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

By L. Vallier, Morgan Alexander, R. Pedersen. Journal of Cell Science, 2005

1,015 citations recorded by the source corpus.

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 TGFβ 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/04028085c4d5585c7044d71717be6e2a57c7641d

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In Molecular Biology

1. R. Derynck
2. K. Miyazono
3. S. Pauklin
4. L. Vallier
5. R. Weinberg
6. Nikolaos G. Frangogiannis
7. J. Massagué

Citations in the corpus

• Resetting Transcription Factor Control Circuitry toward Ground-State Pluripotency in Human (2014, neutral): “They are unresponsive to LIF but rely on growth factors, specifically fibroblast growth factor (FGF) and TGFb/activin (Amit et al., 2000; Vallier et al., 2005).”
• Capture of authentic embryonic stem cells from rat blastocysts. (2008, neutral): “In this respect they resemble primate embryo-derived stem cells (Thomson et al., 1998; Vallier et al., 2005; Xu et al., 2005).”
• Master Transcription Factors Determine Cell-Type-Specific Responses to TGF-β Signaling (2011, neutral): “…to DNA sites co-occupied by the master transcription factor OCT4 in human Cell 147, 565–576, October 28, 2011 ª2011 Elsevier Inc. 565 (h) ESCs, where activation of SMAD2/3 is required to maintain hESC identity (Beattie et al., 2005; James et al., 2005; Vallier et al., 2005, 2009; Xu et al., 2008).”
• Senescence impairs successful reprogramming to pluripotent stem cells. (2009, neutral): “(Bendall et al., 2007). hES cells can also be propagated in feederfree conditions, conditioned media or serum replacement if a combination of Activin plus FGF2 is used (Beattie et al., 2005; Vallier et al., 2005).”
• The Cell-Cycle State of Stem Cells Determines Cell Fate Propensity (2014, positive): “To overcome this limitation, we decided to adapt the FUCCI reporter system to hESCs (Figure 1A) grown in fully defined culture conditions (Vallier et al., 2005).”
• Control of Embryonic Stem Cell State (2011, neutral): “…al., 2003); 4 (Cole et al., 2008; Marson et al., 2008b); 5 (Niwa et al., 1998); 6 (Ying et al., 2003); 7 (Beattie et al., 2005; James et al., 2005; Vallier et al., 2005), 8 (Cartwright et al., 2005); 9 (Ivanova et al., 2006; Zhang et al., 2008); 10 (Wu et al., 2006; Zhang et al., 2006); 11 (Han…”
• TGF-β and the TGF-β Family: Context-Dependent Roles in Cell and Tissue Physiology. (2016, background): “These cells are usually maintained with FGF-2 and activin A (Beattie et al. 2005; James et al. 2005; Vallier et al. 2005), which stabilize the primed pluripotent state.”