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Induction of mouse totipotent stem cells by a defined chemical cocktail
Nature ( IF 64.8 ) Pub Date : 2022-06-21 , DOI: 10.1038/s41586-022-04967-9
Yanyan Hu 1, 2 , Yuanyuan Yang 1, 2 , Pengcheng Tan 1 , Yuxia Zhang 1 , Mengxia Han 1 , Jiawei Yu 1 , Xin Zhang 1 , Zeran Jia 1 , Dan Wang 1 , Ke Yao 1 , Huanhuan Pang 1 , Zeping Hu 1 , Yinqing Li 1 , Tianhua Ma 1 , Kang Liu 1 , Sheng Ding 1, 2
Affiliation  

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 challenging whether and how TotiSCs, representing the very beginning of a life, can be established in vitro in the absence of germline cells. Here, we demonstrate induction and long-term maintenance of TotiSCs from mouse pluripotent stem cells (PSCs) by a combination of three small molecules, TTNPB, 1-Azakenpaullone, and WS6. These cells, which we designated as ciTotiSCs (chemically induced totipotent stem cells), resembled mouse totipotent 2C-embryo stage cells at transcriptome, epigenome and metabolome level. 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 embryo, ciTotiSCs contributed to both embryonic and extraembryonic lineages with high efficiency. Our chemical approach for TotiSCs induction and maintenance provides a defined in vitro system to manipulate and understand totipotent state towards creating life from non-germline.



中文翻译:

通过确定的化学混合物诱导小鼠全能干细胞

在小鼠中,只有来自 2 细胞胚胎的受精卵和卵裂球才是真正的全能干细胞 (TotiSC),能够在胚胎和胚外组织中产生所有分化细胞​​并形成完整的生物体1。然而,代表生命最开始的 TotiSCs 能否以及如何在体外建立仍然具有挑战性在没有生殖细胞的情况下。在这里,我们展示了通过三种小分子 TTNPB、1-Azakenpaullone 和 WS6 的组合从小鼠多能干细胞 (PSC) 诱导和长期维持 TotiSC。我们将这些细胞命名为 ciTotiSC(化学诱导全能干细胞),在转录组、表观基因组和代谢组水平上类似于小鼠全能 2C 胚胎期细胞。此外,ciTotiSCs 表现出双向发育潜力,能够在体外和畸胎瘤产生胚胎和胚胎外细胞。此外,在注入 8 细胞胚胎后,ciTotiSCs 对胚胎和胚胎外谱系均有高效贡献。我们用于 TotiSCs 诱导和维持的化学方法提供了明确的体外系统来操纵和理解从非种系创造生命的全能状态。

更新日期:2022-06-21
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