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First published online October 12, 2006
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2006-0476v1
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Submitted on July 27, 2006
Accepted on September 30, 2006

Embryonic Stem Cells

FGF2 Modulates TGF{beta} Signaling in MEFs and Human ES cells to Support hESC Self-renewal

Boris Greber 1, Hans Lehrach 1, James Adjaye 1*

1 Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Berlin, Germany

* To whom correspondence should be addressed. E-mail: adjaye{at}molgen.mpg.de.


  Abstract

FGF2 is known to promote self-renewal of human embryonic stem cells (hESCs). In addition, it has been shown that TGF{beta} signaling is crucial in that the TGF{beta}/Activin/Nodal branch of the pathway needs to be activated and the GDF/BMP branch repressed to prevent differentiation. This holds particularly true for Serum Replacement-based medium containing BMP-like activity. We have re-investigated a widely used protocol for conditioning hESC medium with mouse embryonic fibroblasts (MEFs). It is shown that FGF2 acts on MEFs to release supportive factors and reduced differentiation-inducing activity. FGF2 stimulation experiments with supportive and non-supportive MEFs followed by genome-wide expression profiling revealed that FGF2 regulates the expression of key members of the TGF{beta} pathway with Inhba, Tgfb1, Grem1, and Bmp4 being the most likely candidates orchestrating the above activities. In addition, re-stimulation experiments in hESCs combined with global expression analysis revealed downstream targets of FGF2 signaling in these cells. Among these were the same factors previously identified in MEFs, thus suggesting that FGF2, at least in part, promotes self-renewal of hESCs via modulating the expression of TGF{beta} ligands which, in turn, act on hESCs in a concerted and autocrine manner.

Key Words. human ES cells, self-renewal, mouse embryonic fibroblasts, FGF2




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