Volume 32, No 6, Jun 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 6, June 2022: 513-529   |  Open Access

ORIGINAL ARTICLES

Derivation of totipotent-like stem cells with blastocyst-like structure forming potential

Yaxing Xu^1,† , Jingru Zhao^1,† , Yixuan Ren^1,† , Xuyang Wang^1,† , Yulin Lyu^2,† , Bingqing Xie¹ , Yiming Sun² , Xiandun Yuan³ , Haiyin Liu¹ , Weifeng Yang⁴ , Yenan Fu⁵ , Yu Yu⁵ , Yinan Liu⁶ , Rong Mu³ , Cheng Li^2,* , Jun Xu^6,* , Hongkui Deng^1,*

¹MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
²School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China
³Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
⁴Beijing Vitalstar Biotechnology Co., Ltd, Beijing, China
⁵5 Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, PKU International Cancer Institute; MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, China
⁶Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University Health Science Center, Peking University, Beijing, China
^†These authors contributed equally: Yaxing Xu, Jingru Zhao, Yixuan Ren, Xuyang Wang, Yulin Lyu
Correspondence: Cheng Li(cheng_li@pku.edu.cn)Jun Xu(jun_xu@bjmu.edu.cn)Hongkui Deng(hongkui_deng@pku.edu.cn)

It is challenging to derive totipotent stem cells in vitro that functionally and molecularly resemble cells from totipotent embryos. Here, we report that a chemical cocktail enables the derivation of totipotent-like stem cells, designated as totipotent potential stem (TPS) cells, from 2-cell mouse embryos and extended pluripotent stem cells, and that these TPS cells can be stably maintained long term in vitro. TPS cells shared features with 2-cell mouse embryos in terms of totipotency markers, transcriptome, chromatin accessibility and DNA methylation patterns. In vivo chimera formation assays show that these cells have embryonic and extraembryonic developmental potentials at the single-cell level. Moreover, TPS cells can be induced into blastocyst-like structures resembling preimplantation mouse blastocysts. Mechanistically, inhibition of HDAC1/2 and DOT1L activity and activation of RARγ signaling are important for inducing and maintaining totipotent features of TPS cells. Our study opens up a new path toward fully capturing totipotent stem cells in vitro.

https://doi.org/10.1038/s41422-022-00668-0

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