Derivation of totipotent-like stem cells with blastocyst-like structure forming potential
Yaxing Xu, Jingru Zhao, Yixuan Ren, Xuyang Wang, Yulin Lyu, Bingqing Xie, Yiming Sun, Xiandun Yuan, Haiyin Liu, Weifeng Yang, Yenan Fu, Yu Yu, Yinan Liu, Rong Mu, Cheng Li, Jun Xu, Hongkui Deng
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.