A sequential EMT-MET mechanism drives the differentiation of human embryonic stem cells towards hepatocytes.
A sequential EMT-MET mechanism drives the differentiation of human embryonic stem cells towards hepatocytes.
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连续的 EMT-MET 机制驱动人胚胎干细胞向肝细胞分化。
DOI：
10.1038/ncomms15166
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发表时间：
2017-05-03
影响因子：
16.6
通讯作者：
Pei D
中科院分区：
文献类型：
--
作者：
Li Q;Hutchins AP;Chen Y;Li S;Shan Y;Liao B;Zheng D;Shi X;Li Y;Chan WY;Pan G;Wei S;Shu X;Pei D
重编程已被证明涉及EMT-MET;然而，其在细胞分化中的作用尚不清楚。我们在这里报告，在体外分化的人胚胎干细胞肝谱系经历了一个连续的EMT-MET与强制性中间间充质阶段。基因表达分析表明，激活素A诱导的定形内胚层（DE）的形成伴随着由自分泌TGFβ信号传导介导的同步EMT，随后是MET过程。TGFβ信号传导的药理学抑制阻断EMT以及DE形成。然后，我们确定SNAI 1作为DE的规范所需的关键EMT转录因子。hESC中SNAI 1的基因消除不影响多能性或神经分化的维持，但完全破坏DE的形成。这些结果揭示了DE获得过程中的关键间充质阶段，突出了顺序EMT-MET在分化和重编程中的作用。重编程已被证明涉及EMT-MET;然而，其在细胞分化中的作用尚不清楚。在此，作者表明，在肝细胞的体外分化过程中，激活素A诱导的定形内胚层的形成需要TGFβ信号传导介导的EMT，然后是MET过程。
Reprogramming has been shown to involve EMT–MET; however, its role in cell differentiation is unclear. We report here that in vitro differentiation of hESCs to hepatic lineage undergoes a sequential EMT–MET with an obligatory intermediate mesenchymal phase. Gene expression analysis reveals that Activin A-induced formation of definitive endoderm (DE) accompanies a synchronous EMT mediated by autocrine TGFβ signalling followed by a MET process. Pharmacological inhibition of TGFβ signalling blocks the EMT as well as DE formation. We then identify SNAI1 as the key EMT transcriptional factor required for the specification of DE. Genetic ablation of SNAI1 in hESCs does not affect the maintenance of pluripotency or neural differentiation, but completely disrupts the formation of DE. These results reveal a critical mesenchymal phase during the acquisition of DE, highlighting a role for sequential EMT–METs in both differentiation and reprogramming. Reprogramming has been shown to involve EMT-MET; however, its role in cell differentiation is unclear. Here the authors show that during in vitro differentiation of hepatocytes, Activin A-induced formation of definitive endoderm requires EMT mediated by TGFβ signalling, followed by a MET process.