QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online September 22, 2005
doi: 10.1242/10.1242/jcs.02553

This Article Figures Only Full Text Full Text (PDF) Supplementary Material Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vallier, L. Articles by Pedersen, R. A. Search for Related Content PubMed PubMed Citation Articles by Vallier, L. Articles by Pedersen, R. A. Social Bookmarking                         What's this?

Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells

Department of Surgery and Cambridge Institute for Medical Research, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK

^* Author for correspondence (e-mail: lv225{at}cam.ac.uk)

Accepted 20 June 2005

Maintenance of pluripotency is crucial to the mammalian embryo's ability to generate the extra-embryonic and embryonic tissues that are needed for intrauterine survival and foetal development. The recent establishment of embryonic stem cells from human blastocysts (hESCs) provides an opportunity to identify the factors supporting pluripotency at early stages of human development. Using this in vitro model, we have recently shown that Nodal can block neuronal differentiation, suggesting that TGFß family members are involved in cell fate decisions of hESCs, including preservation of their pluripotency. Here, we report that Activin/Nodal signalling through Smad2/3 activation is necessary to maintain the pluripotent status of hESCs. Inhibition of Activin/Nodal signalling by follistatin and by overexpression of Lefty or Cerberus-Short, or by the Activin receptor inhibitor SB431542, precipitates hESC differentiation. Nevertheless, neither Nodal nor Activin is sufficient to sustain long-term hESC growth in a chemically defined medium without serum. Recent studies have shown that FGF2 can also maintain long-term expression of pluripotency markers, and we find that inhibition of the FGF signalling pathway by the tyrosine kinase inhibitor SU5402 causes hESC differentiation. However, this effect of FGF on hESC pluripotency depends on Activin/Nodal signalling, because it is blocked by SB431542. Finally, long-term maintenance of in-vitro pluripotency can be achieved with a combination of Activin or Nodal plus FGF2 in the absence of feeder-cell layers, conditioned medium or Serum Replacer. These findings suggest that the Activin/Nodal pathway maintains pluripotency through mechanism(s) in which FGF acts as a competence factor and therefore provide further evidence of distinct mechanisms for preservation of pluripotency in mouse and human ESCs.

Key words: Human embryonic stem cells, Pluripotency, Activin, Nodal, FGF

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				A. F. Schier Nodal Morphogens Cold Spring Harb Perspect Biol, November 1, 2009; 1(5): a003459 - a003459. [Abstract] [Full Text] [PDF]

				Y. Xia and A. L Schneyer The biology of activin: recent advances in structure, regulation and function J. Endocrinol., July 1, 2009; 202(1): 1 - 12. [Abstract] [Full Text] [PDF]

				H.-F. Chen, C.-Y. Chuang, Y.-K. Shieh, H.-W. Chang, H.-N. Ho, and H.-C. Kuo Novel autogenic feeders derived from human embryonic stem cells (hESCs) support an undifferentiated status of hESCs in xeno-free culture conditions Hum. Reprod., May 1, 2009; 24(5): 1114 - 1125. [Abstract] [Full Text] [PDF]

				L. Vallier, S. Mendjan, S. Brown, Z. Chng, A. Teo, L. E. Smithers, M. W. B. Trotter, C. H.-H. Cho, A. Martinez, P. Rugg-Gunn, et al. Activin/Nodal signalling maintains pluripotency by controlling Nanog expression Development, April 15, 2009; 136(8): 1339 - 1349. [Abstract] [Full Text] [PDF]

				S. Wang, Y. Shen, X. Yuan, K. Chen, X. Guo, Y. Chen, Y. Niu, J. Li, R.-H. Xu, X. Yan, et al. Dissecting Signaling Pathways That Govern Self-renewal of Rabbit Embryonic Stem Cells J. Biol. Chem., December 19, 2008; 283(51): 35929 - 35940. [Abstract] [Full Text] [PDF]

				M. K. Furue, J. Na, J. P. Jackson, T. Okamoto, M. Jones, D. Baker, R.-I. Hata, H. D. Moore, J. D. Sato, and P. W. Andrews Heparin promotes the growth of human embryonic stem cells in a defined serum-free medium PNAS, September 9, 2008; 105(36): 13409 - 13414. [Abstract] [Full Text] [PDF]

				Z. Wu, W. Zhang, G. Chen, L. Cheng, J. Liao, N. Jia, Y. Gao, H. Dai, J. Yuan, L. Cheng, et al. Combinatorial Signals of Activin/Nodal and Bone Morphogenic Protein Regulate the Early Lineage Segregation of Human Embryonic Stem Cells J. Biol. Chem., September 5, 2008; 283(36): 24991 - 25002. [Abstract] [Full Text] [PDF]

				B.V. Johnson, N. Shindo, P.D. Rathjen, J. Rathjen, and R.A. Keough Understanding pluripotency--how embryonic stem cells keep their options open Mol. Hum. Reprod., September 1, 2008; 14(9): 513 - 520. [Abstract] [Full Text] [PDF]

				J. Yu and J. A. Thomson Pluripotent stem cell lines Genes & Dev., August 1, 2008; 22(15): 1987 - 1997. [Abstract] [Full Text] [PDF]

