Using an innovative bioreactor as a matrix, mouse stem cells are transformed into embryos full of organs | science

What happens in embryonic development is one of nature’s best kept secrets, which takes place in the mother’s body. Now, researchers have opened a new window on the process. They have made artificial mouse embryos from stem cells (no sperm or eggs required) and used an innovative bioreactor to feed their creations for longer than any previous embryo model. The simulated embryos developed anatomy that matched reality and “very impressive similarities at the cellular level.” The right cells arise at the right time,” says stem cell biologist Niels Geijsen of Leiden University Medical Center, who was not involved in the work.

The feat, reported this week in cell, may allow biologists to delve 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 recaptured parts of early development with embryo mimics made from an assortment of human or mouse stem cells, including embryonic stem (ES) cells, which are derived from normal embryos and they can form all the tissues of a body. They mimicked the blastocyst, the simple developmental stage 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 his colleagues presented a rearing procedure that allowed them to grow standard mouse embryos outside the mother’s body for a record 11 days. (The typical mouse gestation is about 20 days.) A key step involves placing the embryos in an incubator equipped with a Ferris wheel-like device, which spins the embryos inside vials of liquid full of nutrients and growth factors. The setup allows the team to precisely control growth conditions, such as oxygen levels.

However, these embryos came from fertilized mouse eggs. To determine whether the same procedure would allow the stem cells to grow into full-fledged embryos, Hanna’s team mixed basic mouse ES cells with genetically altered ES cell lineages to generate tissues outside the embryo that shape and support their growth. After initially growing the cell congregations in culture plates, the team transferred them to spinner flasks on the fifth day.

By the eighth day, the “embryos” were very similar to natural 8.5-day-old embryos and had a beating heart, distinct head and tail, blocky segments that become skeletal muscles, a brain and a developing spinal cord and the beginnings. of other organs. The researchers also measured gene activity in more than 40,000 embryoid cells, finding all the expected cell types in the right locations, Hanna says.

“This is an important study because it shows that ES cells alone can generate whole embryo-like structures containing all early organs completely in vitro,” says cell biologist Jun Wu of the University of Texas Southwestern Medical Center.

Tissue staining of normal 8.5-day mouse embryos (top) and 8-day “embryoids” derived from mouse stem cells show comparable organ growth and placement.Jacob Hanna Lab/Weizman Institute

For unknown reasons, the artificial embryos stalled on the eighth day of development. Researchers hope to overcome this barrier and extend development even further. Still, stem-cell-derived embryos have an advantage over normal mouse embryos for research because the cells are available in greater numbers and scientists can manipulate them more easily, the biologist says. of stem cells Nicolas Rivron of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences. .

The current procedure for making mock embryos fails most of the time: less than 1% of the initial cell aggregations form mock embryos. But, notes Hanna, “The advantage of this technique is that we can make millions of aggregates in one 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. The cells and tissues of an embryo release factors that orchestrate the proper development of their neighbors. Therefore, 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.

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