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PMID: 21386864 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Turning straw into gold: directing cell fate for regenerative medicine.

Nature reviews. Genetics ·Vol. 12 ·No. 4 ·2011-04-00 ·Pages 243-52

Cohen DE, Melton D

Abstract

Regenerative medicine offers the hope that cells for disease research and therapy might be created from readily available sources. To fulfil this promise, the cells available need to be converted into the desired cell types. We review two main approaches to accomplishing this goal: in vitro directed differentiation, which is used to push pluripotent stem cells, including embryonic stem cells or induced pluripotent stem cells, through steps similar to those that occur during embryonic development; and reprogramming (also known as transdifferentiation), in which a differentiated cell is converted directly into the cell of interest without proceeding through a pluripotent intermediate. We analyse the status of progress made using these strategies and highlight challenges that must be overcome to achieve the goal of cell-replacement therapy.

MeSH Terms
Animals Cell Differentiation/physiology Cellular Reprogramming/physiology Embryonic Stem Cells/cytology,metabolism Humans Induced Pluripotent Stem Cells/cytology,metabolism Models, Biological Pluripotent Stem Cells/cytology,metabolism Regenerative Medicine/methods
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Cohen Dena E
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
Melton Douglas
References (86)
86 references, click to expand
  1. Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population.
    Nature. 2008 May 22;453(7194):524-8 PMID: 18432194
  2. Plasticity of adult stem cells.
    Cell. 2004 Mar 5;116(5):639-48 PMID: 15006347
  3. iPS cell technology in regenerative medicine.
    Ann N Y Acad Sci. 2010 Mar;1192:38-44 PMID: 20392216
  4. The regulation of TGFbeta signal transduction.
    Development. 2009 Nov;136(22):3699-714 PMID: 19855013
  5. Stepwise reprogramming of B cells into macrophages.
    Cell. 2004 May 28;117(5):663-76 PMID: 15163413
  6. Extreme makeover: converting one cell into another.
    Cell Stem Cell. 2008 Oct 9;3(4):382-8 PMID: 18940730
  7. Direct conversion of fibroblasts to functional neurons by defined factors.
    Nature. 2010 Feb 25;463(7284):1035-41 PMID: 20107439
  8. 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
  9. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells.
    Nature. 2009 Apr 9;458(7239):766-70 PMID: 19252478
  10. Stem cells and drug discovery: the beginning of a new era?
    Cell. 2008 Feb 22;132(4):549-52 PMID: 18295572
  11. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells.
    Nat Biotechnol. 2006 Nov;24(11):1392-401 PMID: 17053790
  12. Visceral-endoderm-like cell lines induce differentiation of murine P19 embryonal carcinoma cells.
    Differentiation. 1991 Feb;46(1):51-60 PMID: 1710586
  13. Directed differentiation of embryonic stem cells into motor neurons.
    Cell. 2002 Aug 9;110(3):385-97 PMID: 12176325
  14. Effect of cell history on response to helix-loop-helix family of myogenic regulators.
    Nature. 1990 Mar 29;344(6265):454-8 PMID: 2157160
  15. Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice.
    Cell Stem Cell. 2009 Jan 9;4(1):73-9 PMID: 19128794
  16. Functional diversity of ESC-derived motor neuron subtypes revealed through intraspinal transplantation.
    Cell Stem Cell. 2010 Sep 3;7(3):355-66 PMID: 20804971
  17. Direct conversion of human fibroblasts to multilineage blood progenitors.
    Nature. 2010 Nov 25;468(7323):521-6 PMID: 21057492
  18. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds.
    Cell Stem Cell. 2008 Nov 6;3(5):568-74 PMID: 18983970
  19. Reprogramming of human somatic cells to pluripotency with defined factors.
    Nature. 2008 Jan 10;451(7175):141-6 PMID: 18157115
  20. Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors.
    BMC Dev Biol. 2010 Aug 03;10:81 PMID: 20682060
  21. Inhibition of Activin/Nodal signaling promotes specification of human embryonic stem cells into neuroectoderm.
    Dev Biol. 2008 Jan 1;313(1):107-17 PMID: 18022151
  22. 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
  23. Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells.
    Cell Stem Cell. 2009 Oct 2;5(4):396-408 PMID: 19796620
