TGF-β-superfamily signaling regulates embryonic stem cell heterogeneity: self-renewal as a dynamic and regulated equilibrium.
TGF-β-superfamily signaling regulates embryonic stem cell heterogeneity: self-renewal as a dynamic and regulated equilibrium.
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DOI：
10.1002/stem.1252
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发表时间：
2013-01
期刊：
影响因子：
5.2
通讯作者：
Vivian, Jay L.
中科院分区：
文献类型：
--
作者：
Galvin-Burgess, Katherine E.;Travis, Emily D.;Pierson, Kelsey E.;Vivian, Jay L.
胚胎干细胞在表型状态之间动态波动，如 Nanog 等基因的表达水平所定义，同时保持多能性。干细胞的动态表型部分由基因表达控制决定，并由各种信号通路和转录调节因子决定。我们试图确定两种 TGF-β 相关信号通路（骨形态发生蛋白 (BMP) 和 Nodal 信号通路）在未分化培养条件下调节小鼠胚胎干细胞异质性中的活性。 BMP 和 Nodal 信号通路在不同的 Nanog 亚群中均被认为是活跃的，但活性存在细微的数量差异。通过 Nanog 报告基因的动态表达评估，BMP 或 Nodal 信号传导的药理学和遗传调节强烈影响未分化 ES 细胞的异质状态。 Nodal 信号传导的抑制增强了 BMP 活性，通过下游靶 Id 因子增强了 ES 细胞保持 Nanog 高表观遗传状态的能力。即使在 LIF 存在的情况下，Nodal 和 BMP 信号传导的联合抑制也会导致 Nanog 阴性细胞的积累，揭示了 BMP 和 Nodal 信号传导在维持 Nanog 表达和抑制分化方面的共同作用。这些结果表明，TGF-β相关信号的两个分支对影响血清培养基中未分化ES细胞的动态细胞表型有复杂的要求，并且异质培养物中不同的ES细胞亚群对这些信号传导途径有不同的反应。包括 BMP、Nodal 和 FGF 信号传导在内的多种途径在定义干细胞异质性的稳态分布方面具有重要的调节功能。
Embryonic stem cells dynamically fluctuate between phenotypic states, as defined by expression levels of genes such as Nanog, while remaining pluripotent. The dynamic phenotype of stem cells is in part determined by gene expression control and dictated by various signaling pathways and transcriptional regulators. We sought to define the activities of two TGF-beta-related signaling pathways, Bone morphogenetic protein (BMP) and Nodal signaling, in modulating mouse embryonic stem cell heterogeneity in undifferentiated culture conditions. Both BMP and Nodal signaling pathways were seen to be active in distinct Nanog subpopulations, with subtle quantitative differences in activity. Pharmacological and genetic modulation of BMP or Nodal signaling strongly influenced the heterogeneous state of undifferentiated ES cells, as assessed by dynamic expression of Nanog reporters. Inhibition of Nodal signaling enhanced BMP activity, which through the downstream target Id factors, enhanced the capacity of ES cells to remain in the Nanog-high epigenetic state. The combined inhibition of Nodal and BMP signaling resulted the accumulation of Nanog-negative cells, even in the presence of LIF, uncovering a shared role for BMP and Nodal signaling in maintaining Nanog expression and repression of differentiation. These results demonstrate a complex requirement for both arms of TGF-beta-related signaling to influence the dynamic cellular phenotype of undifferentiated ES cells in serum-based media, and that differing subpopulations of ES cells in heterogeneous culture have distinct responses to these signaling pathways. Several pathways, including BMP, Nodal, and FGF signaling, have important regulatory function in defining the steady-state distribution of heterogeneity of stem cells.
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影响因子：
23.9
作者：
Hayashi K;de Sousa Lopes SMC;Tang F;Lao K;Surani MA
通讯作者：
Surani MA
影响因子：
64.5
作者：
BENEZRA, R;DAVIS, RL;WEINTRAUB, H
通讯作者：
WEINTRAUB, H
DOI：
10.1073/pnas.0401367101
发表时间：
2004-04-20
影响因子：
11.1
作者：
Qi, XX;Li, TG;Zhao, GQ
通讯作者：
Zhao, GQ
影响因子：
4
作者：
Ogawa, Kazuya;Saito, Akira;Miyazono, Kohei
通讯作者：
Miyazono, Kohei
影响因子：
64.5
作者：
Kim, Jonghwan;Chu, Jianlin;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.