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Selection and dynamics of embryonic stem cell integration into early mouse embryos.

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Alexandrova, Stoyana 
Kalkan, Tuzer 
Humphreys, Peter 
Riddell, Andrew 
Scognamiglio, Roberta 


The process by which pluripotent cells incorporate into host embryos is of interest to investigate cell potency and cell fate decisions. Previous studies suggest that only a minority of the embryonic stem cell (ESC) inoculum contributes to the adult chimaera. How incoming cells are chosen for integration or elimination remains unclear. By comparing a heterogeneous mix of undifferentiated and differentiating ESCs (serum/LIF) with more homogeneous undifferentiated culture (2i/LIF), we examine the role of cellular heterogeneity in this process. Time-lapse ex vivo imaging revealed a drastic elimination of serum/LIF ESCs during early development in comparison with 2i/LIF ESCs. Using a fluorescent reporter for naive pluripotency (Rex1-GFP), we established that the acutely eliminated serum/LIF ESCs had started to differentiate. The rejected cells were apparently killed by apoptosis. We conclude that a selection process exists by which unwanted differentiating cells are eliminated from the embryo. However, occasional Rex1(-) cells were able to integrate. Upregulation of Rex1 occurred in a proportion of these cells, reflecting the potential of the embryonic environment to expedite diversion from differentiation priming to enhance the developing embryonic epiblast.



Chimaera, Embryonic stem cell, Live imaging, Mouse blastocyst, Pluripotency, Animals, Apoptosis, Blastocyst, Cell Differentiation, Cells, Cultured, Chimera, Embryo Transfer, Embryonic Development, Embryonic Stem Cells, Mice, Mice, Inbred C57BL, Pluripotent Stem Cells, Time-Lapse Imaging, Transcription Factors

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The Company of Biologists
Wellcome Trust (097922/Z/11/B)
We thank Samuel Jameson and the Stem Cell and Gurdon Institute animal facilities for mouse husbandry, Carla Mulas for providing mKO-Rex1-GFP ESC line and the homozygous Rex1GFPd2 ESC line, Kenneth Jones for expert tissue culture assistance, Bernhard Strauss for instruction in embryo immobilisation, Charles Dumeau and Bill Mansfield for embryo transfers and animal photography. We are also indebted to Tristan Rodriguez and Austin Smith for valuable discussions, and Thorsten Boroviak and Sarra Achourri for helpful comments on the manuscript. This work was supported by the Wellcome Trust, Medical Research Council, University of Cambridge (UK), and by SFB873 funded by the Deutsche Forschungsgemeinschaft (DFG) and the Dietmar Hopp Foundation (to A.T.)