Rolling back human pluripotent stem cells to an eight-cell embryo-like stage

Md. Abdul Mazid (), Carl Ward, Zhiwei Luo, Chuanyu Liu, Yunpan Li, Yiwei Lai, Liang Wu, Jinxiu Li, Wenqi Jia, Yu Jiang, Hao Liu, Lixin Fu, Yueli Yang, David P. Ibañez, Junjian Lai, Xiaoyu Wei, Juan An, Pengcheng Guo, Yue Yuan, Qiuting Deng, Yang Wang, Ying Liu, Fei Gao, Junwen Wang, Shahriar Zaman, Baoming Qin, Guangming Wu, Patrick H. Maxwell, Xun Xu, Longqi Liu (), Wenjuan Li () and Miguel A. Esteban ()
Additional contact information
Md. Abdul Mazid: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Carl Ward: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Zhiwei Luo: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Chuanyu Liu: BGI-Shenzhen
Yunpan Li: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Yiwei Lai: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Liang Wu: University of Chinese Academy of Sciences
Jinxiu Li: University of Chinese Academy of Sciences
Wenqi Jia: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Yu Jiang: Jilin University
Hao Liu: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Lixin Fu: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Yueli Yang: Jilin University
David P. Ibañez: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Junjian Lai: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Xiaoyu Wei: University of Chinese Academy of Sciences
Juan An: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Pengcheng Guo: Jilin University
Yue Yuan: University of Chinese Academy of Sciences
Qiuting Deng: University of Chinese Academy of Sciences
Yang Wang: BGI-Shenzhen
Ying Liu: BGI-Shenzhen
Fei Gao: Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences
Junwen Wang: E-GENE
Shahriar Zaman: University of Rajshahi
Baoming Qin: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Guangming Wu: Guangzhou Laboratory
Patrick H. Maxwell: University of Cambridge
Xun Xu: BGI-Shenzhen
Longqi Liu: BGI-Shenzhen
Wenjuan Li: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Miguel A. Esteban: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences

Nature, 2022, vol. 605, issue 7909, 315-324

Abstract: Abstract After fertilization, the quiescent zygote experiences a burst of genome activation that initiates a short-lived totipotent state. Understanding the process of totipotency in human cells would have broad applications. However, in contrast to in mice1,2, demonstration of the time of zygotic genome activation or the eight-cell (8C) stage in in vitro cultured human cells has not yet been reported, and the study of embryos is limited by ethical and practical considerations. Here we describe a transgene-free, rapid and controllable method for producing 8C-like cells (8CLCs) from human pluripotent stem cells. Single-cell analysis identified key molecular events and gene networks associated with this conversion. Loss-of-function experiments identified fundamental roles for DPPA3, a master regulator of DNA methylation in oocytes3, and TPRX1, a eutherian totipotent cell homeobox (ETCHbox) family transcription factor that is absent in mice4. DPPA3 induces DNA demethylation throughout the 8CLC conversion process, whereas TPRX1 is a key executor of 8CLC gene networks. We further demonstrate that 8CLCs can produce embryonic and extraembryonic lineages in vitro or in vivo in the form of blastoids5 and complex teratomas. Our approach provides a resource to uncover the molecular process of early human embryogenesis.

Date: 2022
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DOI: 10.1038/s41586-022-04625-0

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