Using an innovative bioreactor as a uterus, mouse stem cells are transformed into organ-filled embryos |  Science

Using an innovative bioreactor as a uterus, mouse stem cells are transformed into organ-filled embryos | Science

What happens in embryonic development is one of nature’s best kept secrets, unfolding deep within the mother’s body. Now researchers have opened a new window on the process. They made artificial mouse embryos from stem cells — no sperm or eggs required — and used an innovative bioreactor to nurture their creations 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 are made 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, could allow biologists to delve deeper into developmental mechanisms and better understand what goes wrong in birth defects. And the leader of the team, Weizmann Institute of Science stem cell biologist Jacob Hanna, says he hopes to do the same with comparable human stem cells next.

Researchers have already reproduced parts of early development using mimic embryos made from a variety of mouse or human stem cells, including embryonic stem (ES) cells, which are derived from normal embryos and can form any tissue in the body. They mimicked the blastocyst, the simple developmental stage that implants in the uterus, and mimicked the gastrulation when embryos become multilayered. However, these simulated embryos hit a developmental wall. Their cells begin to specialize but do not fuse into organs.

One obstacle is keeping the replacement embryos alive for more than a few days. Last year, Hanna and colleagues presented a maintenance procedure that allowed them to grow standard mouse embryos outside the mother’s body for a record 11 days. (A mouse’s typical pregnancy lasts about 20 days.) A key step is to place the embryos in an incubator equipped with a Ferris wheel-like device that rotates the embryos in liquid bottles filled with 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 see if the same process would allow stem cells to turn into full-fledged embryos, Hanna’s team mixed basic mouse ES cells with genetically engineered ES cell lines to create tissue outside the embryo that shapes and supports its growth. After the cell clusters were first grown on culture plates, the team transferred them to spinner flasks on the fifth day.

By day eight, the “embryoids” were very similar to 8.5-day-old natural embryos, featuring a beating heart, prominent head and tail ends, the blocky segments that become skeletal muscle, a developing brain and spinal cord, and the beginnings on other organs . The researchers also measured gene activity in more than 40,000 embryoid cells and found all the expected cell types in the right places, says Hanna.

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

Synthetic embryo growth at day 8 (top) is compared to natural embryo growth (bottom) over the same period
Tissue staining of normal 8.5-day-old mouse embryos (above) and 8-day-old “embryoids” derived from mouse stem cells show comparable organ growth and placement.Jacob Hanna Laboratory/Weizman Institute

For unknown reasons, the artificial embryos stagnated on the eighth day of development. The researchers hope to overcome this barrier and take the 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, says stem cell biologist Nicolas Rivron of the Institute for Molecular Biotechnology of the Austrian Academy of Sciences.

The current method of producing the simulated embryos fails most of the time – less than 1% of the initial cell aggregates form embryomimics. But, according to Hanna, “the advantage of this technology is that we can produce 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 offers an ethical and technical alternative to using embryos,” says Rivron.

Hanna co-founded a company that will study whether the approach works using human-induced pluripotent stem cells derived from adult cells rather than embryos. Cells and tissues in an embryo release factors that orchestrate the correct development of their neighbors. So, growing stem cells into artificial embryos may offer 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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