Suying Cao
Liang Zhong
Hanning Wang
Yangli Pei
Qingqing Wei
Bingqiang Wen
Haiyuan Mu
Shaopeng Zhang
Liang Yue
Genhua Yue
Bing Lim
Jianyong Han
1 State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China;
2 Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China;
3 Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore;
4 Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore 138672, Singapore;
5 Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100193, China;
6 State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
Funds: This work was supported by The National Key Research and Development Program of China (2016YFA0100202), National Natural Science Foundation of China (Grant Nos. 31571497 and 31601941), Beijing Natural Science Foundation of China (6152004), The National Thousand Talents Program of China and Research Programs from the State Key Laboratory for Agrobiotechnology, China Agricultural University (grant numbers 2015SKLAB1-4, 2017SKLAB1-2). The authors acknowledge Dr. Andras Nagy, Kristina Vintersten, and Marina Gertsenstein in Mount Sinai Hospital for their support of R1 and G4-DsRed mouse ESCs. We also wish to thank members of our laboratories for their support.
Received Date: 2017-06-26
Rev Recd Date:2017-08-22
Abstract
Abstract
It is not fully clear why there is a higher contribution of pluripotent stem cells (PSCs) to the chimera produced by injection of PSCs into 4-cell or 8-cell stage embryos compared with blastocyst injection. Here, we show that not only embryonic stem cells (ESCs) but also induced pluripotent stem cells (iPSCs) can generate F0 nearly 100% donor cell-derived mice by 4-cell stage embryo injection, and the approach has a "dose effect". Through an analysis of the PSC-secreted proteins, Activin A was found to impede epiblast (EPI) lineage development while promoting trophectoderm (TE) differentiation, resulting in replacement of the EPI lineage of host embryos with PSCs. Interestingly, the injection of ESCs into blastocysts cultured with Activin A (cultured from 4-cell stage to early blastocyst at E3.5) could increase the contribution of ESCs to the chimera. The results indicated that PSCs secrete protein Activin A to improve their EPI competency after injection into recipient embryos through influencing the development of mouse early embryos. This result is useful for optimizing the chimera production system and for a deep understanding of PSCs effects on early embryo development.Keywords: pluripotent stem cells,
4-cell embryo injection,
secreted proteins,
Activin A,
chimeric mice
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