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Blastoïde humain

How does the fetus attach to the walls of the uterus?

Between five and seven days after fertilization, the human embryo adheres to the walls of the uterus. In some cases, this implementation fails. But to study this mechanism, biologists face obvious ethical questions. Therefore, one solution is to artificially reproduce the development of the fetus, without performing fertilization in the laboratory, starting with human pluripotent stem cells (hPSC). So far, the structures corresponding to the phases have been obtained too late to study this phase. The team of Nicholas Riverrun from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) successfully met this challenge.

In 2018, we obtained the first complete mouse embryo model, consisting of embryonic and exogenous structures of stem cells. The stage that intrigued us was the blastocyst stage. In humans, it is reached between five and seven days after fertilization. Corresponds to the stage obtained in fertility clinics in the laboratorySays Nicholas Riverron, before being transplanted into the mother’s womb. We have named these artificial stem cell-derived structures explosives.” Since our first article, six laboratories have embarked on the race to reproduce it in humans. »

It is not insignificant to obtain the spontaneous formation of such a spherical structure of a hundred cells, organized into three cell lines namely the ectoderm (an embryonic structure that will later form the embryo), the ectoderm (a tissue outside the embryo that forms the placenta) and the primitive endoderm (also extraembryonic which will develop to a membrane, the yolk sac, amniotic). “The whole difficulty is getting it as early as possible, which is really the pre-implantation stage. For this, the hPSC cell culture conditions are crucial. Nicholas Riverrun summarizes. With colleagues, building on decades of work in embryonic development, he focused on three signaling pathways of interest, that is, communication systems that regulate intracellular activity. By assembling the most undifferentiated hPSC cells possible and inhibiting the Hippo, ERK and TGF-β pathways, 70% of hPSC aggregates are spontaneously upregulated in blastoids.

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Subsequently, blastula development continues and researchers demonstrated the process of differentiation and organization typically observed for blastocysts. By analyzing the gene expression profile of different cells, the team showed that they actually obtained the three blastocyst cell lines: ectoderm, ectoderm and primitive endoderm.

In this human figure, fluorescent markers indicate the lineages of endoderm cells (in yellow)Tropoctoderm (in cyan) The primitive endoderm (purple).

© N. Rivron / Nature / IMBA

Then the team planted these explosives in the laboratory Their tissue is made up of endometrial cells, characteristic of those in the uterus. If endometrial cells are not stimulated with hormones, estrogen and progesterone, implantation is not successful, but up to 40% with prior stimulation, indicating that there is control on the side of the endometrium to allow implantation or not. In addition, the experiments that have been done have shown that blastocysts, such as blastocysts, adhere to endometrial cells. Across A specific area of ​​the ectoderm that comes into contact with the ectoderm. The signal sent by the latter appears to be necessary for the transplant. “The future embryo is involved in implantation and induces the development of the future placenta, as opposed to afterwards where the placenta is essential for the growth of the fetus. At this point, the key issue is successful implementation Remember Nicolas Riverrun.

The molecular mechanisms involved remain to be resolved. Understanding them will make it possible, for example, to develop non-hormonal contraceptives that prevent implantation activation. A single dose in case of unprotected intercourse makes it possible to dispense with the limitations of daily hormonal contraceptives. It will also be good news for women with breast cancer who cannot take hormonal contraceptives. On the contrary, our work also opens up avenues for improving transplant success in the context of IVF and fertilization. in the laboratory In parallel with this work, the researcher worked, with the International Society for Stem Cell Research (ISSCR), to define new ethical guidelines for framing work on explosives: it would be necessary to obtain approval from local or national ethics committees in order to Conducting research on human explosives and it is prohibited to transfer them to the uterus, human or animal.