				F. Ng, S. Boucher, S. Koh, K. S. R. Sastry, L. Chase, U. Lakshmipathy, C. Choong, Z. Yang, M. C. Vemuri, M. S. Rao, et al. PDGF, TGF-{beta}, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages Blood, July 15, 2008; 112(2): 295 - 307. [Abstract] [Full Text] [PDF]

				C. Unger, H. Skottman, P. Blomberg, M. Sirac Dilber, and O. Hovatta Good manufacturing practice and clinical-grade human embryonic stem cell lines Hum. Mol. Genet., April 15, 2008; 17(R1): R48 - R53. [Abstract] [Full Text] [PDF]

				N. C. Robson, D. J. Phillips, T. McAlpine, A. Shin, S. Svobodova, T. Toy, V. Pillay, N. Kirkpatrick, D. Zanker, K. Wilson, et al. Activin-A: a novel dendritic cell-derived cytokine that potently attenuates CD40 ligand-specific cytokine and chemokine production Blood, March 1, 2008; 111(5): 2733 - 2743. [Abstract] [Full Text] [PDF]

				S. Strom, J. Inzunza, K.-H. Grinnemo, K. Holmberg, E. Matilainen, A.-M. Stromberg, E. Blennow, and O. Hovatta Mechanical isolation of the inner cell mass is effective in derivation of new human embryonic stem cell lines Hum. Reprod., December 1, 2007; 22(12): 3051 - 3058. [Abstract] [Full Text] [PDF]

				L. Wang, T. C. Schulz, E. S. Sherrer, D. S. Dauphin, S. Shin, A. M. Nelson, C. B. Ware, M. Zhan, C.-Z. Song, X. Chen, et al. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling Blood, December 1, 2007; 110(12): 4111 - 4119. [Abstract] [Full Text] [PDF]

				R. Kitamura, T. Takahashi, N. Nakajima, K. Isodono, S. Asada, H. Ueno, T. Ueyama, T. Yoshikawa, H. Matsubara, and H. Oh Stage-Specific Role of Endogenous Smad2 Activation in Cardiomyogenesis of Embryonic Stem Cells Circ. Res., July 6, 2007; 101(1): 78 - 87. [Abstract] [Full Text] [PDF]

				G. A. Follows, M. E. Janes, L. Vallier, A. R. Green, and B. Gottgens Real-time PCR mapping of DNaseI-hypersensitive sites using a novel ligation-mediated amplification technique Nucleic Acids Res., April 3, 2007; 35(8): e56 - e56. [Abstract] [Full Text] [PDF]

				M. M. Shen Nodal signaling: developmental roles and regulation Development, March 15, 2007; 134(6): 1023 - 1034. [Abstract] [Full Text] [PDF]

				C. Allegrucci and L.E. Young Differences between human embryonic stem cell lines Hum. Reprod. Update, March 1, 2007; 13(2): 103 - 120. [Abstract] [Full Text] [PDF]

				A. B. Steiner, M. J. Engleka, Q. Lu, E. C. Piwarzyk, S. Yaklichkin, J. L. Lefebvre, J. W. Walters, L. Pineda-Salgado, P. A. Labosky, and D. S. Kessler FoxD3 regulation of Nodal in the Spemann organizer is essential for Xenopus dorsal mesoderm development Development, December 15, 2006; 133(24): 4827 - 4838. [Abstract] [Full Text] [PDF]

				H. Skottman and O. Hovatta Culture conditions for human embryonic stem cells. Reproduction, November 1, 2006; 132(5): 691 - 698. [Abstract] [Full Text] [PDF]

				Y. Nakatake, N. Fukui, Y. Iwamatsu, S. Masui, K. Takahashi, R. Yagi, K. Yagi, J.-i. Miyazaki, R. Matoba, M. S. H. Ko, et al. Klf4 Cooperates with Oct3/4 and Sox2 To Activate the Lefty1 Core Promoter in Embryonic Stem Cells Mol. Cell. Biol., October 15, 2006; 26(20): 7772 - 7782. [Abstract] [Full Text] [PDF]

				L. Armstrong, O. Hughes, S. Yung, L. Hyslop, R. Stewart, I. Wappler, H. Peters, T. Walter, P. Stojkovic, J. Evans, et al. The role of PI3K/AKT, MAPK/ERK and NF{kappa}{beta} signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis Hum. Mol. Genet., June 1, 2006; 15(11): 1894 - 1913. [Abstract] [Full Text] [PDF]

				S. Yao, S. Chen, J. Clark, E. Hao, G. M. Beattie, A. Hayek, and S. Ding Long-term self-renewal and directed differentiation of human embryonic stem cells in chemically defined conditions PNAS, May 2, 2006; 103(18): 6907 - 6912. [Abstract] [Full Text] [PDF]

				Y.-G. Chen, Q. Wang, S.-L. Lin, C. D. Chang, J. Chung, and S.-Y. Ying Activin Signaling and Its Role in Regulation of Cell Proliferation, Apoptosis, and Carcinogenesis. Experimental Biology and Medicine, May 1, 2006; 231(5): 534 - 544. [Abstract] [Full Text] [PDF]

				J. Lu, R. Hou, C. J. Booth, S.-H. Yang, and M. Snyder Defined culture conditions of human embryonic stem cells PNAS, April 11, 2006; 103(15): 5688 - 5693. [Abstract] [Full Text] [PDF]