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• W2023762552 abstract "The TGFβ/activin signaling pathway is important for the maintenance of human embryonic stem cells. In this issue of Cell Stem Cell, Xu et al., 2008Xu R. Barron T.L. Gu F. Root S. Peck R.M. Pan G. Yu J. Antosiewicz-Bourget J. Tian S. Stewart R. Thomson J.A. Cell Stem Cell. 2008; 3 (this issue): 196-206Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar show that this pathway upregulates the expression of a key pluripotency gene NANOG through SMAD2/3. The TGFβ/activin signaling pathway is important for the maintenance of human embryonic stem cells. In this issue of Cell Stem Cell, Xu et al., 2008Xu R. Barron T.L. Gu F. Root S. Peck R.M. Pan G. Yu J. Antosiewicz-Bourget J. Tian S. Stewart R. Thomson J.A. Cell Stem Cell. 2008; 3 (this issue): 196-206Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar show that this pathway upregulates the expression of a key pluripotency gene NANOG through SMAD2/3. Pluripotent embryonic stem cells (ESCs) have been derived from the blastocysts of various mammals, and they can be propagated in vitro under conditions that promote self-renewal (Rossant, 2008Rossant J. Cell. 2008; 132: 527-531Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). A distinctive difference between human and mouse ESCs is the requirement for different growth factors during the in vitro culture of these cells. Work performed over the past decade has defined the growth factors necessary to propagate ESCs in the absence of serum or feeder cells (Rao and Zandstra, 2005Rao B.M. Zandstra P.W. Curr. Opin. Biotechnol. 2005; 16: 568-576Crossref PubMed Scopus (63) Google Scholar). Mouse ESCs remain undifferentiated in the presence of leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) (Ying et al., 2003Ying Q.L. Nichols J. Chambers I. Smith A. Cell. 2003; 115: 281-292Abstract Full Text Full Text PDF PubMed Scopus (1705) Google Scholar). The LIF and BMP pathways activate Stat3 and Smad1, respectively (Ying et al., 2003Ying Q.L. Nichols J. Chambers I. Smith A. Cell. 2003; 115: 281-292Abstract Full Text Full Text PDF PubMed Scopus (1705) Google Scholar, Boiani and Schöler, 2005Boiani M. Schöler H.R. Nat. Rev. Mol. Cell Biol. 2005; 6: 872-884Crossref PubMed Scopus (561) Google Scholar). In contrast, the propagation of human ESCs does not require LIF, and BMPs promote trophectoderm differentiation. Instead, most feeder-free culture conditions for human ESCs require the supplement of basic fibroblast growth factor (bFGF) and transforming growth factor β (TGFβ)/activin (Rao and Zandstra, 2005Rao B.M. Zandstra P.W. Curr. Opin. Biotechnol. 2005; 16: 568-576Crossref PubMed Scopus (63) Google Scholar). Hence, there is tremendous interest in understanding how the various types of pluripotent stem cells make use of different growth factors that operate through seemingly diverse signaling pathways to maintain the self-renewing state. The TGFβ/activin signaling is transmitted by the phosphorylation of SMAD2/3, which is abundant in undifferentiated human ESCs. Inhibition of TGFβ/activin receptors by the chemical inhibitor SB431542 reduces SMAD2/3 phosphorylation and induces differentiation. The target genes of SMAD2/3 and the roles they play in ESC self-renewal are not known. Both mouse and human ESCs specifically upregulate a set of common transcription factors, such as Oct4, Sox2, and Nanog, which constitute the “core” intrinsic factors that are required to sustain the self-renewing and pluripotent cellular state (Boiani and Schöler, 2005Boiani M. Schöler H.R. Nat. Rev. Mol. Cell Biol. 2005; 6: 872-884Crossref PubMed Scopus (561) Google Scholar). In this issue, Thomson and colleagues show that SMAD2/3 bind directly to the NANOG proximal promoter in human ESCs (Xu et al., 2008Xu R. Barron T.L. Gu F. Root S. Peck R.M. Pan G. Yu J. Antosiewicz-Bourget J. Tian S. Stewart R. Thomson J.A. Cell Stem Cell. 2008; 3 (this