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J. Biol. Chem., Vol. 283, Issue 36, 24991-25002, September 5, 2008

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Combinatorial Signals of Activin/Nodal and Bone Morphogenic Protein Regulate the Early Lineage Segregation of Human Embryonic Stem Cells^*

Zhao Wu¹, Wei Zhang¹, Guibin Chen^¶, Lu Cheng, Jing Liao, Nannan Jia, Yuan Gao, Huiming Dai, Jinduo Yuan, Linzhao Cheng^¶, and Lei Xiao²

From the Laboratory of Molecular Cell Biology, Key Laboratory of Stem Cell Biology, Institute of Biochemistry and Cell Biology, the Cell Bank/Stem Cell Bank, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, the Department of Biotechnology, College of Life Science, Shandong Normal University, Jinan 250014, China, and the ^¶Stem Cell Program, Institute for Cell Engineering, and Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Cell fate commitment of pre-implantation blastocysts, to either the inner cell mass or trophoblast, is the first step in cell lineage segregation of the developing human embryo. However, the intercellular signals that control fate determination of these cells remain obscure. Human embryonic stem cells (hESCs) provide a unique model for studying human early embryonic development. We have previously shown that Activin/Nodal signaling contributes to maintaining pluripotency of hESCs, which are derivatives of the inner cell mass. Here we further demonstrate that the inhibition of Activin/Nodal signaling results in the loss of hESC pluripotency and trophoblast differentiation, similar to BMP4-induced trophoblast differentiation from hESCs. We also show that the trophoblast induction effect of BMP4 correlates with and depends on the inhibition of Activin/Nodal signaling. However, the activation of BMP signaling is still required for trophoblast differentiation when Activin/Nodal signaling is inhibited. These data reveal that the early lineage segregation of hESCs is determined by the combinatorial signals of Activin/Nodal and BMP.

Received for publication, May 21, 2008 , and in revised form, July 1, 2008.

^* This work was supported by Ministry of Science and Technology Grants 2007CB947100 and 2006CB943900, National Natural Science Foundation of China Grant 30600306, and Shanghai Institutes for Biological Sciences Grant 2007KIP101. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Table S1.

¹ Both authors contributed equally to this work.

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² To whom correspondence should be addressed: 320 Yue Yang Rd., Bldg. 41, Rm. 625, Shanghai, 200031, China. Tel.: 86-21-54921386; Fax: 86-21-54921388; E-mail: leixiao{at}sibs.ac.cn.

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