Activin A promotes hematopoietic fated mesoderm development through upregulation of brachyury in human embryonic stem cells.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101197107 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-8534 (Electronic) Linking ISSN: 15473287 NLM ISO Abbreviation: Stem Cells Dev Subsets: MEDLINE
    • Publication Information:
      Original Publication: Larchmont, NY : Mary Ann Liebert, Inc., c2004-
    • Subject Terms:
      Hematopoiesis* ; Up-Regulation*; Activins/*physiology ; Embryoid Bodies/*metabolism ; Fetal Proteins/*metabolism ; Mesoderm/*cytology ; T-Box Domain Proteins/*metabolism; Animals ; Antigens, Differentiation/metabolism ; Bone Morphogenetic Protein 4/metabolism ; Bone Morphogenetic Protein 4/physiology ; Cell Differentiation ; Cells, Cultured ; Embryoid Bodies/cytology ; Embryoid Bodies/physiology ; Fetal Proteins/genetics ; Fibroblast Growth Factor 2/physiology ; Gene Knockdown Techniques ; Humans ; Mesoderm/physiology ; Mice ; RNA Interference ; T-Box Domain Proteins/genetics ; Transcriptional Activation
    • Abstract:
      The development of the hematopoietic system involves multiple cellular steps beginning with the formation of the mesoderm from the primitive streak, followed by emergence of precursor populations that become committed to either the endothelial or hematopoietic lineages. A number of growth factors such as activins and fibroblast growth factors (FGFs) are known to regulate the early specification of hematopoietic fated mesoderm, notably in amphibians. However, the potential roles of these factors in the development of mesoderm and subsequent hematopoiesis in the human have yet to be delineated. Defining the cellular and molecular mechanisms by which combinations of mesoderm-inducing factors regulate this stepwise process in human cells in vitro is central to effectively directing human embryonic stem cell (hESC) hematopoietic differentiation. Herein, using hESC-derived embryoid bodies (EBs), we show that Activin A, but not basic FGF/FGF2 (bFGF), promotes hematopoietic fated mesodermal specification from pluripotent human cells. The effect of Activin A treatment relies on the presence of bone morphogenetic protein 4 (BMP4) and both of the hematopoietic cytokines stem cell factor and fms-like tyrosine kinase receptor-3 ligand, and is the consequence of 2 separate mechanisms occurring at 2 different stages of human EB development from mesoderm to blood. While Activin A promotes the induction of mesoderm, as indicated by the upregulation of Brachyury expression, which represents the mesodermal precursor required for hematopoietic development, it also contributes to the expansion of cells already committed to a hematopoietic fate. As hematopoietic development requires the transition through a Brachyury+ intermediate, we demonstrate that hematopoiesis in hESCs is impaired by the downregulation of Brachyury, but is unaffected by its overexpression. These results demonstrate, for the first time, the functional significance of Brachyury in the developmental program of hematopoietic differentiation from hESCs and provide an in-depth understanding of the molecular cues that orchestrate stepwise development of hematopoiesis in a human system.
    • References:
      Science. 1998 Nov 6;282(5391):1145-7. (PMID: 9804556)
      Immunity. 2004 Jul;21(1):31-41. (PMID: 15345218)
      Development. 1998 May;125(9):1747-57. (PMID: 9521912)
      Nature. 2009 Feb 12;457(7231):892-5. (PMID: 19182774)
      Stem Cells. 2007 Jan;25(1):29-38. (PMID: 17204604)
      Blood. 2004 Apr 1;103(7):2504-12. (PMID: 14656883)
      Development. 2008 Apr;135(8):1525-35. (PMID: 18339678)
      Curr Opin Organ Transplant. 2008 Feb;13(1):44-52. (PMID: 18660706)
      Development. 2010 Sep 1;137(17):2829-39. (PMID: 20659975)
