PMID: 7926743
  42. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4.
    Mol Cell. 2002 Feb;9(2):279-89 PMID: 11864602
  43. Induction of human neuronal cells by defined transcription factors.
    Nature. 2011 May 26;476(7359):220-3 PMID: 21617644
  44. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse.
    Cell Stem Cell. 2008 Mar 6;2(3):230-40 PMID: 18371448
  45. Expression of a single transfected cDNA converts fibroblasts to myoblasts.
    Cell. 1987 Dec 24;51(6):987-1000 PMID: 3690668
  46. GATA-1 but not SCL induces megakaryocytic differentiation in an early myeloid line.
    EMBO J. 1992 Dec;11(12):4557-64 PMID: 1385117
  47. Epigenetic inheritance during the cell cycle.
    Nat Rev Mol Cell Biol. 2009 Mar;10(3):192-206 PMID: 19234478
  48. Neuronal subtype specification in the cerebral cortex.
    Nat Rev Neurosci. 2007 Jun;8(6):427-37 PMID: 17514196
  49. Conversion of mouse and human fibroblasts into functional spinal motor neurons.
    Cell Stem Cell. 2011 Sep 2;9(3):205-18 PMID: 21852222
  50. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors.
    Development. 2002 May;129(10):2447-57 PMID: 11973276
  51. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha.
    Immunity. 2004 Dec;21(6):853-63 PMID: 15589173
  52. A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog.
    Cell Stem Cell. 2009 Nov 6;5(5):491-503 PMID: 19818703
  53. Reprogramming of mouse and human cells to pluripotency using mature microRNAs.
    Cell Stem Cell. 2011 Jun 3;8(6):633-8 PMID: 21620789
  54. Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia.
    J Neurosci. 2007 Aug 8;27(32):8654-64 PMID: 17687043
  55. When fibroblasts MET iPSCs.
    Cell Stem Cell. 2010 Jul 2;7(1):5-6 PMID: 20621040
  56. Hematopoiesis: an evolving paradigm for stem cell biology.
    Cell. 2008 Feb 22;132(4):631-44 PMID: 18295580
  57. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas.
    Cell. 2008 Jan 25;132(2):197-207 PMID: 18243096
  58. Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts.
    Cell. 1986 Dec 5;47(5):649-56 PMID: 2430720
  59. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy.
    Nat Cell Biol. 2011 Mar;13(3):215-22 PMID: 21278734
  60. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development.
    Nature. 2009 Jul 30;460(7255):642-6 PMID: 19561591
  61. Gene regulatory networks in the evolution and development of the heart.
    Science. 2006 Sep 29;313(5795):1922-7 PMID: 17008524
  62. Pancreatic beta cells require NeuroD to achieve and maintain functional maturity.
    Cell Metab. 2010 Apr 7;11(4):298-310 PMID: 20374962
  63. MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene.
    J Biol Chem. 2002 Dec 20;277(51):49903-10 PMID: 12368292
  64. Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs' Eggs.
    Proc Natl Acad Sci U S A. 1952 May;38(5):455-63 PMID: 16589125
  65. Directing astroglia from the cerebral cortex into subtype specific functional neurons.
    PLoS Biol. 2010 May 18;8(5):e1000373 PMID: 20502524
  66. Posttranslational mechanisms control the timing of bHLH function and regulate retinal cell fate.
    Neuron. 2002 Apr 11;34(2):183-95 PMID: 11970861
  67. Experimental conversion of liver to pancreas.
    Curr Biol. 2003 Jan 21;13(2):105-15 PMID: 12546783
  68. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors.
    Cell. 2010 Aug 6;142(3):375-86 PMID: 20691899
  69. MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes.
    Proc Natl Acad Sci U S A. 1990 Oct;87(20):7988-92 PMID: 2172969
  70. Altered histone acetylation is associated with age-dependent memory impairment in mice.
    Science. 2010 May 7;328(5979):753-6 PMID: 20448184
  71. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes.
    Nature. 2012 May 31;485(7400):593-8 PMID: 22522929
  72. Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits.
    Cell. 2013 Jan 17;152(1-2):82-96 PMID: 23313552
  73. The multipolar stage and disruptions in neuronal migration.
    Trends Neurosci. 2006 Jul;29(7):407-413 PMID: 16713637
  74. A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration.
    Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3225-30 PMID: 19218428
  75. Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein.
    Science. 1995 May 12;268(5212):836-44 PMID: 7754368
  76. The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages.
    Genes Dev. 2006 Nov 1;20(21):3010-21 PMID: 17079688
  77. X-MyT1, a Xenopus C2HC-type zinc finger protein with a regulatory function in neuronal differentiation.
    Cell. 1996 Dec 27;87(7):1191-202 PMID: 8980226
  78. Direct conversion of human fibroblasts to dopaminergic neurons.
    Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10343-8 PMID: 21646515
  79. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts.
