A sequential EMT-MET mechanism drives the differentiation of human embryonic stem cells towards hepatocytes

Qiuhong Li, Andrew P. Hutchins, Yong Chen, Shengbiao Li, Yongli Shan, Baojian Liao, Dejin Zheng, Xi Shi, Yinxiong Li, Wai-Yee Chan, Guangjin Pan, Shicheng Wei, Xiaodong Shu () and Duanqing Pei ()
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Qiuhong Li: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Andrew P. Hutchins: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Yong Chen: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Shengbiao Li: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Yongli Shan: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Baojian Liao: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Dejin Zheng: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Xi Shi: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Yinxiong Li: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Wai-Yee Chan: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Guangjin Pan: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Shicheng Wei: Central Laboratory, School and Hospital of Stomatology, Peking University
Xiaodong Shu: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Duanqing Pei: CAS Key laboratory of Regenerative Biology, Guangdong Key laboratory of Stem Cell and Regenerative Medicine and CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute of Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15166

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