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

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

  • Cell Res. 2022 Jun;32(6):513-529. doi: 10.1038/s41422-022-00668-0.
Yaxing Xu  # 1,  Jingru Zhao  # 1,  Yixuan Ren  # 1,  Xuyang Wang  # 1,  Yulin Lyu  # 2,  Bingqing Xie 1,  Yiming Sun 2,  Xiandun Yuan 3,  Haiyin Liu 1,  Weifeng Yang 4,  Yenan Fu 5,  Yu Yu 5,  Yinan Liu 6,  Rong Mu 3,  Cheng Li 7,  Jun Xu 8,  Hongkui Deng 9
Affiliations

Affiliations

  • 1 MOE 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.
  • 2 School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China.
  • 3 Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China.
  • 4 Beijing Vitalstar Biotechnology Co., Ltd, Beijing, China.
  • 5 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.
  • 6 Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University Health Science Center, Peking University, Beijing, China.
  • 7 School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China. cheng_li@pku.edu.cn.
  • 8 Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University Health Science Center, Peking University, Beijing, China. jun_xu@bjmu.edu.cn.
  • 9 MOE 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. hongkui_deng@pku.edu.cn.
  • # Contributed equally.
PMID: 35508506 DOI: 10.1038/s41422-022-00668-0
Abstract

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.

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