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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2007-1037v1 26/3/767    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Google Scholar Articles by Mayshar, Y. Articles by Benvenisty, N. PubMed PubMed Citation Articles by Mayshar, Y. Articles by Benvenisty, N.

EMBRYONIC STEM CELLS

Fibroblast Growth Factor 4 and Its Novel Splice Isoform Have Opposing Effects on the Maintenance of Human Embryonic Stem Cell Self-Renewal

^aDepartment of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel;
^bProChon Biotech Ltd., Nes Ziona, Israel

Key Words. Human embryonic stem cells • Self-renewal • Fibroblast growth factor 4 • Signaling • Erk

Correspondence: Nissim Benvenisty, M.D., Ph.D., Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem 91904, Israel. Telephone: 972-2-6586774; Fax: 972-2-6584972; e-mail: nissimb{at}mail.ls.huji.ac.il

Received December 18, 2007; accepted for publication December 27, 2007.
First published online in STEM CELLS EXPRESS   January 10, 2008.



Human embryonic stem cells (HESCs) are unique in their capacity to self-renew while remaining pluripotent. This undifferentiated state must be actively maintained by secreted factors. To identify autocrine factors that may support HESC growth, we have taken a global genetic approach. Microarray analysis identified fibroblast growth factor 4 (FGF4) as a prime candidate for autocrine signaling. Furthermore, the addition of recombinant FGF4 to HESCs supports their proliferation. We show that FGF4 is produced by multiple undifferentiated HESC lines, along with a novel fibroblast growth factor 4 splice isoform (FGF4si) that codes for the amino-terminal half of FGF4. Strikingly, although FGF4 supports the undifferentiated growth of HESCs, FGF4si effectively counters its effect. Furthermore, we show that FGF4si is an antagonist of FGF4, shutting down FGF4-induced Erk1/2 phosphorylation. Expression analysis shows that both isoforms are expressed in HESCs and early differentiated cells. However, whereas FGF4 ceases to be expressed in mature differentiated cells, FGF4si continues to be expressed after cell differentiation. Targeted knockdown of FGF4 using small interfering RNA increased differentiation of HESCs, demonstrating the importance of endogenous FGF4 signaling in maintaining their pluripotency. Taken together, these results suggest a growth-promoting role for FGF4 in HESCs and a putative feedback inhibition mechanism by a novel FGF4 splice isoform that may serve to promote differentiation at later stages of development.

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