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ralston_lab_fig_1_embryonic_stem_cell_origins
Figure 1. The origins of stem cells during mouse development. The blastocyst contains three cell types: 1) epiblast cells (yellow), which are pluripotent and give rise to embryonic stem (ES) cells or to the fetus, 2) the primitive endoderm (red) cells that will contribute to the yolk sac, and 3) the trophectoderm (blue) cells that will contribute to the placenta. By understanding the intracellular interactions during early mouse development, we can understand how to improve fertility, birth defect prevention, and stem cell therapies.

In many animals, the first cell fate decisions lead to specification of the body axes: head/tail and back/belly. However, mammals have an altogether different first priority. The first cell fate decisions in the mammalian embryo lead to specification of extraembryonic tissues, such as placenta and yolk sac. The extraembryonic tissues establish implantation, help specify the body axes, and nourish the growing fetus. Therefore to prevent miscarriage and birth defects, we must understand how the first cell fate decisions are regulated. The first cell fate decisions also lead to specification of pluripotent cells. These pluripotent cells are the source of embryonic stem (ES) cells. While pluripotent cells can be created in vitro by reprogramming, the process is neither rapid nor efficient. By contrast, the embryo establishes pluripotent cells robustly. By understanding how the first cell fate decisions are regulated, we will also identify better ways to make and use pluripotent stem cells. In spite of the importance of understanding how the first cell fate decisions are made in the mammal, many aspects of this problem are unsolved.

The mouse blastocyst provides an ideal model for discovering how mammals regulate the first cell fate decisions during development. Techniques for altering gene expression levels at discrete times and in specific cell types are well established in the mouse. In addition, the blastocyst is small and transparent, which enables resolution of cell fate at the level of individual cells. Finally, the ability to derive stem cells from the blastocyst enables use of genomic approaches, such as ChIP-seq and RNA-seq to discover how proteins regulate gene expression to regulate cell fate. In the Ralston Lab we use imaging, genetics, molecular biology, and systems biology approaches to study mouse embryos, stem cells, and reprogramming. By combining classical embryology and modern genomic approaches, we have gained new insight into mammalian developmental and stem cell biology. We are now applying lessons from the embryo to reprogramming to monitor and improve the quality of induced pluripotent stem (iPS) cells.