With an innovative womb-like bioreactor, mouse stem cells transform into organ-filled embryos Science

What happens in fetal 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 created artificial mouse embryos from stem cells – no sperm or eggs required – and used an innovative bioreactor to nurture their creations longer than previous embryo models. The simulated embryos developed an anatomy that matched the real thing and “very impressive similarities at the cellular level. The right cells are generated at the right time,” says Niels Geijen, a stem cell biologist at Leiden University Medical Center who was not involved in the work.

achievement, reported this week Cell, could allow biologists to delve deeper into developmental mechanisms and better understand what goes wrong in birth defects. And team leader Jacob Hanna, a stem cell biologist at the Weizmann Institute of Science, says that next, he hopes to do the same with comparable human stem cells.

Researchers have already recapitulated parts of early development with embryo clones made from an assortment of mouse or human stem cells, including embryonic stem (ES) cells that are derived from normal embryos and can form all body tissues. They have simulated the blastocyst, a simple developmental stage that implants in the uterus, and recreated gastrulation when the embryos are multi-layered. However, these simulated embryos hit a developmental wall. Their cells begin to specialize but do not fuse into organs.

A barrier has kept the ersatz embryos alive for more than a few days. Last year, Hanna and colleagues unveiled a fostering process that allowed them to grow standard mouse embryos outside their mother’s body for a record 11 days. (A typical mouse pregnancy is about 20 days.) One key step involves placing the embryos in an incubator filled with a Ferris wheel-like device, which spins the embryos inside a bottle of liquid filled with nutrients and growth factors. The setup enables the team to precisely control growth conditions such as oxygen levels.

However, those embryos came from fertilized mouse eggs. To determine whether the same process allows stem cells to transform into fully developed embryos, Hanna’s team combined basic mouse ES cells with ES cell lineages to genetically alter tissues outside the embryo to shape and support its development. After initially growing cell colonies on culture plates, the team transferred them to spinner flasks on day five.

By day eight, the “embryo” was very similar to an 8.5-day-old natural fetus and had a beating heart, head and tail tips, block-like segments that would become skeletal muscles, brain and spinal cord development, and the beginnings. of other organs. The researchers also measured gene activity in more than 40,000 embryonic cells, finding all the expected cell types in the right places, Hanna says.

“This is an important study because they show that ES cells alone can generate entire embryonic structures with all the early organs fully incorporated in vitro,” says cell biologist Jun Wu of the University of Texas Southwestern Medical Center.

Tissue staining of a normal 8.5-day-old mouse embryo (top) and an 8-day-old “embryo” derived from mouse stem cells show comparable organ growth and location.Jacob Hanna Lab/Weizmann Institute

For unknown reasons, the artificial embryo stopped on the eighth day of development. Researchers hope to overcome this hurdle and expand development further. Still, stem cell-derived embryos offer an advantage over normal mouse embryos for research because the cells are available in large numbers and scientists can easily manipulate them, says stem cell biologist Nicolas Riveron at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences. .

Current procedures for making simulated embryos fail most of the time—less than 1% of the initial cell aggregation forms an embryo mimic. But, Hanna notes, “the advantage of this technique is that we can make millions of aggregates in one batch.”

Achieving the same feat with human ES cells may avoid some of the controversies of research in human embryos. “It’s providing an ethical and technical alternative to the use of embryos,” Riveron says.

Hannah has co-founded a company that will investigate whether this approach works with human induced pluripotent stem cells, which are derived from adult cells rather than embryos. Cells and tissues in the embryo release the correct growth factors from their neighbors. Therefore, first growing stem cells in artificial embryos may provide a better way to produce cell types that can be transplanted to treat human diseases. It’s “more physical,” says Hannah.

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