      Blood. 2008 Feb 15;111(4):1933-41. (PMID: 18042803)
      Int J Dev Biol. 1999 Sep;43(6):501-8. (PMID: 10610023)
      Cell Stem Cell. 2011 Jul 8;9(1):24-36. (PMID: 21726831)
      Stem Cells. 2007 Sep;25(9):2206-14. (PMID: 17556598)
      Mol Ther. 2006 Aug;14(2):255-67. (PMID: 16632408)
      Stem Cells. 2008 Feb;26(2):401-11. (PMID: 17991917)
      Stem Cell Rev Rep. 2009 Jun;5(2):159-73. (PMID: 19263252)
      Development. 2000 May;127(9):1931-41. (PMID: 10751181)
      Development. 1995 Aug;121(8):2429-37. (PMID: 7671807)
      Development. 2003 Sep;130(17):4217-27. (PMID: 12874139)
      Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12301-6. (PMID: 18719101)
      Dev Biol. 2008 Jan 1;313(1):107-17. (PMID: 18022151)
      Nat Biotechnol. 2001 Oct;19(10):971-4. (PMID: 11581665)
      J Cell Sci. 2005 Oct 1;118(Pt 19):4495-509. (PMID: 16179608)
      Trends Cardiovasc Med. 2004 Nov;14(8):314-7. (PMID: 15596108)
      J Cell Sci. 2011 May 1;124(Pt 9):1445-52. (PMID: 21486943)
      Nature. 1990 Feb 15;343(6259):617-22. (PMID: 2154694)
      Blood. 2005 Aug 1;106(3):860-70. (PMID: 15831705)
      Exp Hematol. 2005 Sep;33(9):987-96. (PMID: 16140146)
      Genes Dev. 1997 Dec 1;11(23):3265-76. (PMID: 9389657)
      J Immunol. 1984 Oct;133(4):1710-5. (PMID: 6206131)
      Exp Hematol. 2005 Sep;33(9):955-64. (PMID: 16140142)
      Stem Cells. 2002;20(6):493-500. (PMID: 12456957)
      EMBO J. 1994 Oct 3;13(19):4469-81. (PMID: 7925289)
      Dev Biol. 1995 Apr;168(2):406-15. (PMID: 7729577)
      Development. 2004 Apr;131(7):1651-62. (PMID: 14998924)
      Curr Opin Hematol. 2008 Jul;15(4):312-8. (PMID: 18536568)
      Nat Biotechnol. 2005 Dec;23(12):1534-41. (PMID: 16258519)
      Blood. 1998 Dec 1;92(11):4128-37. (PMID: 9834218)
      Biochem Biophys Res Commun. 1994 Mar 15;199(2):552-63. (PMID: 7907867)
      Development. 1994 Aug;120(8):2339-46. (PMID: 7925034)
      Mol Ther. 2010 Dec;18(12):2173-81. (PMID: 20736931)
      Prog Growth Factor Res. 1995;6(1):35-48. (PMID: 8714368)
      Differentiation. 2008 Sep;76(7):745-59. (PMID: 18177426)
      Stem Cells. 2010 Mar 31;28(3):419-30. (PMID: 20054863)
      Cell. 1991 Oct 4;67(1):79-87. (PMID: 1717160)
      Hematology Am Soc Hematol Educ Program. 2007;:11-6. (PMID: 18024603)
      Biochim Biophys Acta. 1997 Oct 24;1333(2):F73-84. (PMID: 9395282)
      Development. 1994 Apr;120(4):1009-15. (PMID: 7600949)
      Cell. 1992 Nov 27;71(5):731-9. (PMID: 1423628)
      PLoS One. 2009 Jun 30;4(6):e6082. (PMID: 19564924)
      Blood. 2003 Aug 1;102(3):906-15. (PMID: 12702499)
      Stem Cells. 2009 Aug;27(8):1847-57. (PMID: 19544431)
      Nature. 2004 Dec 2;432(7017):625-30. (PMID: 15577911)
      Nature. 1992 Jul 30;358(6385):427-30. (PMID: 1641026)
      Cell Stem Cell. 2009 Mar 6;4(3):248-62. (PMID: 19265664)
      Cell Stem Cell. 2008 Jan 10;2(1):60-71. (PMID: 18371422)
      Development. 1994 Feb;120(2):453-62. (PMID: 8149920)
      Development. 2004 Oct;131(19):4687-96. (PMID: 15329341)
      Philos Trans R Soc Lond B Biol Sci. 1993 Jun 29;340(1293):287-96. (PMID: 8103931)
      Nature. 2007 Aug 30;448(7157):1015-21. (PMID: 17625568)
      Stem Cells. 2007 Jul;25(7):1664-74. (PMID: 17446562)
      Cell Stem Cell. 2011 Aug 5;9(2):144-55. (PMID: 21816365)
    • Accession Number:
      0 (Antigens, Differentiation)
      0 (BMP4 protein, human)
      0 (Bone Morphogenetic Protein 4)
      0 (Fetal Proteins)
      0 (T-Box Domain Proteins)
      0 (activin A)
      103107-01-3 (Fibroblast Growth Factor 2)
      104625-48-1 (Activins)
      EQ43SC3GDB (Brachyury protein)
    • Publication Date:
      Date Created: 20120503 Date Completed: 20130301 Latest Revision: 20211021
    • Publication Date:
      20240513
    • Accession Number:
      PMC3464075
    • Accession Number:
      10.1089/scd.2012.0053
    • Accession Number:
      22548442