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Nat Commun. 2017 May 3;8:15166. doi: 10.1038/ncomms15166.

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

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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, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
Central Laboratory, School and Hospital of Stomatology, Peking University, Beijing 100871, China.
Center for Biomedical Materials and Tissue Engineering, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China.


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.

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