  24. Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines.
    Nature. 2000 Sep 21;407(6802):383-6 PMID: 11014194
  25. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors.
    Nature. 2007 Sep 27;449(7161):473-7 PMID: 17851532
  26. Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes.
    Circulation. 2003 Apr 15;107(14):1912-6 PMID: 12668514
  27. Small-molecule inducers of insulin expression in pancreatic alpha-cells.
    Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15099-104 PMID: 20696901
  28. Human induced pluripotent stem cells free of vector and transgene sequences.
    Science. 2009 May 8;324(5928):797-801 PMID: 19325077
  29. Robust enhancement of neural differentiation from human ES and iPS cells regardless of their innate difference in differentiation propensity.
    Stem Cell Rev Rep. 2010 Jun;6(2):270-81 PMID: 20376579
  30. Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells.
    Cell Stem Cell. 2009 Apr 3;4(4):348-58 PMID: 19341624
  31. A role for chemistry in stem cell biology.
    Nat Biotechnol. 2004 Jul;22(7):833-40 PMID: 15229546
  32. Directed differentiation of human embryonic stem cells toward chondrocytes.
    Nat Biotechnol. 2010 Nov;28(11):1187-94 PMID: 20967028
  33. Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression.
    Mol Pharmacol. 2006 Feb;69(2):597-607 PMID: 16288083
  34. Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells.
    Stem Cells. 2009 Nov;27(11):2667-74 PMID: 19697349
  35. Expression of a single transfected cDNA converts fibroblasts to myoblasts.
    Cell. 1987 Dec 24;51(6):987-1000 PMID: 3690668
  36. Stage-specific role for shh in dopaminergic differentiation of human embryonic stem cells induced by stromal cells.
    Stem Cells Dev. 2010 Jan;19(1):71-82 PMID: 19788370
  37. Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development.
    Hepatology. 2010 May;51(5):1754-65 PMID: 20301097
  38. Development of defective and persistent Sendai virus vector: a unique gene delivery/expression system ideal for cell reprogramming.
    J Biol Chem. 2011 Feb 11;286(6):4760-71 PMID: 21138846
  39. A small molecule that directs differentiation of human ESCs into the pancreatic lineage.
    Nat Chem Biol. 2009 Apr;5(4):258-65 PMID: 19287398
  40. A small molecule primes embryonic stem cells for differentiation.
    Cell Stem Cell. 2009 May 8;4(5):416-26 PMID: 19427291
  41. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2.
    Nat Biotechnol. 2008 Nov;26(11):1269-75 PMID: 18849973
  42. Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4.
    Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):8912-7 PMID: 19447925
  43. Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression.
    J Clin Invest. 2007 Apr;117(4):961-70 PMID: 17404619
  44. An updated overview on Wnt signaling pathways: a prelude for more.
    Circ Res. 2010 Jun 25;106(12):1798-806 PMID: 20576942
  45. Generation of Rx+/Pax6+ neural retinal precursors from embryonic stem cells.
    Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11331-6 PMID: 16076961
  46. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo.
    Nat Biotechnol. 2008 Apr;26(4):443-52 PMID: 18288110
  47. Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation.
    Blood. 2005 Sep 1;106(5):1601-3 PMID: 15914555
  48. MC3T3-G2/PA6 preadipocytes support in vitro proliferation of hemopoietic stem cells through a mechanism different from that of interleukin 3.
    J Cell Physiol. 1986 Oct;129(1):20-6 PMID: 3489721
  49. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins.
    Cell Stem Cell. 2009 Jun 5;4(6):472-6 PMID: 19481515
  50. NANOG reporter cell lines generated by gene targeting in human embryonic stem cells.
    PLoS One. 2010 Sep 02;5(9): PMID: 20824089
  51. In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction.
    J Cell Sci. 2009 Sep 1;122(Pt 17):3169-79 PMID: 19671662
  52. Efficient differentiation of human embryonic stem cells to definitive endoderm.
    Nat Biotechnol. 2005 Dec;23(12):1534-41 PMID: 16258519
  53. A novel combination of factors, termed SPIE, which promotes dopaminergic neuron differentiation from human embryonic stem cells.
    PLoS One. 2009 Aug 12;4(8):e6606 PMID: 19672298
  54. Derivation of midbrain dopamine neurons from human embryonic stem cells.
    Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12543-8 PMID: 15310843
  55. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes.
