Researchers form human embryos without fertilization and observe …

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Dallas, Melbourne and Tel Aviv – 2 research groups from the USA and Australia have succeeded in producing artificial blastocysts from human stem cells, which according to their reports in Nature (2021; DOI: 10.1038 / s41586-021-03356-y and 03372-y) resemble a 5 to 6 day old embryo just before implantation in the uterus.

A team from Israel managed to keep a mouse fetus alive outside the uterus for 20 days, which is half the gestation period for rodents (Nature, 2021; DOI: 10.1038 / s41586-021-03416-3). The researchers hope to gain new insights into embryogenesis, which could be used to elucidate the causes of disease.

A blastocyst is an early stage in embryogenesis that is crucial for further development. It is a fluid-filled ball made up of around 200 cells. The outer shell forms the trophoectoderm, from which the placenta and the amniotic membrane form after implantation in the mucous membrane of the uterus. Inside the ball there is the so-called “inner cell mass” (ICM), from which the embryo is formed.

Even in the blastocyst stage, the ICM is divided into epiblast and hypoblast. After the implantation, during the so-called gastrulation, the three germ layers (endoderm, mesoderm and ectoderm) are formed, from which the organs and various tissues are later formed. The stage of the blastocyst is of interest from a medical point of view, since disorders in the phase are believed to be the cause of many miscarriages in early pregnancy. In addition, 2/3 of all monozygous twins separate at this stage.

Artificial blastocysts, which researchers refer to as blastoids, could provide interesting insights into early embryogenesis. The use of natural blastocysts that could be obtained from fertilized egg cells has failed in many countries due to ethical concerns and legal prohibitions. Artificial production from stem cells could bypass these hurdles. A few years ago it was already possible to produce blastoids from stem cells in mice.

Leqian Yu from Texas Southwestern Medical Center in Dallas and coworkers have now succeeded in doing this on the one hand with human embryonic stem cells that were removed from blastocysts. They later also made induced pluripotent stem cells (iPS) differentiate into blastoids.

Xiaodong Liu from Monash University in Melbourne and colleagues, on the other hand, used reprogrammed fibroblasts from skin samples from an adult to form their “iBlastoids” (DOI: 10.1038 / s41586-021-03372-y).

It took both teams about 6 to 8 days for the blastoids to form from the individual cells. Cultivation turned out to be complicated. The success rate was only around 20%. However, the human blastoids were similar in size and shape to natural blastocysts with a similar total number of cells, which the researchers confirmed through transcriptome analyzes. The shape was also similar to that of a natural blastocyst. They contained a cavity and an ICM-like cluster of cells. The outer layer was similar to the trophectoderm and in the ICM epiblasts and hypoblasts could be distinguished.

In the next step, the implantation in the uterus was simulated in the laboratory. The blastoids established a connection with the environment and began to develop in the direction of placental cells. A central proamniotic cavity was formed in the epiblast, which is the prerequisite for the formation of the 3 germ layers. The development ended after about 4 to 5 days. Without a suitable replacement for the uterus, the researchers reached the limits of their possibilities. They also have to adhere to the rules that prohibit the cultivation of human embryos beyond day 14.

These restrictions do not apply to experiments on mouse embryos. Jacob Hanna’s team from the Weizmann Institute of Science in Tel Aviv started where Yu and Liu’s workgroups had to end. Your mouse blastocysts were first developed further in a special growth medium up to gastrulation.

When the embryos had developed the endoderm, mesoderm and ectoderm, they were placed in a glass uterus. It’s a glass bulb that kept moving to keep the embryos from sticking to the surface. The fluid they were in provided them with oxygen and nutrients, and removed carbon dioxide and metabolic waste products. The embryos continued to develop even without a blood supply from a placenta. Organ development and, externally, the extremities developed.

By integrating fluorescent markers into the genes, the researchers were able to display the individual structures of the embryos in color. In doing so, they created the prerequisites for genetic manipulations with which, for example, the effects of certain genetic defects can be examined more closely over time. This could, for example, make animal testing superfluous, argues Hanna.

So far, the researchers have removed the embryos from pregnant animals. In the future, they want to grow them from stem cells. The “production” of living mice is currently not planned, according to Hanna. The system currently reaches its limits about halfway through pregnancy. A supply of oxygen and nutrients would then no longer be possible without a placenta. © rme / aerzteblatt.de

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