Home LiteratureArticle Details
PMID: 21513877 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review

Regenerative chemical biology: current challenges and future potential.

Chemistry & biology ·Vol. 18 ·No. 4 ·2011-04-22 ·Pages 413-24

Ao A, Hao J, Hong CC

Abstract

The enthusiasm surrounding the clinical potential of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) is tempered by the fact that key issues regarding their safety, efficacy, and long-term benefits have thus far been suboptimal. Small molecules can potentially relieve these problems at major junctions of stem cell biology and regenerative therapy. In this review we will introduce recent advances in these important areas and the first generation of small molecules used in the regenerative context. Current chemical biology studies will provide the archetype for future interdisciplinary collaborations and improve clinical benefits of cell-based therapies.

MeSH Terms
Animals Biology/methods Cell Differentiation Humans Regenerative Medicine/methods Small Molecule Libraries/metabolism,pharmacology,therapeutic use
Chemicals
Small Molecule Libraries
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Ao Ada
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 383 PRB, Nashville, TN 37232, USA.
Hao Jijun
Hong Charles C
References (97)
97 references, click to expand
  1. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors.
    Cell Stem Cell. 2009 Jan 9;4(1):16-9 PMID: 19097958
  2. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro.
    Nat Biotechnol. 2000 Apr;18(4):399-404 PMID: 10748519
  3. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells.
    Nat Cell Biol. 2007 Jun;9(6):625-35 PMID: 17515932
  4. Endogenous Wnt/beta-catenin signaling is required for cardiac differentiation in human embryonic stem cells.
    PLoS One. 2010 Jun 15;5(6):e11134 PMID: 20559569
  5. Generation of mouse induced pluripotent stem cells without viral vectors.
    Science. 2008 Nov 7;322(5903):949-53 PMID: 18845712
  6. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.
    Nature. 2003 Oct 30;425(6961):968-73 PMID: 14555960
  7. Epigenetic memory in induced pluripotent stem cells.
    Nature. 2010 Sep 16;467(7313):285-90 PMID: 20644535
  8. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures.
    Cell Stem Cell. 2009 Jul 2;5(1):111-23 PMID: 19570518
  9. 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
  10. Derivation of pluripotent epiblast stem cells from mammalian embryos.
    Nature. 2007 Jul 12;448(7150):191-5 PMID: 17597762
  11. Isolation and expansion of adult cardiac stem cells from human and murine heart.
    Circ Res. 2004 Oct 29;95(9):911-21 PMID: 15472116
  12. Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression.
    Nucleic Acids Res. 2009 Jan;37(1):172-83 PMID: 19033359
  13. The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/beta-catenin pathway.
    Cell Stem Cell. 2007 Aug 16;1(2):165-79 PMID: 18371348
  14. The Aurora B kinase activity is required for the maintenance of the differentiated state of murine myoblasts.
    Cell Death Differ. 2009 Feb;16(2):321-30 PMID: 18974773
  15. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression.
    Cell. 1993 May 21;73(4):713-24 PMID: 8500165
  16. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism.
    Nat Chem Biol. 2008 Jan;4(1):33-41 PMID: 18026094
  17. The FGF family: biology, pathophysiology and therapy.
    Nat Rev Drug Discov. 2009 Mar;8(3):235-53 PMID: 19247306
  18. Molecular signatures define myogenic stem cell populations.
    Stem Cell Rev. 2006;2(1):37-42 PMID: 17142885
  19. Wnt/beta-catenin signaling: components, mechanisms, and diseases.
    Dev Cell. 2009 Jul;17(1):9-26 PMID: 19619488
  20. 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
  21. Emerging use of stem cells in regenerative medicine.
    Biochem J. 2010 Apr 28;428(1):11-23 PMID: 20423328
  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. A niche for adult neural stem cells.
    Curr Opin Genet Dev. 2003 Oct;13(5):543-50 PMID: 14550422
  24. Intestinal stem cells in mammals and Drosophila.
    Cell Stem Cell. 2009 Feb 6;4(2):124-7 PMID: 19200801
  25. The tumorigenicity of human embryonic stem cells.
    Adv Cancer Res. 2008;100:133-58 PMID: 18620095
  26. Naive and primed pluripotent states.
    Cell Stem Cell. 2009 Jun 5;4(6):487-92 PMID: 19497275
  27. Embryonic stem cell lines derived from human blastocysts.
    Science. 1998 Nov 6;282(5391):1145-7 PMID: 9804556
  28. Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells.
    Mol Cancer Ther. 2008 May;7(5):1140-9 PMID: 18483302
  29. 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
  30. Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells.
    J Cell Sci. 2005 Oct 1;118(Pt 19):4495-509 PMID: 16179608
  31. A role for chemistry in stem cell biology.
