Induction of mouse totipotent stem cells by a defined chemical cocktail

Yanyan Hu, Yuanyuan Yang, Pengcheng Tan, Yuxia Zhang, Mengxia Han, Jiawei Yu, Xin Zhang, Zeran Jia, Dan Wang, Ke Yao, Huanhuan Pang, Zeping Hu, Yinqing Li, Tianhua Ma (), Kang Liu () and Sheng Ding ()
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Yanyan Hu: Tsinghua University
Yuanyuan Yang: Tsinghua University
Pengcheng Tan: Tsinghua University
Yuxia Zhang: Tsinghua University
Mengxia Han: Tsinghua University
Jiawei Yu: Tsinghua University
Xin Zhang: Tsinghua University
Zeran Jia: Tsinghua University
Dan Wang: Tsinghua University
Ke Yao: Tsinghua University
Huanhuan Pang: Tsinghua University
Zeping Hu: Tsinghua University
Yinqing Li: Tsinghua University
Tianhua Ma: Tsinghua University
Kang Liu: Tsinghua University
Sheng Ding: Tsinghua University

Nature, 2023, vol. 617, issue 7962, 792-797

Abstract: Abstract In mice, only the zygotes and blastomeres from 2-cell embryos are authentic totipotent stem cells (TotiSCs) capable of producing all the differentiated cells in both embryonic and extraembryonic tissues and forming an entire organism1. However, it remains unknown whether and how totipotent stem cells can be established in vitro in the absence of germline cells. Here we demonstrate the induction and long-term maintenance of TotiSCs from mouse pluripotent stem cells using a combination of three small molecules: the retinoic acid analogue TTNPB, 1-azakenpaullone and the kinase blocker WS6. The resulting chemically induced totipotent stem cells (ciTotiSCs), resembled mouse totipotent 2-cell embryo cells at the transcriptome, epigenome and metabolome levels. In addition, ciTotiSCs exhibited bidirectional developmental potentials and were able to produce both embryonic and extraembryonic cells in vitro and in teratoma. Furthermore, following injection into 8-cell embryos, ciTotiSCs contributed to both embryonic and extraembryonic lineages with high efficiency. Our chemical approach to totipotent stem cell induction and maintenance provides a defined in vitro system for manipulating and developing understanding of the totipotent state and the development of multicellular organisms from non-germline cells.

Date: 2023
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DOI: 10.1038/s41586-022-04967-9

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