    J Clin Invest. 2001 Aug;108(3):407-14 PMID: 11489934
  56. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors.
    Cell. 2010 Aug 6;142(3):375-86 PMID: 20691899
  57. Targeting the Hedgehog pathway in cancer.
    Nat Rev Drug Discov. 2006 Dec;5(12):1026-33 PMID: 17139287
  58. Transdetermination: a new trend in cellular reprogramming.
    Mol Ther. 2009 Jun;17(6):936-8 PMID: 19483768
  59. Human iPS cell-based therapy: considerations before clinical applications.
    Cell Cycle. 2010 Mar 1;9(5):880-5 PMID: 20160515
  60. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds.
    Nat Biotechnol. 2008 Jul;26(7):795-7 PMID: 18568017
  61. Progress toward the clinical application of patient-specific pluripotent stem cells.
    J Clin Invest. 2010 Jan;120(1):51-9 PMID: 20051636
  62. Induced pluripotent stem cells generated without viral integration.
    Science. 2008 Nov 7;322(5903):945-9 PMID: 18818365
  63. Neural differentiation of human embryonic stem cells.
    J Cell Biochem. 2008 Oct 15;105(3):633-40 PMID: 18759328
  64. Efficient generation of retinal progenitor cells from human embryonic stem cells.
    Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12769-74 PMID: 16908856
  65. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells.
    J Clin Invest. 2010 Sep;120(9):3127-36 PMID: 20739751
  66. Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation.
    Cell Stem Cell. 2008 Dec 4;3(6):637-48 PMID: 19041780
  67. Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity.
    Neuron. 2000 Oct;28(1):31-40 PMID: 11086981
  68. A robust and highly efficient immune cell reprogramming system.
    Cell Stem Cell. 2009 Nov 6;5(5):554-66 PMID: 19896445
  69. Activin a efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed.
    Stem Cells. 2007 Jan;25(1):29-38 PMID: 17204604
  70. Human pluripotent stem cells in drug discovery and predictive toxicology.
    Biochem Soc Trans. 2010 Aug;38(4):1051-7 PMID: 20659002
  71. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA.
    Cell Stem Cell. 2010 Nov 5;7(5):618-30 PMID: 20888316
  72. Generation of mouse induced pluripotent stem cells without viral vectors.
    Science. 2008 Nov 7;322(5903):949-53 PMID: 18845712
  73. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells.
    Cell. 2009 Aug 7;138(3):449-62 PMID: 19665969
  74. Induction of pluripotent stem cells from adult human fibroblasts by defined factors.
    Cell. 2007 Nov 30;131(5):861-72 PMID: 18035408
  75. Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture.
    Nat Biotechnol. 2003 Feb;21(2):183-6 PMID: 12524553
  76. Marked differences in differentiation propensity among human embryonic stem cell lines.
    Nat Biotechnol. 2008 Mar;26(3):313-5 PMID: 18278034
  77. Fibroblast growth factor signalling: from development to cancer.
    Nat Rev Cancer. 2010 Feb;10(2):116-29 PMID: 20094046
  78. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.
    Nature. 2008 Oct 2;455(7213):627-32 PMID: 18754011
  79. Nanog safeguards pluripotency and mediates germline development.
    Nature. 2007 Dec 20;450(7173):1230-4 PMID: 18097409
  80. Murine cardiac progenitor cells require visceral embryonic endoderm and primitive streak for terminal differentiation.
    Dev Dyn. 1997 Nov;210(3):344-53 PMID: 9389458
  81. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542.
    Mol Pharmacol. 2002 Jul;62(1):58-64 PMID: 12065755
  82. Disease-specific induced pluripotent stem cells.
    Cell. 2008 Sep 5;134(5):877-86 PMID: 18691744
  83. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells.
    Circulation. 2003 Jun 3;107(21):2733-40 PMID: 12742992
  84. Stromal cell-secreted factors promote the survival of embryonic stem cell-derived early neural stem/progenitor cells via the activation of MAPK and PI3K-Akt pathways.
    J Neurosci Res. 2010 Mar;88(4):722-34 PMID: 19798745
  85. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists.
    J Biol. 2002 Nov 06;1(2):10 PMID: 12437772
  86. Induced pluripotent stem cell lines derived from human somatic cells.
    Science. 2007 Dec 21;318(5858):1917-20 PMID: 18029452
Article Info
Journal
Nature reviews. Genetics
Abbr.
Nat Rev Genet
ISSN
1471-0064
Published
2011-04-00
Epub
2011-00-09
Pages
243-52
Language
English
Region
England
NLM ID
100962779
Subset
IM
Grants
Howard Hughes Medical Institute · United States
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