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Mol. Hum. Reprod. Advance Access published online on February 7, 2008
Molecular Human Reproduction, doi:10.1093/molehr/gan001
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

GSK-3-specific inhibitor-supplemented hESC medium prevents the epithelial-mesenchymal transition process and the upregulation of matrix metalloproteinases in hESCs cultured in feeder-free conditions

U. Ullmann1,3, C. Gilles2, M. De Rycke1, H. Van de Velde1, K. Sermon1 and I. Liebaers1

1Department of Embryology and Genetics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Belgium 2Laboratory of Developmental and Tumour Biology, Université de Liège, Belgium

3 To whom correspondence should be addressed at: Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Department of Embryology and Genetics, Laarbeeklaan 101, 1090 Brussels, Belgium. E-mail: urielle.ullmann{at}uzbrussel.be

Feeder-free culture induces spontaneous differentiation of human embryonic stem cells (hESCs), identified as an epithelial to mesenchymal transition (EMT). The maintenance of pluripotency of hESCs in feeder-free cultures through the activation of the WNT proto-oncogene pathway using a glycogen synthase kinase (GSK)-3-specific inhibitor (BIO) was reported. The aim of this study was to determine the effect of BIO on the EMT process.

In contrast with those grown in feeder-free conditions with control medium, hESC colonies cultured with BIO-supplemented hESC medium did not show any fibroblast-like cells at the periphery. Transmission electron microscopy, relative quantitative real-time RT-PCR and immunostaining analyses showed the presence of epithelial features and a diminution of mesenchymal features in the BIO-treated hESCs such as a strong E-cadherin expression, the downregulation of Vimentin, Snail and Slug expressions and a cytoplasmic β-catenin expression. An upregulation of matrix metalloproteinases (MMP) MMP-2, MMP-9, MT-1MMP (membrane-type 1 MMP) and EMMPRIN (extracellular MMP inducer) expression was also found associated with the EMT occurring in feeder-free hESCs cultures using mouse embryonic fibroblasts conditioned medium (MEF CM). The presence of BIO clearly downregulated the expression of these MMPs.

This study showed that BIO, a GSK-3 specific inhibitor, prevents the EMT process which is associated with the feeder-free hESC culture. Nevertheless, BIO was not sufficient to expand hESCs in a long-term culture system.

Key Words: Epithelial-mesenchymal transition/GSK-3 inhibitor/human embryonic stem cells/feeder-free culture/matrix metalloproteinases

This study was presented orally at the 23rd Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Lyon (1-4 July 2007) (abstract O-166)

Submitted on July 31, 2007; resubmitted on December 28, 2007; accepted on January 3, 2008.


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