Embryonic Stem Cells/Induced Pluripotent Stem Cells

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The Role of SMAD4 in Human Embryonic Stem Cell Self-Renewal and Stem Cell Fate†‡§

  1. Stuart Avery1,2,¶,*,
  2. Gaetano Zafarana1,3,
  3. Paul J. Gokhale1,
  4. Peter W. Andrews1

Article first published online: 16 MAR 2010

DOI: 10.1002/stem.409

Issue

STEM CELLS

STEM CELLS

Volume 28, Issue 5, pages 863–873, May 2010

Additional Information

How to Cite

Avery, S., Zafarana, G., Gokhale, P. J. and Andrews, P. W. (2010), The Role of SMAD4 in Human Embryonic Stem Cell Self-Renewal and Stem Cell Fate. STEM CELLS, 28: 863–873. doi: 10.1002/stem.409

Author Information

  1. 1

    Department of Biomedical Science, Centre for Stem Cell Biology, University of Sheffield, Western Bank, Sheffield, S10 2TN, United Kingdom

  2. 2

    Institute of Medical Biology, A*STAR, 8A Biomedical Grove, Immunos 05-40, Singapore 138648, Singapore

  3. 3

    Princess Margaret Hospital (University Health Network) Department of Radiation Oncology, 610 University Ave, Toronto, ON M5G 2M9, Canada

  1. Telephone: +65 64070235; Fax: +65-64642006

*Institute of Medical Biology, A*STAR, 8A Biomedical Grove, Immunos #05-40, Singapore 138648

  1. †

    Disclosure of potential conflicts of interest is found at the end of this article.

  2. ‡

    S.A.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing; G.Z.: conception and design, collection and assembly of data; P.G.: collection and assembly of data, data analysis and interpretation; P.A.: financial support, provision of study material, conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript.

  3. §

    First published online in STEM CELLS EXPRESS March 16, 2010.

Publication History

  1. Issue published online: 10 MAY 2010
  2. Article first published online: 16 MAR 2010
  3. Accepted manuscript online: 16 MAR 2010 12:00AM EST
  4. Manuscript Accepted: 4 MAR 2010
  5. Manuscript Received: 9 DEC 2009

Funded by

  • Duncan Baker of the North Trent Clinical Cytogenetics Service for performing routine karyotype analysis on our hESCs
  • BBSRC, A*STAR, Singapore
  • ESTOOLS consortium under the Sixth Research Framework Programme of the European Union. Grant Number: LSHG-CT-2006-018739
  • Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, ON M5G 2M9, Canada

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Keywords:

  • Embryonic stem cell;
  • Pluripotency;
  • Self-renewal;
  • SMAD4;
  • Transforming growth factor-β;
  • Signaling

Abstract

Transforming growth factor (TGF)-β superfamily proteins play a key role in the regulation of human embryonic stem cells (hESCs). Those of the TGFβ/activin/nodal branch seem to support self-renewal and pluripotency, whereas those of the bone morphogenic protein (BMP) branch induce differentiation. In contrast to this generalization, we found that hESC remained undifferentiated after knockdown of SMAD4 with inducible short hairpin RNA interference, although the knockdown inhibited TGFβ signaling and rendered the cells nonresponsive to BMP-induced differentiation. Moreover, the rapid differentiation of hESC after pharmacological inhibition of TGFβ/activin/nodal receptor signaling was restricted after SMAD4 knockdown. These results suggest that TGFβ/activin/nodal signaling supports the undifferentiated phenotype of hESC by suppressing BMP activity. During long-term culture, SMAD4 knockdown cell populations became less stable and more permissive to neural induction, a situation that was rescued by re-establishment of SMAD4 expression. These results suggest that SMAD4 is not required for maintenance of the undifferentiated state of hESC, but rather to stabilize that state. STEM CELLS 2010;28:863–873

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