A study from the Weizmann Institute of Sciences, published in Cell, shows the development of synthetic embryo models of mice outside the uterus with stem cells grown in a Petri dish, that is, without fertilized eggs.
The method opens new horizons for studying how stem cells form various organs in the embryo and may one day make it possible to grow tissues and organs for transplantation using synthetic fetal models.
“The embryo is the best machine for making organs and the best 3D bioprinter; we try to emulate what it does,” explained Jacob Hanna, from the Department of Molecular Genetics at the Weizmann Institute, who led the research team.
He pointed out that scientists already know how to restore mature cells to their “stem”: the pioneers of this reprogramming won a Nobel Prize in 2012. But going in the opposite direction, that is, by making stem cells differentiate into specialized body cells, has proven to be much more problematic.
“Until now, in most studies, specialized cells were often difficult to produce and tended to form a mixture rather than well-structured tissue suitable for transplantation. We were able to overcome these obstacles by unlocking the self-organizing potential encoded in stem cells,” he noted.
Hanna’s team built on two previous advances in her lab: an efficient method to reprogram stem cells back to their earliest stage, when they have the greatest potential to specialize into different cell types; the other, described in Nature in March 2021, was the electronically controlled device for growing natural mouse embryos outside the womb. In previous research it had been successfully used to grow these natural fetuses from day 5 to day 11.
In the new study, the team set out to grow a synthetic embryo model from naïve mouse stem cells grown for years in a Petri dish, dispensing with a fertilized egg. This approach is extremely valuable because it could, to a large extent, avoid the technical and ethical problems associated with the use of natural embryos in research and biotechnology. Even in the case of rodents, certain experiments are infeasible because they would require thousands of embryos, while access to models derived from mouse embryonic cells, grown in lab incubators by the millions, is virtually limitless.
Overexpress two types of genes
Before placing the stem cells in the device, the researchers separated them into three groups. In one, which contained cells destined to become embryonic organs, the cells were left as they were. Cells from the other two groups were pretreated for 48 hours to overexpress one of two types of genes: placental or yolk sac master regulators.
“We gave these two groups of cells a temporary boost to give rise to extra-embryonic tissues that support the developing embryo,” Hanna said.
Shortly after mixing inside the device, the three groups of cells joined together into aggregates, the vast majority of which failed to develop properly. However, about 0.5 percent, 50 of about 10,000, went on to form spheres, each of which became an elongated, embryo-like structure.
Since the researchers had labeled each group of cells with a different color, they were able to observe the formation of the placenta and yolk sacs outside the embryos and the development of the model as in a natural embryo. The synthetic models developed normally until day 8 (nearly half of the mouse’s 20-day gestation), by which time all of the early organ progenitors had formed, including a beating heart, circulating blood stem cells, a brain with well-formed folds, a nerve tube, and an intestinal tract.
Compared with wild-type mouse embryos, the synthetic models showed 95 percent similarity in both the shape of internal structures and gene expression patterns of different cell types. The organs seen in the models gave every indication of being functional.
For Hanna and other researchers, the “next challenge is to understand how stem cells know what to do, how they self-assemble into organs and find their way to their assigned places within an embryo. Because our system, unlike a uterus, is transparent, it may be useful for modeling birth defects and implantation of human embryos.”
This research was co-directed by Shadi Tarazi, Alejandro Aguilera-Castrejón and Carine Joubran, from the Department of Molecular Genetics at the Weizmann Institute.
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