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Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT–MET mechanism for optimal reprogramming

Liu, Xiaopeng, Sun, Hao, Qi, Jing, Wang, Linli, He, Songwei, Liu, Jing, Feng, Chengqian, Chen, Chunlan, Li, Wen, Guo, Yunqian, Qin, Dajiang, Pan, Guangjin, Chen, Jiekai, Pei, Duanqing, Zheng, Hui·2013·Nature Cell Biology
DOI 10.1038/ncb2765
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Abstract

Present practices for reprogramming somatic cells to induced pluripotent stem cells involve simultaneous introduction of reprogramming factors. Here we report that a sequential introduction protocol (Oct4-Klf4 first, then c-Myc and finally Sox2) outperforms the simultaneous one. Surprisingly, the sequential protocol activates an early epithelial-to-mesenchymal transition (EMT) as indicated by the upregulation of Slug and N-cadherin followed by a delayed mesenchymal-to-epithelial transition (MET). An early EMT induced by 1.5-day TGF-β treatment enhances reprogramming with the simultaneous protocol, whereas 12-day treatment blocks reprogramming. Consistent results were obtained when the TGF-β antagonist Repsox was applied in the sequential protocol. These results reveal a time-sensitive role of individual factors for optimal reprogramming and a sequential EMT-MET mechanism at the start of reprogramming. Our studies provide a rationale for further optimizing reprogramming, and introduce the concept of a sequential EMT-MET mechanism for cell fate decision that should be investigated further in other systems, both in vitro and in vivo.

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  • Cells transition from the mesenchymal-to-epithelial state that is actively induced during the early phase and is required to progress through the reprogramming process.

    “At this point, cells also transition from the mesenchymal-to-epithelial state that is actively induced during this early phase and are required to progress through the reprogramming process [94][95][96] .”

    From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [95]

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Metadata

Authors
Liu, X., Sun, H., Qi, J., Wang, L., He, S., Liu, J., Feng, C., Chen, C., Li, W., Guo, Y., Qin, D., Pan, G., Chen, J., Pei, D., & Zheng, H.
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2013-05-26
Volume
15
Issue
7
Pages
829-838
ISSN
  • 1465-7392
  • 1476-4679
DOI
10.1038/ncb2765
Cited by
208
References
2
Language
en
Licence
www.springer.com/tdm (tdm)

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