World news – Advanced mouse embryos grown outside the uterus


To watch a tiny ball of identical cells first attach to an expected uterine wall on its way to the mammalian embryo and then develop into the nervous system, heart, stomach, and limbs: This was a coveted grail in the field of embryo development for almost 100 years. Prof. Jacob Hanna from the Weizmann Institute of Science and his group have now accomplished this feat. The method they developed for the growth of mouse embryos outside the womb in the initial stages after embryo implantation to more advanced stages provides researchers with an unprecedented tool for understanding the developmental program encoded in genes and can provide detailed insights into birth and developmental disorders as well those involved in embryo implantation. The results of this research were published in Nature.

Hanna, who works in the Institute’s Molecular Genetics Department, explains that much of what is known today about mammalian embryonic development is either from observing the process in non- Mammals like frogs or fish that lay transparent eggs, or static images of dissected mice, take embryos and add them up. The idea of ​​growing early embryos outside the uterus to advanced stages existed well before the 1930s, but experiments based on these suggestions had limited success and the embryos tended to be abnormal.

Hanna’s team decided to renew these efforts to advance research in his laboratory, which is focused on the way the development program is carried out in embryonic stem cells. Over seven years, through trial and error, fine-tuning, and double-checking, his team developed a two-step process that made it possible to grow normally developing mouse embryos outside of the uterus for six days – about a third of which was 20-day gestation – to this one At the time, the embryos already had a precisely defined body plan and visible organs. « For us this is the most mysterious and interesting part of embryonic development, and we can now observe it and experiment with amazing details, » says Hanna.

The research was led by Alejandro Aguilera-Castrejon, Dr. Bernardo Oldak, the late Dr. Rada Massarwa and Dr. Noa Novershtern in Hanna’s laboratory and Dr. Itay Maza, a former student of Hanna who is now on the Technion’s Rambam Health Care Campus, headed – Israel Institute of Technology.

You can inject elements into cells, and the system will provide results that are consistent with development match within a mouse uterus

For the first step, which took about two days, the researchers started with mouse embryos several days old – right after they were implanted in the uterus. At this point the embryos were spheres consisting of 250 identical stem cells. These were placed on a special growth medium in a laboratory dish and the team was given the balls to attach to this medium as if they were to the wall of the uterus. With this step, they managed to duplicate the first stage of embryonic development, in which the embryo doubles and triples as it is divided into three layers: inner, middle and outer.

After two days, when the embryos in When the next stage of development came – the formation of organs from each of the layers – they needed additional conditions. For this second step, the scientists placed the embryos in a nutrient solution in tiny cups and placed the cups on rollers, which kept the solutions moving and mixed them continuously. This intermingling appears to have helped the embryos that grew to the placenta without maternal blood flow to be bathed in the nutrients. In addition to carefully regulating the nutrients in the cups, the team learned in further experiments to precisely control the gases, oxygen and carbon dioxide – not just the quantities, but also the gas pressure.

A mouse embryo that is six days outside the Uterus is stained for developmental markers at the endpoint (day 11), revealing normal expression patterns of these markers.

To check whether the developmental processes they observed during the two steps were normal, the team made careful comparisons carried out on embryos removed from pregnant mice in the relevant period and showed that both the separation into layers and organ formation were almost identical in the two groups. In subsequent experiments, they inserted genes into the embryo that marked the growing organs in fluorescent colors. The success of this attempt suggested that further experiments with this system, involving various genetic and other manipulations, should yield reliable results. “We believe you can inject genes or other elements into cells, change conditions, or infect the embryo with a virus. The system we have presented provides results that correspond to the development in the uterus of a mouse, « says Hanna.

 » If you give an embryo the right conditions, its genetic code works like a preset line of dominoes that arranged to fall one after the other, ”he adds. « Our goal was to restore these conditions and now we can watch in real time as each domino hits the next in line. » Among other things, Hanna explains, the method will lower costs and accelerate the research process in the field of developmental biology, as well as reduce the need for laboratory animals.

The next step in Hanna’s laboratory will be to see if she can take the step of removing of embryos from pregnant mice. He and his team want to try to create artificial embryos from stem cells for this research. Among other things, they hope to be able to answer questions with their new method, such as why so many pregnancies cannot be implanted, why the window for implantation is so short, how stem cells gradually lose their “stem-like character” as differentiation progresses which conditions in pregnancy can later lead to developmental disorders.

Tom Shani, Shadi Tarazi, Jonathan Bayerl, Valeriya Chugaeva, Dr. Muneef Ayyash, Shahd Ashouokhi, Daoud Sheban, Nir Livnat, Dr. Lior Lasman, Sergey Viukov and Dr. Mirie Zerbib from the Weizmann Institute of Science part of the Molecular Genetics Department; Dr. Yonatan Stelzer, Dr. Yoach Rais and Dr. Saifeng Cheng from the Department of Molecular Cell Biology; Dr. Yoseph Addadi and Dr. Hadas Keren-Shaul from the Life Sciences Core Facilities Department; Dr. Nadir Ghanem and Chen Itzkovich from Rambam Medical Center; Dr. Sharon Slomovich from the Technion – Israel Institute of Technology; and Raanan Shlomo from Arad Technologies.

Prof. Jacob Hanna’s research is supported by the Kekst Family Institute for Medical Genetics. the Helen and Martin Kimmel Institute for Stem Cell Research; the Dr. Barry Sherman Institute for Medicinal Chemistry; Pascal and Ilana Mantoux; the Maurice and Vivienne Wohl Biology Foundation; the Dr. Beth Rom-Rymer Stem Cell Research Fund; the Edmond de Rothschild Foundations; the Zantker Charitable Foundation; the estate of Zvia Zeroni; the New York Stem Cell Foundation (NYSCF); the Flight Attendant Medical Research Institute (FAMRI); an ERC Consolidator Grant; the Israel Research Foundation (ISF), BSF; and the Israel Cancer Research Fund (ICRF).

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