    Nat Biotechnol. 2004 Jul;22(7):833-40 PMID: 15229546
  32. Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis.
    Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19812-7 PMID: 17170140
  33. Extrinsic regulation of pluripotent stem cells.
    Nature. 2010 Jun 10;465(7299):713-20 PMID: 20535200
  34. Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines.
    Cell Stem Cell. 2011 Feb 4;8(2):228-40 PMID: 21295278
  35. Reversine increases the plasticity of lineage-committed cells toward neuroectodermal lineage.
    J Biol Chem. 2009 Jan 30;284(5):2891-2901 PMID: 19015271
  36. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts.
    Nat Biotechnol. 2008 Jan;26(1):101-6 PMID: 18059259
  37. Comparison of reprogramming efficiency between transduction of reprogramming factors, cell-cell fusion, and cytoplast fusion.
    Stem Cells. 2010 Aug;28(8):1338-48 PMID: 20572011
  38. Establishment in culture of pluripotential cells from mouse embryos.
    Nature. 1981 Jul 9;292(5819):154-6 PMID: 7242681
  39. BMP-4 inhibits neural differentiation of murine embryonic stem cells.
    J Neurobiol. 1999 Sep 5;40(3):271-87 PMID: 10440729
  40. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3.
    Genes Dev. 1998 Jul 1;12(13):2048-60 PMID: 9649508
  41. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases.
    Science. 2002 Dec 6;298(5600):1911-2 PMID: 12471242
  42. Chemical induction of cardiac differentiation in p19 embryonal carcinoma stem cells.
    Stem Cells Dev. 2010 Mar;19(3):403-12 PMID: 20163207
  43. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.
    Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8424-8 PMID: 8378314
  44. Lineage choice and differentiation in mouse embryos and embryonic stem cells.
    Dev Biol. 2003 Dec 1;264(1):1-14 PMID: 14623228
  45. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse.
    Genes Dev. 1995 Sep 1;9(17):2105-16 PMID: 7657163
  46. A small molecule that directs differentiation of human ESCs into the pancreatic lineage.
    Nat Chem Biol. 2009 Apr;5(4):258-65 PMID: 19287398
  47. 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
  48. Development of definitive endoderm from embryonic stem cells in culture.
    Development. 2004 Apr;131(7):1651-62 PMID: 14998924
  49. A small molecule primes embryonic stem cells for differentiation.
    Cell Stem Cell. 2009 May 8;4(5):416-26 PMID: 19427291
  50. New cell lines from mouse epiblast share defining features with human embryonic stem cells.
    Nature. 2007 Jul 12;448(7150):196-9 PMID: 17597760
  51. The ground state of embryonic stem cell self-renewal.
    Nature. 2008 May 22;453(7194):519-23 PMID: 18497825
  52. Cardiac induction of embryonic stem cells by a small molecule inhibitor of Wnt/β-catenin signaling.
    ACS Chem Biol. 2011 Feb 18;6(2):192-7 PMID: 21077691
  53. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3.
    Cell. 2003 Oct 31;115(3):281-92 PMID: 14636556
  54. Derivation of human embryonic stem cells in defined conditions.
    Nat Biotechnol. 2006 Feb;24(2):185-7 PMID: 16388305
  55. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells.
    PLoS One. 2010 Feb 01;5(2):e8975 PMID: 20126639
  56. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor.
    Nat Med. 2004 Jan;10(1):55-63 PMID: 14702635
  57. Improved generation of C57BL/6J mouse embryonic stem cells in a defined serum-free media.
    Genesis. 2004 Jun;39(2):100-4 PMID: 15170695
  58. Self-renewal of embryonic stem cells by a small molecule.
    Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17266-71 PMID: 17088537
  59. Reprogramming of human primary somatic cells by OCT4 and chemical compounds.
    Cell Stem Cell. 2010 Dec 3;7(6):651-5 PMID: 21112560
  60. The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo.
    Genes Dev. 1998 Jan 1;12(1):107-19 PMID: 9420335
  61. Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells.
    Nature. 2009 Oct 29;461(7268):1292-5 PMID: 19816418
  62. Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification.
    Cell Stem Cell. 2008 Jul 3;3(1):69-84 PMID: 18593560
  63. Induced human pluripotent stem cells: promises and open questions.
    Biol Chem. 2009 Sep;390(9):845-9 PMID: 19558327
  64. Therapeutic effects of human mesenchymal stem cells on traumatic brain injury in rats: secretion of neurotrophic factors and inhibition of apoptosis.
    J Neurotrauma. 2010 Jan;27(1):131-8 PMID: 19508155
  65. Small molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells.
    Neurosci Lett. 2011 Jan 13;488(1):36-40 PMID: 21056624
  66. Comprehensive methylome map of lineage commitment from haematopoietic progenitors.
    Nature. 2010 Sep 16;467(7313):338-42 PMID: 20720541
  67. Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2.
    Stem Cells. 2009 Dec;27(12):2992-3000 PMID: 19839055
  68. A chemical platform for improved induction of human iPSCs.
