Just two weeks after announcing the development of a mouse embryo model, complete with beating hearts and the basis for the brain and other organs, from mouse stem cells, researchers in the lab of Magdalena Zernitska-Goetz, professor of biology and of Brenn Engineering, published new findings on another mouse embryo model that reached similar stages of development but was created only from mouse embryonic stem cells. This modification simplified the protocol and facilitates the use of the embryo model in other laboratories.
The new study is published in the journal Cellular stem cell September 8. The research was led by graduate students Casey Lau and Hernan Rubinstein from the University of Cambridge and the Weizmann Institute of Science, respectively.
“This discovery opens up new avenues for understanding why the vast majority of human pregnancies end, and for creating knowledge to prevent this,” says Zernichka-Goetz, who is also Professor of Mammalian Development and Stem Cell Biology at the University of Cambridge in the Department physiology, development and neuroscience. “This knowledge will also allow us to regenerate tissues and organs over time much more efficiently than we can do now.”
“As these models continue to be developed, we will learn more about the signals that initiate and direct organ development, which will provide avenues to help create organs in culture that will eventually find applications in transplant surgery or regenerative medicine,” she explains. .
In an article published in the journal Nature On August 25, the team detailed how to create a mouse embryo model from mouse embryonic and extraembryonic stem cells. Instead of creating mouse embryos by the natural biological method of combining egg and sperm, the team directed three populations of cultured stem cells to interact, causing the expression of specific genes and creating an environment for the cells to “talk” to each other. As a result, the stem cells self-organized into structures that then went through successive stages of development until, in the mouse embryo model, a heartbeat appeared and the basis for the brain and all the other organs, in addition to the yolk sac, facilitated gas formation and nutrient exchange between the embryo and mother This is the most advanced stage of development achieved to date in a stem cell-derived model.
Naturally, in the first few days after fertilization, the early mouse embryo develops three main types of tissue: one will eventually become body tissue, and the other two will support the development of the embryo. One of these two latter types, known as the trophectoderm, will become the placenta, which connects the fetus to the mother and provides oxygen and nutrients. The other, known as the primitive endoderm, will give rise to the yolk sac, where the embryo grows and from which it receives nutrients during the early stages of development.
Three types of stem cells can be obtained from each of these three tissues in a mouse embryo and cultured indefinitely in the laboratory.
Building on previous research, the mouse embryo model reported in the new paper consists of only one type of cultured stem cell: embryonic stem cells (ESCs). Unprocessed ESCs become the body of the embryo. The researchers coaxed another ESC line to become similar to the extraembryonic stem cells of the endoderm, which provide one set of developmental signals. The team also directs a third line of ESCs to become like trophoblast stem cells, which provide a second set of developmental signals. In this way, the team can recreate the three main tissues of a developing mouse embryo, starting with just ESCs. This simplified the protocol while preserving the important signaling events between the three tissues that are critical for building the embryonic body plan.
“Of the three types of stem cells, only ESCs are pluripotent — that is, only ESCs have the potential to turn into any tissue in the body,” explains Zernicka-Goetz. “But they need two other types of extraembryonic stem cells to do that. ESCs can be directed to become those two other extraembryonic cell types. So we end up with three original cell types, all derived from a single ESC line.”
The paper is titled “A Mouse Embryo Model Derived Exclusively From Embryonic Stem Cells Undergoes Neuralization and Heart Development.” Lau and Rubinstein are the first authors of the study. Additional co-authors are Carlos Gantner of the University of Cambridge, Caltech postdoctoral fellow Ron Hadas, Gianluca Amadei of the University of Cambridge, Yonatan Stelzer of the Weizmann Institute of Science in Israel, and Zernika-Goetz. Funding was provided by the National Institutes of Health, the Allen Discovery Center, the European Research Council, the Wellcome Trust, Open Philanthropy/Silicon Valley Community Foundation, and the Weston Havens Foundation.