Activation of the amino acid response modulates lineage specification during differentiation of murine embryonic stem cells.
Activation of the amino acid response modulates lineage specification during differentiation of murine embryonic stem cells.
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氨基酸反应的激活调节小鼠胚胎干细胞分化过程中的谱系规范。
DOI：
10.1152/ajpendo.00136.2013
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Kilberg,MichaelS
中科院分区：
文献类型：
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作者：
Shan,Jixiu;Hamazaki,Takashi;Tang,TiffanyA;Terada,Naohiro;Kilberg,MichaelS
在体细胞中，一系列由氨基酸限制激活的信号传导途径已被鉴定出来，并被称为氨基酸反应（AAR）。尽管体外培养期间营养限制可能产生有害影响很重要，但尚未在胚胎干细胞 (ESC) 中研究 AAR。 AAR 激活导致介导特定 AAR 途径的转录因子的预期增加，以及诱导 AAR 末端靶基因天冬酰胺合成酶。 AAR 的激活和 AAR 转录介质激活转录因子 (Atf) 4 的稳定敲低都不会对 ESC 的自我更新或多能性产生不利影响。在胚状体分化的 12 天期间，AAR 的低水平诱导确实改变了谱系规范，使得原始内胚层、内脏内胚层和内胚层谱系受到青睐，而中胚层和某些外胚层谱系受到抑制。 Atf4 的敲低进一步增强了 AAR 诱导的内胚层形成的增加，表明这种现象是由 Atf4 独立机制介导的。总的来说，结果表明，在培养物中小鼠胚体的分化过程中，氨基酸等营养物质的可用性可以影响特定细胞谱系的形成。
In somatic cells, a collection of signaling pathways activated by amino acid limitation have been identified and referred to as the amino acid response (AAR). Despite the importance of possible detrimental effects of nutrient limitation during in vitro culture, the AAR has not been investigated in embryonic stem cells (ESC). AAR activation caused the expected increase in transcription factors that mediate specific AAR pathways, as well as the induction of asparagine synthetase, a terminal AAR target gene. Neither AAR activation nor stable knockdown of activating transcription factor (Atf) 4, a transcriptional mediator of the AAR, adversely affected ESC self-renewal or pluripotency. Low-level induction of the AAR over a 12-day period of embryoid body differentiation did alter lineage specification such that the primitive endodermal, visceral endodermal, and endodermal lineages were favored, whereas mesodermal and certain ectodermal lineages were suppressed. Knockdown of Atf4 further enhanced the AAR-induced increase in endodermal formation, suggesting that this phenomenon is mediated by an Atf4-independent mechanism. Collectively, the results indicate that, during differentiation of mouse embryoid bodies in culture, the availability of nutrients, such as amino acids, can influence the formation of specific cell lineages.