Synthetic Mouse Embryo Models From Stem Cells

Without eggs, sperm or uterus: synthetic embryo models could enable growing organs for transplantation

Synthetic mouse embryo models from stem cells

Credit: Weizmann Institute of Science

Without eggs, sperm, or uterus: synthetic mouse embryo models created solely from stem cells

An egg meets a sperm – it is a necessary first step in the beginning of life. In embryonic development research, it is also a common first step. But in a new study published on August 1, 2022 in the journal Cell, researchers from the Weizmann Institute of Science have grown synthetic embryo models of mice outside the womb by starting only with stem cells grown in a petri dish. This means they are grown 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 at day 8 of its development; it has a beating heart, a yolk sac, a placenta, and emerging blood circulation.

“The embryo is the best organ-making machine and the best 3D bioprinter – we tried to mimic what it does,” says Prof. Jacob Hanna from the Weizmann Department of Molecular Genetics, who led the research team.

Hanna explains that scientists already know how to restore mature cells to “stemness”. In fact, the pioneers of this cellular reprogramming won a Nobel Prize in 2012. But going in the opposite direction, that is, getting stem cells to differentiate into specialized body cells, not to mention whole organs, has proven much more difficult.

“Until now, in most studies, the specialized cells were often either difficult to produce or aberrant, and they tended to form a mishmash instead of well-structured tissue suitable for transplantation. We managed to overcome these obstacles by unlocking the potential for self-organization encoded in the stem cells.”

Synthetic Mouse Embryo Researchers

(Left to right): Dr. Noa Novershtern, 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 effective method for reprogramming stem cells back to a naïve state—that is, to their earliest stage—when they have the greatest potential to specialize into different cell types. The other onedescribed in a scientific article i Nature in March 2021, was the electronically controlled device the team had developed over seven years of trial and error to grow natural mouse embryos outside the womb. The device keeps the embryos bathed in a nutrient solution inside cups that move continuously, simulating how nutrients are delivered by material blood flow to the placenta, and carefully controls oxygen exchange and atmospheric pressure. In the previous research, the team had successfully used this device to grow natural mouse embryos from day 5 to day 11.

How synthetic mouse embryo models were grown outside the womb: a video showing the device in action. Continuously moving beakers simulate the natural nutrient supply, while oxygen exchange and atmospheric pressure are carefully controlled.

In the new study, the team decided to grow a synthetic embryo model solely from naïve mouse stem cells that had been grown for years in a petri dish, avoiding the need to start with a fertilized egg. This approach is extremely valuable because it could largely circumvent the technical and ethical issues involved in the use of natural embryos in research and biotechnology. Even in the case of mice, some experiments are currently impossible because they would require thousands of embryos, while the availability of models derived from embryonic mouse cells, which grow in lab incubators by the millions, is practically unlimited.

“The 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 divided them into three groups. In one, which contained cells destined to develop into embryonic organs themselves, the cells were left as they were. Cells in the other two groups were pretreated for only 48 hours to overexpress one of two types of genes: master regulators of either the placenta or the yolk sac. “We gave these two groups of cells a transient push to give rise to extraembryonic tissues that sustain the developing embryo,” says Hanna.

Development of synthetic mouse embryo models

Development of synthetic embryo models from day 1 (top left) to day 8 (bottom right). All of their early organ progenitors had formed, including a beating heart, a nascent blood circulation, a brain, a neural tube, and an intestinal tract. Credit: Weizmann Institute of Science

Soon after mixing together inside the unit, the three groups of cells gathered into aggregates, the vast majority of which did not develop properly. But about 0.5 percent—50 out of about 10,000—went on to form spheres, each of which later became an elongated, embryo-like structure. Because the researchers had labeled each group of cells with a different color, they were able to observe placentas and yolk sacs forming outside the embryos, and the model’s development proceeds as in a natural embryo. These synthetic models developed normally until day 8.5—nearly half of the mouse’s 20-day gestation—by which stage all early organ progenitors had formed, including a beating heart, blood stem cell circulation, a brain with well-formed folds, a neural tube, and an intestinal tract. 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 seen in the models all gave indications that they were functional.

Day 8 mouse embryos

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 researchers in stem cell and embryonic development, the study presents a new arena: “Our next challenge is to understand how stem cells know what to do – how they assemble themselves into organs and find their way to their assigned places in an embryo. And because our system, unlike a uterus, is transparent, it may prove useful for modeling birth and implantation defects of human embryos.”

In addition to helping to reduce the use of animals in research, synthetic embryo models may in the future become a reliable source of cells, tissues and organs for transplantation. “Instead of developing a different protocol for growing each cell type—for example, those in the kidney or liver—maybe one day we can create a synthetic embryo-like model and then isolate the cells we need. We don’t have to dictate to the nascent organs how they must develop. The embryo itself does this best.”

Innovative method for growing synthetic mouse embryo models from stem cells

A diagram showing the innovative method of growing synthetic mouse embryo models from stem cells – without eggs, sperm or uterus – developed in Professor Jacob Hanna’s laboratory. Credit: Weizmann Institute of Science

Reference: “Post-Gastrulation Synthetic Embryos Generated Ex Utero from Mouse Naive ESCs” by Shadi Tarazi, Alejandro Aguilera-Castrejon, Carine Joubran, Nadir Ghanem, Shahd Ashouokhi, Francesco Roncato, Emilie Wildschutz, Montaser Haddad, Bernardo Oldz-Cdetsar, , Nir Livnat, Sergey Viukov, Dmitry 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 1, 2022 , Cell.
DOI: 10.1016/j.cell.2022.07.028

This research was co-led by Shadi Tarazi, Alejandro Aguilera-Castrejon and Carine Joubran from the Weizmann Department of Molecular Genetics. Study participants also included 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. Noa Novershtern from Weizmann’s Molecular Genetics Department; Montaser Haddad and Prof. Tsvee Lapidot of the Weizmann Department of Immunology and Regenerative Biology; Dr. Merav Kedmi of Weizmann’s Life Sciences Core Facilities Department; Dr. Hadas Keren-Shaul of the Nancy and Stephen Grand Israel National Center for Personalized Medicine; and Dr. Nadir Ghanem, Dr. Suhair Hanna and Dr. Itay Maza from Rambam Health Care Campus.

Prof. Jacob Hanna’s research is supported by Dr. Barry Sherman Institute for Medicinal Chemistry; Helen and Martin Kimmel Institute for Stem Cell Research; and Pascal and Ilana Mantoux.

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