Two to three weeks after conception, an embryo faces a critical point in its development. In the stage known as gastrulation, the transformation of embryonic cells into specialized cells begins. This initiates an explosion of cellular diversity in which the embryonic cells later become the precursors of future blood, tissue, muscle, and more types of cells, and the primitive body axes start to form. Studying this process in the human-specific context has posed significant challenges to biologists, but new research offers an unprecedented window into this point in time in human development.
A recent strategy to combat these challenges is to model embryo development using stem cell technologies, with many valuable approaches emerging from research groups across the globe. But embryos don’t grow in isolation and most previous developmental models have lacked crucial supporting tissues for embryonic growth. A groundbreaking model that includes both embryonic and extraembryonic components will allow researchers to study how these two parts interact around gastrulation stages—providing a unique look at the molecular and cellular processes that occur, and offering potential new insights into why pregnancies can fail as well as the origins of congenital disorders. The team, including Berna Sozen, PhD, and Zachary Smith, PhD, both assistant professors of genetics at Yale School of Medicine (YSM), published its findings in Nature on June 27.
“This work is extremely important as it provides an ethical approach to understand the earliest stages of human growth,” says Valentina Greco, PhD, Carolyn Walch Slayman Professor of Genetics at YSM and incoming president-elect of the International Society for Stem Cell Research (ISSCR), who was not involved in the study. “This stem cell model provides an excellent alternative to start to understand aspects of our own early development that is normally hidden within the mother’s body.”
“The Sozen and Smith groups have achieved a milestone in developing in vitro models to study the earliest stages of human development that are unfeasible yet so important for understanding health and disease,” says Haifan Lin, PhD, Eugene Higgins Professor of Cell Biology, director of the Yale Stem Cell Center, and president of ISSCR. “I commend their exceptional accomplishment as well as their sensitivity to ethical issues by limiting the model’s ability to develop further”
The ethical questions are profound, including whether these models have the potential to develop into human beings. Sozen, the principal investigator of the study, emphasizes that they do not. The published paper demonstrates that this model lacks trophectodermal cells, which are required for an embryo to implant in the uterus. Sozen says this model also represents a developmental stage beyond the time frame in which embryos can implant. “It is very important to focus on the fact that our model cannot grow further or implant and therefore is not considered a human embryo,” she says. But as a reductionist strategy to mimic and study aspects of natural development, its potential is immense, especially where universal guidelines severely limit scientists’ ability to study actual embryos.
New Model Contains Embryonic and Extraembryonic Tissues
All embryos have two components—embryonic and extraembryonic. The tissues we have now in our adult bodies grew from the embryonic component. The extraembryonic component includes the tissues that offer nutritional and other support, such as the placenta and yolk sac. The majority of previous embryo models of developmental stages around gastrulation were single-tissue models that only contained the embryonic component.
In the new study, the Yale-led team grew embryonic stem cells in vitro in the lab to generate their new model. They transferred these cells into a 3D culture system and exposed them to a conditions which stimulated the cells to spontaneously self-organize and differentiate. The cells diverged into two lineages—embryonic and extraembryonic precursors. The extraembryonic cells in this model were precursors for the yolk sac. The researchers grew these cellular lineages in the culture for approximately one week and analyzed how they guided each other as they developed. “We started looking into very mechanistic details, such as what signals they are giving each other and how specific genes are impacting one another,” says Sozen. “This has been limited in the literature previously.”
The Need for Models of Human Development
While researchers have learned a great deal from embryos of other species such as mice, the lack of accessibility to human embryos has left significant knowledge gaps about our development. “If you want to understand human development, you need to look at the human system,” says Sozen. “This work is really important because it’s giving us direct information about our own species.” Not only does this model give access into the human gastrulation window, but will also allow for a greater quantity of research. The ability to generate as many as thousands of these models will allow for mass analysis that is not possible with human embryos. “I’m one scientist with one vision,” says Sozen. “But thinking about what other scientists are envisioning globally and what we can all accomplish is just really, really exciting to me.”
The new model has over 70% efficiency—in other words, the stem cells aggregate correctly over roughly 70% of the time. As noted by the authors, there are some limitations to the strategy, and it is challenging to benchmark some findings against the natural embryo itself. Sozen hopes to continue to work on the models so that they become more standardized in the future.
The team believes the models will transform scientists’ knowledge around human developmental biology. In their latest publication, the team explored some of the molecular paths underlying human gastrulation onset. In future studies, they hope to delve even deeper into the developmental pathways, including whether pregnancy loss and congenital disorders may stem from failures during gastrulation stages. Sozen believes her model can be used to look at some of these disorders and learn more about what is going awry. “Previous model systems have been able to look at this, but our model is unique because it has this extra tissue that allows us to analyze a bit deeper,” she says.