TGFβ/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells

By D. James, Ariel J. Levine, D. Besser, A. Hemmati‐Brivanlou. 2005

833 citations recorded by the source corpus.

Human embryonic stem cells (hESCs) self-renew indefinitely and give rise to derivatives of all three primary germ layers, yet little is known about the signaling cascades that govern their pluripotent character. Because it plays a prominent role in the early cell fate decisions of embryonic development, we have examined the role of TGFβ superfamily signaling in hESCs. We found that, in undifferentiated cells, the TGFβ/activin/nodal branch is activated (through the signal transducer SMAD2/3) while the BMP/GDF branch (SMAD1/5) is only active in isolated mitotic cells. Upon early differentiation, SMAD2/3 signaling is decreased while SMAD1/5 signaling is activated. We next tested the functional role of TGFβ/activin/nodal signaling in hESCs and found that it is required for the maintenance of markers of the undifferentiated state. We extend these findings to show that SMAD2/3 activation is required downstream of WNT signaling, which we have previously shown to be sufficient to maintain the undifferentiated state of hESCs. Strikingly, we show that in ex vivo mouse blastocyst cultures, SMAD2/3 signaling is also required to maintain the inner cell mass (from which stem cells are derived). These data reveal a crucial role for TGFβ signaling in the earliest stages of cell fate determination and demonstrate an interconnection between TGFβ and WNT signaling in these contexts.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/567365c2522a4d88c7ef4a75e24668829f602b65

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Citations in the corpus

Feeder-independent culture of human embryonic stem cells (2006, background): “, and based on inhibitor studies, it has been suggested that TGFβ/activin signaling is essential for human embryonic stem cell self-renewa”
Efficient differentiation of human embryonic stem cells to definitive endoderm (2005, background): “It appears that under conditions optimized for growth of undifferentiated hES cells, TGFβ ligands promote maintenance of pluripotenc”
Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits (2009, background): “and have demonstrated its essential role in maintaining the pluripotency of human embryonic stem cell”
Core transcriptional regulatory circuitry in human embryonic stem cells. (2005, background): “All ive of these genes have been implicated in pluripoency (James et al., 2005; Mitsui et al., 2003; Chambers t al., 2003; Nichols et al., 1998; Bortvin et al., 2003). oreover, several genes that encode developmentally mportant homeodomain proteins such as DLX5, HOXB1, HX5, TITF1, LBX1, and HOP…”
Control of Embryonic Stem Cell State (2011, neutral): “…al., 2004; Mitsui et 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…”
Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells (2005, background): “…regulate these mechanisms, however the function and the interaction of these pathways are still largely unexplored (Amit et al., 2000; Amit et al., 2004; Beattie et al., 2005; James et al., 2005; Schuldiner et al., 2000; Wang et al., 2005a; Wang et al., 2005b; Xu et al., 2005a; Xu et al., 2005b).”
TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal (2008, neutral): “, whereas self-renewal of hESCs requires Activin/Nodal/TGFβ-regulated Smad2/3 (ref”
Master Transcription Factors Determine Cell-Type-Specific Responses to TGF-β Signaling (2011, neutral): “Although human and murine (m) ESCs respond differently to TGF-b signaling (James et al., 2005), both cell types require the master transcription factor Oct4 to maintain cell identity (Chambers and Smith, 2004), so we investigated whether Smad3 also co-occupies sites with Oct4 in mESCs.”
Molecular definition of breast tumor heterogeneity. (2007, background): “…activated in CD44+ breast cancer cells is the TGF-b signaling pathway, known to play an important role in human embryonic stem cells as well as in tumorigenesis (James et al., 2005; Moses and Serra, 1996; Muraoka-Cook et al., 2005; Roberts and Wakefield, 2003; Siegel and Massague, 2003).”