Synthetic embryo model could enable growing organs for transplantation

Synthetic Mouse Embryonic Model from Stem Cells

credit: Weisman Institute of Science

Without eggs, sperm or womb: Synthetic mouse embryo model created from stem cells only

An egg meets a sperm – this is an essential first step at the beginning of life. In embryonic development research, this is also a common first step. However, in a new study published on August 1, 2022 in the journal roomResearchers at the Weisman Institute of Science have developed synthetic embryonic models of mice outside the womb, starting with stem cells cultured entirely in Petri dishes. This means that they are grown without the use of fertilized eggs. This method opens up new horizons for studying how stem cells form various organs in the developing embryo. It may also one day make it possible to develop tissues and organs for transplantation using a synthetic embryo model.

a video showing the synthetic mouse embryo model on day 8 of its development; It has a beating heart, a yolk sac, a placenta, and budding circulation.

“The embryo is the best organ-making machine and the best 3D bioprinter – we tried to emulate it,” said Prof. Jacob Hanna, 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 the Nobel Prize in 2012. However, going the opposite direction, i.e. differentiating stem cells into specialized body cells, not to mention whole organs, has proved far more difficult.

“Until now, in most studies, specialized cells were either difficult to produce or they would have detached, and they formed a mishmash, rather than a well-structured tissue suitable for transplantation. We have been able to overcome these obstacles.” managed, by uncovering the self-organization potential encoded in stem cells.”

synthetic mouse embryo researcher

(left to right): Noah Noverschtern, Prof. Jacob Hannah, Alexander Aguilera-Castrejon, Shadi Tarazzi and Carine Joubran. credit: Weisman Institute of Science

Hannah’s team builds on two previous advances in her lab. One There was an efficient way to return stem cells to a nave state – that is, in their early stages – when they have the greatest potential for specialization into different cell types. otherdescribed in a scientific paper in Nature In March 2021, there was an electronically controlled device that the team developed over seven years of trial and error to grow natural mouse embryos outside the womb. The device places an embryo bathed in a nutrient solution inside the beaker that is constantly moving, the way the placenta is supplied with nutrients by the material blood flow, and closely controls oxygen exchange and atmospheric pressure. Is. In earlier research, the team successfully used this tool to develop natural mouse embryos from day 5 to day 11.

This is how artificial mouse embryo models were grown outside the womb: a video showing the device in action. Continuously running beakers simulate natural nutrient supply, while oxygen exchange and atmospheric pressure are tightly controlled.

In the new study, the team set out to develop a synthetic embryonic model entirely from nave mouse stem cells, which had been cultured for years in a Petri dish, with delivery with no need to start from a fertilized egg. This approach is extremely valuable as it can 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 infeasible because they would require thousands of embryos, while access to models derived from mouse embryonic cells, which grow in laboratory incubators by the millions, is virtually unlimited.

“The Embryo is the best organ maker and the best 3D bioprinter – we tried to emulate what it does.”

Before placing the stem cells into the device, the researchers divided them into three groups. In one, in which the cells themselves were intended to develop into embryonic organs, the cells were left as they were. Cells in the other two groups were only pretreated for 48 hours to overexpress one of two types of genes: master regulators of the placenta or yolk sac. “We gave these two groups of cells a momentary push to give rise to the extra-embryonic tissue that sustains the developing embryo,” Hanna says.

Development of a synthetic mouse embryo model

Development of the synthetic embryo model from day 1 (top left) to day 8 (bottom right). All of their early organ progenitors were formed, including a beating heart, a booming circulation, a brain, a neural tube, and an intestinal tract. credit: Weisman Institute of Science

Immediately after being mixed together inside the device, three groups of cells called aggregates, most of which failed to grow properly. But about 0.5 percent—about 50 out of 10,000—formed spheres, each of which later became an elongated, embryo-like structure. Because the researchers labeled each group of cells with a different color, they were able to observe the process of the placenta and yolk sac forming outside the embryo and the development of the model as a natural embryo. These synthetic models developed normally by day 8.5 – about half of the mouse 20-day gestation – the stage at which all early organ progenitors were formed, including a beating heart, circulating blood stem cells, and well-folds. Contains a brain, a nerve. tubes and an intestinal tract. Compared to natural mouse embryos, the synthetic model displayed 95 percent similarity in both the size of the internal structures and the gene expression patterns of the different cell types. The organs observed in the models gave every indication of being functional.

mouse embryonic day 8

Day 8 in mouse embryonic life: a synthetic model (top) and a natural embryo (bottom). The synthetic model displayed 95 percent similarity in both the size of the internal structures and the gene expression patterns of the different cell types. credit: Weisman Institute of Science

For Hanna and other stem cell and embryonic development researchers, the study presents a new area: “Our next challenge is to understand how stem cells know what to do — how they self-assemble into organs and determine what they do.” find their way inside places. Embryos. And because our system, unlike the womb, is transparent, it could 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 could become a reliable source of cells, tissues and organs for future transplantation. “Instead of developing a separate protocol to grow each cell type – for example, of the kidney or liver – we may one day be able to create a synthetic embryo-like model and then isolate the cells we need. We won’t need to instruct emerging organs on how they should develop. The embryo itself does this best.”

Innovative Method to Develop Synthetic Mouse Embryonic Models from Stem Cells

Pro. A diagram showing the innovative method for developing a synthetic mouse embryo model from stem cells – without eggs, sperm or womb – developed in the laboratory of Jacob Hanna. credit: Weisman Institute of Science

References: “Post-gastrulation Synthetic Embryos Generated X Uterine from Naive Mouse ESC” Shadi Tarazzi, Alejandro Aguilera-Castrejon, Carine Joubran, Nadir Ghanam, Shahad Ashuochi, Francesco Roncato, Emily Wildschutz, Montessor Haddad, Bernardo Oldek, Alizard , Nir Livnat, Sergei Vyukov, Dmitry Lukstanov, Segev Nave-Tssa, Max Rose, Suhair Hanna, Kalanit Ranan, Ori Brenner, Merav Kedmi, Hadas Keren-Saul, Tsvi Lapidot, Ite Mazza, Noah Nvershern and Jakob H. Hannah, August 2022, room,
DOI: 10.1016/j.cell.2022.07.028

The research was co-led by Shadi Tarazzi, Alejandro Aguilera-Castrejn and Karine Jaubran of Weisman’s Department of Molecular Genetics. Study participants included Shahad Ashuochi, Dr. Francesco Roncato, Emily Wildschutz, Dr. Bernardo Oldek, Elidette Gomez-Caesar, Nir Livnat, Sergey Vyukov, Dmitry Lokshtanov, Segev Naveh-Tssa, Max Rose and Dr. Weizmann’s Dr. of Molecular Genetics. . Noah Nowershattan was also involved. Department; Professor of Montessor Haddad and Weisman’s Department of Immunology and Regenerative Biology. Tsvi lapidot; Dr. Merav Kedmi of Weizmann’s Department of Life Sciences Core Facilities; Dr. Hadas Keren-Shall of Nancy and Stephen Grand Israel National Center for Individualized Medicine; and Dr. Nadir Ghanam, Dr. Suhair Hanna and Dr. Itay Mazza of Rambam Health Care Campus.

Pro. Jacob Hanna’s research is supported by the 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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