    Nat Methods. 2009 Nov;6(11):805-8 PMID: 19838168
  69. Derivation and propagation of embryonic stem cells in serum- and feeder-free culture.
    Methods Mol Biol. 2006;329:91-8 PMID: 16845986
  70. A combined chemical and genetic approach for the generation of induced pluripotent stem cells.
    Cell Stem Cell. 2008 Jun 5;2(6):525-8 PMID: 18522845
  71. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells.
    Cell. 2003 May 30;113(5):631-42 PMID: 12787504
  72. 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
  73. Dedifferentiation of lineage-committed cells by a small molecule.
    J Am Chem Soc. 2004 Jan 21;126(2):410-1 PMID: 14719906
  74. Regulation of the Warburg effect in early-passage breast cancer cells.
    Neoplasia. 2008 Aug;10(8):745-56 PMID: 18670636
  75. Characterization of the paracrine effects of human skeletal myoblasts transplanted in infarcted myocardium.
    Eur J Heart Fail. 2008 Nov;10(11):1065-72 PMID: 18805052
  76. Tgf-beta superfamily signaling in embryonic development and homeostasis.
    Dev Cell. 2009 Mar;16(3):329-43 PMID: 19289080
  77. Notch signaling in development and cancer.
    Endocr Rev. 2007 May;28(3):339-63 PMID: 17409286
  78. 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
  79. Comparative analysis of endoderm formation efficiency between mouse ES cells and iPS cells.
    Cell Transplant. 2010;19(6):831-9 PMID: 20955658
  80. Growth of teratomas derived from human pluripotent stem cells is influenced by the graft site.
    Stem Cells Dev. 2006 Apr;15(2):254-9 PMID: 16646671
  81. Hedgehog signaling in development and cancer.
    Dev Cell. 2008 Dec;15(6):801-12 PMID: 19081070
  82. Defining the role of Wnt/beta-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells.
    Stem Cells. 2005 Nov-Dec;23(10):1489-501 PMID: 16002782
  83. Conversion of mouse epiblast stem cells to an earlier pluripotency state by small molecules.
    J Biol Chem. 2010 Sep 24;285(39):29676-80 PMID: 20705612
  84. An alliance between Ras GTPase-activating protein, filamin C, and Ras GTPase-activating protein SH3 domain-binding protein regulates myocyte growth.
    J Biol Chem. 2005 Jul 8;280(27):25717-28 PMID: 15886195
  85. Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency.
    Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5668-73 PMID: 17372190
  86. Survival, integration, and differentiation of cardiomyocyte grafts: a study in normal and injured rat hearts.
    Circulation. 1999 Jul 13;100(2):193-202 PMID: 10402450
  87. Nanog and transcriptional networks in embryonic stem cell pluripotency.
    Cell Res. 2007 Jan;17(1):42-9 PMID: 17211451
  88. Defined conditions for neural commitment and differentiation.
    Methods Enzymol. 2003;365:327-41 PMID: 14696356
  89. A small molecule accelerates neuronal differentiation in the adult rat.
    Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16542-7 PMID: 20823227
  90. The growth factor environment defines distinct pluripotent ground states in novel blastocyst-derived stem cells.
    Cell. 2008 Oct 31;135(3):449-61 PMID: 18984157
  91. Induction of pluripotent stem cells from adult somatic cells by protein-based reprogramming without genetic manipulation.
    Blood. 2010 Jul 22;116(3):386-95 PMID: 20439621
  92. A synthetic small molecule that induces neuronal differentiation of adult hippocampal neural progenitor cells.
    Angew Chem Int Ed Engl. 2006 Jan 16;45(4):591-3 PMID: 16323231
  93. Small molecules that induce cardiomyogenesis in embryonic stem cells.
    J Am Chem Soc. 2004 Feb 18;126(6):1590-1 PMID: 14871063
  94. Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs.
    Proc Natl Acad Sci U S A. 2010 May 18;107(20):9222-7 PMID: 20442331
  95. Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells.
    PLoS One. 2008 Aug 06;3(8):e2904 PMID: 18682835
  96. Induced pluripotent stem cell lines derived from human somatic cells.
    Science. 2007 Dec 21;318(5858):1917-20 PMID: 18029452
  97. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche.
    Nature. 2009 Jan 1;457(7225):92-6 PMID: 19052546
Article Info
Journal
Chemistry & biology
Abbr.
Chem Biol
ISSN
1879-1301
DOI
10.1016/j.chembiol.2011.03.011
Published
2011-04-22
Pages
413-24
Language
English
Region
United States
NLM ID
9500160
PMCID
PMC3082739
Subset
IM
Grants
NHLBI NIH HHS · 1R01HL104040 · United States
NHLBI NIH HHS · R01 HL104040 · United States
BLRD VA · I01 BX000771 · United States
NHLBI NIH HHS · U01 HL100398 · United States
NHLBI NIH HHS · 5U01HL100398 · United States
NHLBI NIH HHS · U01 HL100398-01 · United States
NHLBI NIH HHS · R01 HL104040-01 · United States
External Links
PubMed source DOI: 10.1016/j.chembiol.2011.03.011 PMC Full Text
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: product@genelibs.com

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