issue): 196-206Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar). Mutations introduced to the SMAD-binding elements reduced NANOG proximal promoter activity, indicating that the SMAD binding sites are important cis-regulatory elements. Furthermore, the NANOG promoter activity is less active when human ESCs are treated with the SB431542 inhibitor or upon TGFβ1 withdrawal. This study also sets the stage for addressing some interesting questions. What are the other target genes of SMAD2/3 in human ESCs? Besides SMAD2/3, what other transcription factors are controlled by the TGFβ/activin pathway? Strikingly, the authors also show that overexpression of NANOG can bypass the requirement for TGFβ/activin and bFGF. This finding strongly suggests that the two signaling pathways promote pluripotency of human ESCs through the sustained expression of NANOG. This result raises the possibility that the FGF pathway may also directly regulate pluripotency genes such as NANOG. Overall, this interesting study provides the first key evidence that the TGFβ/activin signaling cascade activates a critical pluripotency gene in human ESCs via SMAD2/3 (Figure 1A). Unlike SMAD2/3, BMP-responsive SMADs such as SMAD1, SMAD5, and SMAD8 appear to have a repressive role for the expression of pluripotency-associated genes in human ESCs. Xu et al. also demonstrate that SMAD1 binds to the NANOG promoter (Xu et al., 2008Xu R. Barron T.L. Gu F. Root S. Peck R.M. Pan G. Yu J. Antosiewicz-Bourget J. Tian S. Stewart R. Thomson J.A. Cell Stem Cell. 2008; 3 (this issue): 196-206Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar). BMP4 treatment, which induces trophectoderm differentiation, leads to increased SMAD1 occupancy. Although it is not clear if SMAD2/3 compete with SMAD1/5/8 for the Smad-binding elements at the NANOG promoter, the result suggests that an intricate balance of SMAD2/3 and SMAD1/5/8 could modulate the expression of NANOG and potentially determine the choice between undifferentiated and lineage-committed fates. The findings of Xu et al. also underscore the potential impact of slight variances in the culture conditions used to maintain human ESCs in different settings. That is, as the specific combination and concentration of growth factors present in human ESC cultures is likely to impact directly on the expression of pluripotency gene(s), comparisons of the proliferative or pluripotent state of these cells between protocols may not be accurate or reliable. The BMP/Smad1 pathway appears to function differently in mouse ESCs. Smad1 has been shown to interact with Nanog and bind to the Nanog enhancer element in a BMP4-dependent manner (Suzuki et al., 2006Suzuki A. Raya A. Kawakami Y. Morita M. Matsui T. Nakashima K. Gage F.H. Rodríguez-Esteban C. Izpisúa Belmonte J.C. Proc. Natl. Acad. Sci. USA. 2006; 103: 10294-10299Crossref PubMed Scopus (207) Google Scholar, Chen et al., 2008Chen X. Xu H. Yuan P. Fang F. Huss M. Vega V.B. Wong E. Orlov Y.L. Zhang W. Jiang J. et al.Cell. 2008; 133: 1106-1117Abstract Full Text Full Text PDF PubMed Scopus (1940) Google Scholar; Figure 1B). Genome-wide mapping of Smad1- and Nanog-binding locations reveal that the two transcriptional regulatory circuitries are integrated through extensive co-occupancy across the entire genome (Chen et al., 2008Chen X. Xu H. Yuan P. Fang F. Huss M. Vega V.B. Wong E. Orlov Y.L. Zhang W. Jiang J. et al.Cell. 2008; 133: 1106-1117Abstract Full Text Full Text PDF PubMed Scopus (1940) Google Scholar). Hence, it will be of interest to examine if human NANOG interacts with SMAD2/3 or SMAD1/5/8 (Figure 1A) and whether NANOG-binding loci overlap substantially with the SMADs in human ESCs. If such a biochemical link is found, then it will further connect NANOG to the SMAD pathway in a manner that has been described in mouse ESCs. Although signal-modulated transcriptional regulation is important to mediate rapid control over the expression of