What happens in embryonic development is one of nature’s best kept secrets, unfolding deep inside the mother’s body. Now, researchers have opened a new window on the process. They’ve made artificial mouse embryos from stem cells – no sperm or eggs required – and used an innovative bioreactor to nurture their creations for longer than any previous embryo model. The simulated embryos developed anatomy that matched the real thing and “very impressive similarities at the cellular level. The right cells are born at the right time,” says stem cell biologist Niels Geijsen of Leiden University Medical Center, who was not involved in the work.
The achievement, reported this week in Cell, could allow biologists to dig deeper into developmental mechanisms and better understand what goes wrong in birth defects. And the team’s leader, stem cell biologist Jacob Hanna of the Weizmann Institute of Science, says that next, he hopes to do the same with comparable human stem cells.
Researchers have already re-evaluated parts of early development with embryonic mimics made from a variety of mouse or human stem cells, including embryonic stem (ES) cells, which are derived from normal embryos and can form all body tissues. They have mimicked the blastocyst, the simple stage of development that implants in the uterus, and recreated gastrulation, when embryos become multi-layered. However, these simulated embryos hit a developmental wall. Their cells begin to specialize, but do not join into organs.
One obstacle has been keeping the ersatz embryos alive for more than a few days. Last year, Hanna and colleagues discovered a nurturing procedure that allowed them to grow standard mouse embryos outside the mother’s body for a record 11 days. (A typical mouse pregnancy is about 20 days.) A key step involves placing the embryos in an incubator equipped with a Ferris wheel-like device that spins the embryos inside vials of liquid filled with nutrients and growth factors. The setup allows the team to precisely control growth conditions such as oxygen levels.
However, those embryos came from fertilized mouse eggs. To determine whether the same procedure would allow stem cells to transform into full-fledged embryos, Hana’s team mixed basic mouse ES cells with genetically altered ES cell lines to create tissues outside the embryo that form and support the growth of his. After initially growing congregations of cells in culture plates, the team moved them to spinner flasks on day five.
By day eight, the “embryoids” were very similar to natural 8.5-day-old embryos and boasted a beating heart, distinct head and tail ends, block-like segments that become skeletal muscles, a developing brain and spinal cord and beginnings. of other bodies. The researchers also measured gene activity in more than 40,000 embryoid cells, finding all the expected cell types in the right places, Hanna says.
“This is an important study as it demonstrates that only ES cells can generate whole embryonic structures containing all early organs completely in vitro,” says cell biologist Jun Wu of the University of Texas Southwestern Medical Center.
For unknown reasons, the artificial embryos stalled on the eighth day of development. The researchers hope to overcome this obstacle and extend the development even further. However, stem cell-derived embryos have an advantage over normal mouse embryos for research because the cells are available in greater numbers and scientists can more easily manipulate them, says stem cell biologist Nicolas Rivron of the Institute of of Molecular Biotechnology of the Austrian Academy of Sciences. .
The current procedure for producing simulated embryos fails most of the time – less than 1% of the initial cell collections from embryo mimics. But, notes Hanna, “The advantage of this technique is that we can make millions of aggregates in a batch.”
Achieving the same feat with human ES cells could avoid some of the controversies of human embryo research. “This is providing an ethical and technical alternative to using embryos,” says Rivron.
Hanna has co-founded a company that will investigate whether the approach will work with human induced pluripotent stem cells, which are derived from adult cells rather than embryos. Cells and tissues in an embryo release factors that orchestrate the proper development of their neighbors. So growing stem cells in artificial embryos first may provide a better way to produce cell types that can be transplanted to treat human diseases. It’s “more physiological,” says Hanna.