Just two weeks after announcing the development of synthetic mouse embryos, complete with beating hearts and the foundations for a brain and other organs, from stem cells, researchers in the laboratory of Magdalena Zernicka-Goetz, Bren Professor of Biology and Biological Engineering, have published new findings about creating synthetic embryos out of only a single type of stem cell.
The new study appears in the journal Cell Stem Cell on September 8. The research was led by graduate students Kasey Lau and Hernan Rubinstein of the University of Cambridge and the Weizmann Institute of Science, respectively.
"This discovery opens up new avenues for understanding why the great majority of human pregnancies are lost and to create knowledge that will prevent this from happening," says Zernicka-Goetz, who is also a professor of mammalian development and stem cell biology at Cambridge University in the Department of Physiology, Development and Neuroscience. "This knowledge will also let us, with time, repair tissues and organs much more effectively than we can do now."
"As we develop these models further, we will learn more about the signals that imitate the development of organs, which will give us routes for helping to generate organs in culture that will ultimately find application in transplant surgery or in regenerative medicine," she explains.
In a paper published in the journal Nature on August 25, the team detailed how to develop synthetic embryo models out of three types of cultured stem cells. Instead of creating mouse embryos by the natural biological method of combining egg and sperm, the team guided three types of cultured stem cells to interact, inducing the expression of certain genes and establishing an environment for the cells to "talk" to each other. As a result, the stem cells self-organized into structures that then progressed through successive developmental stages until the synthetic embryos had beating hearts and the foundations for a brain and all other organs, in addition to the yolk sac where the embryo develops and receives nutrients in its first weeks. This is the most advanced stage of development achieved to date in a stem cell-derived model.
Naturally, in the first week after fertilization, three types of natural stem cells develop in the embryo: one will eventually become the tissues of the body, and the other two will support the embryo's development. One of these latter two types, known as trophectoderm cells, will become the placenta, which connects the fetus to the mother and provides oxygen and nutrients. The other, known as extra-embryonic endoderm cells, will become the yolk sac, where the embryo grows and from which it receives nutrients in early development.
Each of the three stem cell types can be taken from the embryo and cultured indefinitely in the laboratory.
Building off of the previous research, the synthetic embryos reported in the new paper are only made of a single type of cultured stem cell: the extraembryonic stem cells (ESCs). Untreated ESCs become the body of the embryo. Another ESC line is coaxed by researchers to become like trophectoderm stem cells, which provide one set of developmental signals. The team drives a third ESC line to become like the extra-embryonic endoderm, which provides a second set of developmental signals.
"Of the three stem cell types, only the ESCs are pluripotent-that is to say, only the ESCs have the potential to develop into any tissue of the body," explains Zernicka-Goetz. "But to do this, they require the other two types of extra-embryonic stem cell. As the ESCs are pluripotent, we can direct them to become these other two extra-embryonic cell types. In this way, we end up with three starting cell types all generated from the single ESC line."
The paper is titled "Mouse embryo model derived exclusively from embryonic stem cells undergoes neurulation and heart development." Lau and Rubinstein are the study's first authors. Additional co-authors are Carlos Gantner of the University of Cambridge, Caltech postdoctoral scholar Ron Hadas, Gianluca Amadei of the University of Cambridge, Yonatan Stelzer of the Weizmann Institute of Science in Israel, and Zernicka-Goetz. Funding was provided by the National Institutes of Health, the Allen Discovery Center for Lineage Tracing, the European Research Council, the Wellcome Trust, Open Philanthropy/Silicon Valley Community Foundation, and Weston Havens Foundation.