Nanog, a recent study uncovered a novel mode of regulating Nanog at the posttranslational level (Fujita et al., 2008Fujita J. Crane A.M. Souza M.K. Dejosez M. Kyba M. Flavell R.A. Thomson J.A. Zwaka T.P. Cell Stem Cell. 2008; 2: 595-601Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar). Zwaka and colleagues show that Caspase-3 is involved in cleaving Nanog, which provides an efficient way to destroy the gene product controlling pluripotency. This pathway may allow ESCs to respond rapidly to disassemble the pluripotency regulatory network upon differentiation. Pluripotent mouse cell lines that are capable of expansion in human ESC media (containing FGF2 and activin or a serum replacement supplement) have been derived from the late epiblast layer of postimplantation mouse embryos (Brons et al., 2007Brons I.G. Smithers L.E. Trotter M.W. Rugg-Gunn P. Sun B. Chuva de Sousa Lopes S.M. Howlett S.K. Clarkson A. Ahrlund-Richter L. Pedersen R.A. et al.Nature. 2007; 448: 191-195Crossref PubMed Scopus (1547) Google Scholar, Tesar et al., 2007Tesar P.J. Chenoweth J.G. Brook F.A. Davies T.J. Evans E.P. Mack D.L. Gardner R.L. McKay R.D. Nature. 2007; 448: 196-199Crossref PubMed Scopus (1676) Google Scholar). These cell lines are known as epiblast stem cells (EpiSCs). Although the growth factor requirements for mouse ESCs and EpiSCs are different, both cell types express pluripotency markers such as Oct4, Sox2, and Nanog. Given the current findings of Xu et al., it will be of interest to investigate if the TGFβ/activin/Smad2/3 pathway regulates Nanog and other pluripotency genes in EpiSCs (Figure 1C). If so, EpiSCs will be revealed to utilize the same molecular pathway as human ESCs to mediate self-renewal. The binding sites of Oct4 in human ESCs, mouse ESCs, and EpiSCs have been profiled by chromatin immunoprecipitation coupled to microarray analysis (Tesar et al., 2007Tesar P.J. Chenoweth J.G. Brook F.A. Davies T.J. Evans E.P. Mack D.L. Gardner R.L. McKay R.D. Nature. 2007; 448: 196-199Crossref PubMed Scopus (1676) Google Scholar). While limited overlap of Oct4 targets was observed between mouse and human ESCs, mouse EpiSCs share more similar binding profiles with human ESCs. This finding raises the possibility that specific growth factor-induced signaling pathways may modulate the repertoire of binding sites used in different pluripotent cells. Hence, the utilization of distinct signal cascades during the maintenance of human and mouse pluripotent cells provides an interesting paradigm that demonstrates the impact of extrinsically mediated transcription factor activation on the intrinsic pluripotent cell gene and transcription factor network. Comparative studies using pluripotent stem cells from different sources and in different growth conditions should yield interesting insights into the universality of the transcriptional regulatory networks that mediate pluripotency. Such lessons could then be applied to efforts designed to induce pluripotency in somatic cells and also regulate their subsequent directed differentiation to specific desired lineages. NANOG Is a Direct Target of TGFβ/Activin-Mediated SMAD Signaling in Human ESCsXu et al.Cell Stem CellAugust 07, 2008In BriefSelf-renewal of human embryonic stem cells (ESCs) is promoted by FGF and TGFβ/Activin signaling, and differentiation is promoted by BMP signaling, but how these signals regulate genes critical to the maintenance of pluripotency has been unclear. Using a defined medium, we show here that both TGFβ and FGF signals synergize to inhibit BMP signaling; sustain expression of pluripotency-associated genes such as NANOG, OCT4, and SOX2; and promote long-term undifferentiated proliferation of human ESCs. Full-Text PDF Open Archive" @default.
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• W2023762552 title "TGFβ and SMADs Talk to NANOG in Human Embryonic Stem Cells" @default.
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