Credit: Weizmann Institute of Science
Without Egg, Sperm, and Uterus: Synthetic Mouse Embryo Models Generated From Stem Cells Only
An egg meets a sperm – this is the necessary first step in the beginning of life. It is also a common first step in embryonic development research. However, in a new study published on August 1, 2022 in the journal Cell, researchers at the Weizmann Institute of Science grew synthetic embryo models outside the womb of mice, starting only with stem cells grown in a petri dish. This means that they are bred without the use of fertilized eggs. This method opens up new horizons for studying how stem cells form different organs in the developing embryo. It may also one day make it possible to grow tissues and organs for transplantation using synthetic embryo models.
A video showing a synthetic mouse embryo model on day 8 of development; it has a beating heart, a yolk sac, a placenta, and a nascent circulatory system.
“Rushheim is the best organ-making machine and the best 3D bioprinter – we tried to imitate what it does,” said Prof. Jacob Hanna of Weizmann’s Department of Molecular Genetics led the research team.
Hanna explains that scientists already know how to restore adult cells to the “stem”. In fact, the pioneers of this cell reprogramming won the Nobel Prize in 2012. However, going in the opposite direction, that is, causing stem cells to differentiate into specific body cells, let alone whole organs, has proven much more difficult.
“Until now, in most studies, specialized cells were often either difficult to produce or abnormal, and they tended to create clutter instead of well-organized tissue suitable for transplantation. We were able to overcome these obstacles by uncovering the self-organizing potential encoded in stem cells.”
(From left to right): Dr. Noah Noverstern, Prof. Jacob Hanna, Alejandro Aguilera-Castrejon, Shadi Tarazi and Carine Joubran. Credit: Weizmann Institute of Science
Hanna’s team built on two previous advances in his lab. one was an efficient way to reprogram stem cells to a naïve state, i.e., their earliest stage, when they have the greatest potential to specialize into different cell types. Otherdescribed in a scientific article Nature In March 2021, it was an electronically controlled device that the team developed after seven years of trial and error to grow natural mouse embryos outside the womb. The device keeps embryos in a nutrient solution in continuously moving cups, mimicking the supply of nutrients to the placenta by material blood flow, and closely monitors oxygen exchange and atmospheric pressure. In a previous study, the team successfully used the device to grow natural mouse embryos from day 5 to day 11.
This is how synthetic mouse embryo models were grown outside the womb: a video showing the device in action. Continuously moving cups simulate natural food supply, while oxygen exchange and atmospheric pressure are strictly controlled.
In the new study, the team set out to grow a synthetic embryo model only from naïve mouse stem cells that had been cultured for years in a petri dish, eliminating the need to start with a fertilized egg. This approach is extremely valuable because it can largely bypass the technical and ethical issues surrounding the use of natural embryos in research and biotechnology. Even in the case of mice, some experiments are currently impossible because they require thousands of embryos, while access to models derived from millions of mouse embryonic cells growing in laboratory incubators is almost unlimited.
Embryo is the best organ-making machine and the best 3D bioprinter – we tried to mimic what it does.
Before placing the stem cells in the device, the researchers separated them into three groups. In one with cells destined to develop into embryonic organs, the cells remained as they were. Cells in two other groups were pretreated for just 48 hours to overexpress one of two types of genes: key regulators of the placenta or yolk sac. “We transiently induced these two groups of cells to form extraembryonic tissues that support the developing embryo,” says Hanna.
Development of synthetic embryo models from day 1 (top left) to day 8 (bottom right). All of their early organ derivatives were formed, including a beating heart, nascent bloodstream, brain, neural tube, and intestinal system. Credit: Weizmann Institute of Science
Soon after mixing inside the device, the three groups of cells gathered into aggregates, the vast majority of which failed to grow properly. But about 0.5%—about 50 out of 10,000—formed spheres, each of which later grew into an elongated, embryo-like structure. Because the researchers labeled each group of cells with a different color, they were able to observe the placenta and yolk sacs that formed outside the embryos and the development of the model as in a natural embryo. These synthetic models developed normally until day 8.5 — about halfway through a mouse’s 20-day gestation — at which point all early organ derivatives have formed, including a beating heart, a blood stem cell cycle, a brain with well-formed folds, and a nervous system. tube and intestinal tract. When compared to natural mouse embryos, the synthetic models showed 95 percent similarity in both the shape of internal structures and the gene expression patterns of different cell types. The organs visible on the models give every indication that they are functional.
Day 8 in the life of a mouse embryo: a synthetic model (top) and a natural embryo (bottom). The synthetic models showed 95 percent similarity in both the shape of internal structures and the gene expression patterns of different cell types. Credit: Weizmann Institute of Science
For Hanna and other stem cell and embryonic development researchers, the research provides a new arena: “Our next challenge is to understand how stem cells know what to do—how they self-assemble into organs and find their way to destinations within the cell. Because the embryo And our system, unlike the womb, is transparent, it may be useful for modeling birth and implantation defects in human embryos.
In addition to helping to reduce the use of animals in research, synthetic embryo models may become a reliable source of cells, tissues and organs for transplantation in the future. “Instead of developing a different protocol for the growth of each type of cell—for example, a kidney or a liver—we could one day create a synthetic embryo-like model and then isolate the cells we need. We wouldn’t need to dictate to the resulting organs how they should develop. the best way is done by the embryo itself.
Prof. Jacob Hanna. Credit: Weizmann Institute of Science
Reference: Shadi Tarazi, Alejandro Aguilera-Castrejon, Carine Joubran, Nadir Ghanem, Shahd Ashouokhi, Francesco Roncato, Emilie Wildschutz, Emilie Wildschutz, Emilie Wildschutz, Emilie Haddmezak, E. Haddmezak, EH , Nir Livnat, Sergey Viukov, Dmitri Lukshtanov, Segev Naveh-Tassa, Max Rose, Suhair Hanna, Calanit Raanan, Ori Brenner, Merav Kedmi, Hadas Keren-Shaul, Tsvee Lapidot, Itay Maza, Noa Novershtern, and Jacob H. Hanna, August 2022, Cell.
DOI: 10.1016/j.cell.2022.07.028
This research was led by Shadi Tarazi, Alejandro Aguilera-Castrejon, and Carine Joubran from Weizmann’s Department of Molecular Genetics. Research participants also Shahd Ashouokhi, Dr. Francesco Roncato, Emilie Wildschutz, Dr. Bernardo Oldak, Elidet Gomez-Cesar, Nir Livnat, Sergey Viukov, Dmitry Lokshtanov, Segev Naveh-Tassa, Max Rose and Dr. Noah Noverstern of Weizmann’s Department of Molecular Genetics; Montaser Haddad and Prof. Tsvee Lapidot of the Weizmann Department of Immunology and Regenerative Biology; Dr. Merav Kedmi of Weizmann’s Department of Life Sciences Core Facilities; Dr. Hadas Keren-Shaul of the Nancy and Stephen Grand Israel National Center for Personalized Medicine; and dr. Nadir Ganem, Dr. Suhair Hanna and Dr. Itay Maza from Rambam Health Campus.
Prof. Jacob Hanna’s research Dr. Barry Sherman Institute of Medicinal Chemistry; Helen and Martin Kimmel Institute for Stem Cell Research; and Pascal and Ilana Mantu.
