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EMBRYONIC STEM CELLS: CHARACTERIZATION SERIES

Fibroblast Growth Factor 2 Modulates Transforming Growth Factor ß Signaling in Mouse Embryonic Fibroblasts and Human ESCs (hESCs) to Support hESC Self-Renewal

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

Key Words. Human ESCs • Self-renewal • Mouse embryonic fibroblasts • Basic fibroblast growth factor

Correspondence: James Adjaye, Ph.D., Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin D-14195, Germany. Telephone: 49-30-8413-1203; Fax: 49-30-8413-1128; e-mail: adjaye{at}molgen.mpg.de or Boris Greber, Ph.D., Telephone: 49-30-8413-1237; Fax: 49-30-8413-1128; e-mail: greber{at}molgen.mpg.de

Received July 27, 2006; accepted for publication September 30, 2006.
First published online in STEM CELLS EXPRESS   October 12, 2006.



Fibroblast growth factor 2 (FGF2) is known to promote self-renewal of human embryonic stem cells (hESCs). In addition, it has been shown that transforming growth factor ß (TGFß) signaling is crucial in that the TGFß/Activin/Nodal branch of the pathway needs to be activated and the bone morphogenic protein (BMP)/GDF branch repressed to prevent differentiation. This holds particularly true for Serum Replacement-based medium containing BMP-like activity. We have reinvestigated a widely used protocol for conditioning hESC medium with mouse embryonic fibroblasts (MEFs). We show that FGF2 acts on MEFs to release supportive factors and reduce differentiation-inducing activity. FGF2 stimulation experiments with supportive and nonsupportive MEFs followed by genome-wide expression profiling revealed that FGF2 regulates the expression of key members of the TGFß pathway, with Inhba, Tgfb1, Grem1, and Bmp4 being the most likely candidates orchestrating the above activities. In addition, restimulation 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 by modulating the expression of TGFß ligands, which, in turn, act on hESCs in a concerted and autocrine manner.

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