    Genes Dev. 1995 May 15;9(10):1250-62 PMID: 7758949
  80. Making or breaking the heart: from lineage determination to morphogenesis.
    Cell. 2006 Sep 22;126(6):1037-48 PMID: 16990131
  81. Neural stem cells directly differentiated from partially reprogrammed fibroblasts rapidly acquire gliogenic competency.
    Stem Cells. 2012 Jun;30(6):1109-19 PMID: 22467474
  82. Growth and regeneration of adult beta cells does not involve specialized progenitors.
    Dev Cell. 2007 May;12(5):817-26 PMID: 17488631
  83. A robust and highly efficient immune cell reprogramming system.
    Cell Stem Cell. 2009 Nov 6;5(5):554-66 PMID: 19896445
  84. Multiple new phenotypes induced in 10T1/2 and 3T3 cells treated with 5-azacytidine.
    Cell. 1979 Aug;17(4):771-9 PMID: 90553
  85. Embryonic lethality, decreased erythropoiesis, and defective octamer-dependent promoter activation in Oct-1-deficient mice.
    Mol Cell Biol. 2004 Feb;24(3):1022-32 PMID: 14729950
  86. Pioneer factors in embryonic stem cells and differentiation.
    Curr Opin Genet Dev. 2010 Oct;20(5):519-26 PMID: 20638836
  87. Stem cells, cancer, and cancer stem cells.
    Nature. 2001 Nov 1;414(6859):105-11 PMID: 11689955
  88. Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells.
    Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2527-32 PMID: 22308465
  89. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors.
    Nature. 2011 May 11;475(7356):386-9 PMID: 21562492
  90. The mammalian epigenome.
    Cell. 2007 Feb 23;128(4):669-81 PMID: 17320505
  91. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors.
    Nature. 2011 Jun 29;475(7356):390-3 PMID: 21716291
  92. Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei.
    Nature. 1958 Jul 5;182(4627):64-5 PMID: 13566187
  93. What determines neurogenic competence in glia?
    Brain Res Rev. 2010 May;63(1-2):47-59 PMID: 20096728
  94. Oct-2, although not required for early B-cell development, is critical for later B-cell maturation and for postnatal survival.
    Genes Dev. 1993 Apr;7(4):570-82 PMID: 8096198
  95. Direct conversion of fibroblasts into stably expandable neural stem cells.
    Cell Stem Cell. 2012 Apr 6;10(4):473-9 PMID: 22445518
  96. Heart repair by reprogramming non-myocytes with cardiac transcription factors.
    Nature. 2012 May 13;485(7400):599-604 PMID: 22660318
  97. Neuronal specification in the spinal cord: inductive signals and transcriptional codes.
    Nat Rev Genet. 2000 Oct;1(1):20-9 PMID: 11262869
  98. Direct reprogramming of fibroblasts into neural stem cells by defined factors.
    Cell Stem Cell. 2012 Apr 6;10(4):465-72 PMID: 22445517
  99. Direct reprogramming of Sertoli cells into multipotent neural stem cells by defined factors.
    Cell Res. 2012 Jan;22(1):208-18 PMID: 22064700
  100. Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus.
    Neurosci Res. 2006 Jul;55(3):223-33 PMID: 16621079
  101. Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells.
    Mol Cell Biol. 2003 Sep;23(17):6049-62 PMID: 12917329
  102. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts.
    Nature. 2011 Jul 03;476(7359):224-7 PMID: 21725324
  103. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.
    Nature. 2008 Oct 2;455(7213):627-32 PMID: 18754011
  104. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor.
    Cell Stem Cell. 2012 Jul 6;11(1):100-9 PMID: 22683203
  105. Epigenetic memory in induced pluripotent stem cells.
    Nature. 2010 Sep 16;467(7313):285-90 PMID: 20644535
  106. MafA is a key regulator of glucose-stimulated insulin secretion.
    Mol Cell Biol. 2005 Jun;25(12):4969-76 PMID: 15923615
  107. Dissecting direct reprogramming through integrative genomic analysis.
    Nature. 2008 Jul 3;454(7200):49-55 PMID: 18509334
  108. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.
    Nat Biotechnol. 2010 Aug;28(8):848-55 PMID: 20644536
  109. Maintaining cell identity through global control of genomic organization.
    Immunity. 2010 Jul 23;33(1):12-24 PMID: 20643336
  110. Direct conversion of fibroblasts to functional neurons by defined factors.
    Nature. 2010 Feb 25;463(7284):1035-41 PMID: 20107439
  111. Direct lineage conversion of terminally differentiated hepatocytes to functional neurons.
    Cell Stem Cell. 2011 Oct 4;9(4):374-82 PMID: 21962918
  112. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors.
    Proc Natl Acad Sci U S A. 2011 May 17;108(20):8299-304 PMID: 21525408
Article Info
Journal
Nature reviews. Molecular cell biology
Abbr.
Nat Rev Mol Cell Biol
ISSN
1471-0080
DOI
10.1038/nrm3543
Published
2013-04-00
Epub
2013-00-13
Pages
225-36
Language
English
Region
England
NLM ID
100962782
Subset
IM
External Links
PubMed source DOI: 10.1038/nrm3543 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2