Journal
CELL DISCOVERY
Volume 3, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/celldisc.2017.17
Keywords
TuJ(+) cells; sequential EMT-MET; proliferation; Sox2
Categories
Funding
- National Natural Science Foundation of China [31422032, 31671475, U1601228, 91519305, 31421004]
- CAS [QYZDB-SSW-SMC031]
- Guangdong Natural Science Foundation [2014A030308002]
- Guangzhou Science and Technology Program [201607010239]
- Guangzhou Health Care Collaborative Innovation Program [201508020250]
- Guangdong Special Support Program [2014TQ01R157]
- Ministry of Finance [ZDYZ2012-3]
- Guangzhou Branch of the Supercomputing Center of CAS
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Direct neuronal conversion can be achieved with combinations of small-molecule compounds and growth factors. Here, by studying the first or induction phase of the neuronal conversion induced by defined 5C medium, we show that the Sox2-mediated switch from early epithelial-mesenchymal transition (EMT) to late mesenchymal-epithelial transition (MET) within a high proliferation context is essential and sufficient for the conversion from mouse embryonic fibroblasts (MEFs) to TuJ(+) cells. At the early stage, insulin and basic fibroblast growth factor (bFGF)-induced cell proliferation, early EMT, the up-regulation of Stat3 and Sox2, and the subsequent activation of neuron projection. Up-regulated Sox2 then induced MET and directed cells towards a neuronal fate at the late stage. Inhibiting either stage of this sequential EMT-MET impaired the conversion. In addition, Sox2 could replace sequential EMT-MET to induce a similar conversion within a high proliferation context, and its functions were confirmed with other neuronal conversion protocols and MEFs reprogramming. Therefore, the critical roles of the sequential EMT-MET were implicated in direct cell fate conversion in addition to reprogramming, embryonic development and cancer progression.
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