Without eggs, sperm, or uterus: Artificial embryo models may enable organ transplantation

Artificial mouse embryo models from stem cells

Credit: Weizmann Institute of Science

Without an egg, sperm, or uterus: Artificial mouse embryo models created from stem cells only

The egg meets the sperm – this is a necessary first step in the beginning of life. In embryogenesis research, it is also a common first step. However, in a new study published on August 1, 2022 in the journal cellResearchers from the Weizmann Institute of Science have developed models of artificial mouse embryos outside the womb by starting only with stem cells cultured in a petri dish. This means that they are grown without the use of fertilized eggs. This method opens new avenues 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 implantation using artificial embryo models.

Video showing a model of an artificial mouse embryo on the eighth day of its development; It has a beating heart, yolk sac, placenta, and an emerging circulatory system.

“The embryo is the best organ-making machine and the best biological 3D printer – we’ve tried to simulate what it does,” says Professor Jacob Hanna of the Department of Molecular Genetics at Weizmann, who led the research team.

Hanna explains that scientists already know how to return mature cells to the ‘stem’. In fact, the pioneers of this cellular reprogramming won the Nobel Prize in 2012. However, going in the opposite direction, i.e. causing stem cells to differentiate into specialized body cells, not to mention the formation of whole organs, has proven more difficult.

To date, in most studies, specialized cells were often either difficult to produce or skewed, and tended to form an admixture rather than the well-organized tissue suitable for transplantation. We were able to overcome these obstacles by unleashing the self-regulatory potential encoded in stem cells.”

Artificial mouse embryo researchers

(from left to right): Noah Noferstern, A. Jacob Hanna, Alexander Aguilera-Castergon, Shadi Tarazi, and Karen Gibran. 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 to a naive state – that is, to their earliest stages – when they have the greatest potential to specialize into different types of cells. The other, described in a scientific paper at temper nature In March 2021, the electronically controlled device the team had developed over seven years of trial and error to grow normal mouse embryos outside the womb. The device keeps fetuses immersed in a nutrient solution inside the constantly moving cups, mimicking the way nutrients are supplied by blood flow to the placenta, closely controlling the exchange of oxygen and atmospheric pressure. In previous research, the team successfully used this device to grow normal mouse embryos from day five to day eleven.

This is how models of artificial mouse embryos grew outside the womb: video showing the device in action. The constantly moving cups mimic the natural nutrient supply, while the exchange of oxygen and atmospheric pressure are tightly controlled.

In the new study, the team set out to grow an artificial embryo model only from naive 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 very valuable because it can, to a large extent, bypass the technical and ethical issues involved in using natural embryos in research and biotechnology. Even in the case of mice, some experiments are currently useless because they 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-making machine and the best 3D bio-printer – we tried to simulate what it does.”

Before placing the stem cells in the device, the researchers separated them into three groups. In one of them, which contained cells intended to develop into embryonic organs themselves, the cells were left as they are. Cells in the other two groups underwent pretreatment for only 48 hours to overexpress one of two types of genes: the placenta or yolk sac master regulators. “We gave these two groups of cells a transient impulse to cause tissue outside the embryo that sustains fetal development,” Hanna says.

Development of artificial mouse embryo models

Development of artificial embryo models from day 1 (top left) to day 8 (lower right). All of their early ancestors formed, including the beating heart, emerging circulatory system, brain, neural tube, and intestinal tract. Credit: Weizmann Institute of Science

Soon after mixing them together within the device, the three groups of cells came together into clumps, the vast majority of which failed to develop properly. But about 0.5 percent—50 of about 10,000—continued to form balls, each of which later became an oblong, embryo-like structure. Because the researchers labeled each group of cells a different colour, they were able to observe the placenta and yolk sacs that form outside the embryos and how the pattern progressed as in a normal fetus. These synthetic models developed normally until day 8.5—roughly half of a mouse’s 20-day gestation period—at which point all of the early organ progenitors had formed, including the beating heart, circulating blood stem cells, brain with well-shaped folds, and neurites. Intestinal tube and tube. When compared to normal mouse embryos, the synthetic models showed a 95 percent similarity in both the shape of the internal structures and gene expression patterns of the different cell types. The organs that appear in the models each gave an indication of being functional.

Mouse embryo day 8

Eighth day in the life of a mouse embryo: an artificial model (top) and a normal embryo (bottom). The ultrastructural models showed 95 percent similarity in both the shape of the internal structures and the gene expression patterns of the different cell types. Credit: Weizmann Institute of Science

For Hanna and other researchers in the field of stem cells and embryonic development, the study presents a new field: “The next challenge is understanding how stem cells know what to do — how they self-assemble into organs and find their way to their designated places within the embryo. Because our system, on the Inverted uterus, transparent, may be useful for modeling birth defects and implantation of human embryos.”

In addition to helping reduce the use of animals in research, models of artificial embryos may in the future become a reliable source of cells, tissues, and organs for transplantation. “Instead of developing a different protocol for growing each type of cell – for example, kidney or liver cells – we may one day be able to create a model similar to an artificial embryo and then isolate the cells we need. We won’t need to dictate to emerging organs how they should develop. The fetus itself does it better.”

An innovative method for growing artificial mouse embryo models from stem cells

Diagram showing the innovative method for growing models of artificial mouse embryos from stem cells – without egg, sperm or uterus – developed in Professor Jacob Hanna’s laboratory. Credit: Weizmann Institute of Science

Reference: “Post-gastric artificial embryos born ectopic from naïve mouse ESCs” by Shadi Tarazi, Alejandro Aguilera Castrigón, Karen Jubran, Nader Ghanem, Shahd El Choukhi, Francesco Roncato, Emily Wildschutz, Montaser Haddad, Bernardo Oldschutz, Eldit Ghanem, Nir Levinat Sergey Vyukov, Dmitriy Lokshtanov, Segev Naveh-Tasa, Max Rose, Suhair Hanna, Kalanit Raanan, Uri Brenner, Merav Kidmi, Hadas Keren Shaul, Zvi Lapidot, Itai Mazza, Noah Noferstern, and Jacob H. 2022, cell.
DOI: 10.1016 / j.cell.2022.07.028

This research was co-led by Shadi Tarazi, Alejandro Aguilera-Castrijón and Karen Gibran from the Weizmann Department of Molecular Genetics. Study participants also included Shahd Achoukhi, Dr. Division; Montaser Haddad and Professor Zvi Lapidot from the Department of Immunology and Regenerative Biology at Weizmann; Merav Kadi of the Weizmann Life Sciences Basic Facilities Division; Hadas Keren Shaul of the Israeli Nancy and Stephen Grand Center for Personalized Medicine; Dr.. Nader Ghanem, Dr. Soheir Hanna, and Dr. Itai Maza from Rambam Healthcare Complex.

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


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