Trying to mimic the early stages of reproduction, Cambridge University researchers cultivated two types of mouse stem cells in a Petri dish and watched an embryo emerge — one that closely resembled a natural mouse embryo in its architecture, its development process and its ability to assemble itself.
The artificial structure shows promise as a tool for medical research, though it cannot develop into an actual baby.
“I not only want to understand the basic biology of development but also why it goes awry in the early stages of up to 70% of human pregnancies,” said Magdalena Zernicka-Goetz, senior author of the research, which was published Thursday in the journal Science.
After an egg is fertilized by a sperm, it begins to divide multiple times. This process generates a small, free-floating ball of stem cells: a blastocyst.
Within a mammalian blastocyst, the cells that will become the body of the embryo (embryonic stem cells) begin to cluster at one end. Two other types of cells, the extra-embryonic trophoblast stem cells and the endoderm stem cells, begin to form patterns that will eventually become a placenta and a yolk sac, respectively.
To develop further, the blastocyst has to implant in the womb, where it transforms into a more complex architecture. However, implantation hides the embryo from view — and from experimentation.
In the study, Zernicka-Goetz wanted to replicate developing embryonic events using stem cells.
Other scientists who have attempted the same thing have used only embryonic stem cells, but these experiments, though they have yielded embryoid bodies, have not been entirely successful. The artificial bodies never follow the same chain of events found in nature, and they lack the structure of a natural embryo.
Zernicka-Goetz, a professor in Cambridge’s Department of Physiology, Development and Neuroscience, hypothesized that the trophoblast stem cells communicate with the embryonic stem cells and guide their development.
She and her colleagues placed embryonic and trophoblast stem cells within an extra-cellular matrix: the non-cell component found in all tissues and organs that provides biochemical support to cells. This formed a scaffold on which the two stem cell types could co-develop.
The embryonic stem cells sent chemical messages to the trophoblast stem cells and vice versa, said Zernicka-Goetz. Essentially, the different stem cells began to “talk to each other,” and this helped the embryonic stem cells, she explained.
“They respond by turning on particular developmental gene circuits or by physically changing shape to accomplish some architectural remodeling,” she wrote in an email. “This happens in normal embryogenesis and it is what we are trying to recreate in the culture dish.”
Ultimately, the cells organized themselves into a structure that not only looked like an embryo, it behaved like one, with anatomically correct regions developing at the right time and in the right place.
“The results were spectacular — they formed structures that developed in a way strongly resembling embryos in their architecture and expressing specific genes in the right place and at the right time,” Zernicka-Goetz wrote.
Despite its resemblance to a real embryo, this artificial embryo will not develop into a healthy fetus, the researchers said. That would require the endoderm stem cells, which “does other things that are most likely necessary for further development,” said Zernicka-Goetz.
“Whether adding these to the system would be enough to achieve further development, I don’t know,” she said.
“Correct placental development” is essential for proper implantation into “either the womb or a substitute for the womb,” she said. “To achieve this will be some time off.”
Robin Lovell-Badge, an embryologist and head of the Division of Stem Cell Biology and Developmental Genetics at the Francis Crick Institute, found the new research to be interesting “on a number of counts.”
He wrote in a commentary published with the study on the website of the journal Science that past research suggests that the cells fated to become support structures (placenta and yolk sac) for the embryo in fact organize the cell types within the embryo. Meanwhile, the new research suggests that “it is the combination of the two cell types (embryonic and trophectoderm) that is important” while the third cell type, endoderm, may not be essential.
According to Dr. Christos Coutifaris, president-elect of the American Society for Reproductive Medicine and a professor at the University of Pennsylvania, the new study is significant because it shows how “the cells that are extra-embryonic — the ones that are going to give rise to the placenta — actually play a role” in the development of cells that eventually become the fetus.
“It’s not two completely separate entities,” Coutifaris said, referring to the embryo and its support structure. Understanding how the two types of cells interact and the chemical signals they exchange is “really, really critical.”
Zernicka-Goetz’s model has practical applications in research, where it can be used to better understand the conversation between embryonic stem cells and trophoblast stem cells, he said. “You can manipulate these cells molecularly to try to understand these interactions and how early development occurs pre-implantation.”
According to Kyle E. Orwig, an associate professor of obstetrics, gynecology and reproductive sciences, and molecular genetics and biochemistry at the University of Pittsburgh, Zernicka-Goetz’s model “will enable investigators to investigate the effects of genetic manipulations, environmental toxins, therapeutics and factors on embryo development.” Artificial embryos “represent a powerful tool for research that might reduce (but not eliminate) the need for human embryos,” Orwig said.
Dr. David Adamson, a reproductive endocrinologist, an adjunct clinical professor at Stanford University and chairman of the International Committee Monitoring Assisted Reproductive Technologies, believes that it’s “very important to continue to do basic science research in reproductive medicine.”
“How our species reproduces is very important to know,” Adamson said. “When you learn about reproduction and learn how cells reproduce and how cells differentiate and what makes things happen normally and what makes thing happen abnormally, then there clearly are a lot of potential therapeutic applications.”
Past advances in reproductive medicine have helped scientists prevent genetic-based diseases, he said. Specifically, in vitro fertilization techniques have allowed doctors to biopsy and conduct genetic tests on embryos to prevent inherited illnesses, including Huntington’s.
In vitro fertilization is “fundamentally transformative,” said Adamson, who sees the new research as adding to the wealth of knowledge about this procedure.
In fact, Zernicka-Goetz works in the same nondescript brick building on the Cambridge campus where Robert Edwards, a reproductive medicine pioneer, once toiled. Edwards developed the Nobel Prize-winning technique of in vitro fertilization, which eventually resulted in the birth of the first “test tube” baby, Louise Brown.
Helping families have babies is the most obvious contribution of in vitro fertilization. Today, Adamson said, there have been approximately 6.5 million babies born using in vitro fertilization since the procedure was first developed. An exact number is not known because many countries, including China, do not have registries to count them, explained Adamson.
Meanwhile, Zernicka-Goetz said she will continue her work on embryonic development as she and the members of her lab are “totally driven by a curiosity to understand these fundamental aspects of life.”
She plans to use human stem cells to create a similar embryonic model. Then she plans to use that model to learn more about normal embryonic development and understand when it goes wrong without needing to experiment on an actual human embryo.
The work also “continually teaches us about the properties of stem cells,” Zernicka-Goetz said. She added that this knowledge is useful for developing “therapies to replace faulty tissues in so-called regenerative medicine.”