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, Sheng Ding

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)792-797
Number of pages6
JournalNature
Volume617
Issue number7962
DOIs
StatePublished - May 25 2023
Externally publishedYes

ASJC Scopus subject areas

  • General

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