The first steps of human development—those that occur within the first few weeks of pregnancy—remain mysterious in many ways. Within a week of fertilization, human embryos form a blastocyst, which implants into the uterine wall. An experimental model of early human development would advance our understanding of the early stages of this process and facilitate the development of therapeutics for infertility or contraceptives.

The generation of analogs of blastocysts using stem cells is a promising approach, but previous attempts presented limitations. Now, a group of researchers has developed a model to study how human embryos form and implant into the uterus. They showed that human blastoids—structures that mimic the early human embryo—faithfully replicate key phases of early development of the human embryo, including the attachment to cultured uterine cells. The in vitro models enabled them to study the basic principles of early human development and search for new therapeutics.

The work is published in Nature, in the article, “Human blastoids model blastocyst development and implantation.

Nicolas Rivron, PhD, group leader at the Institute of Molecular Biotechnology at the Austrian Academy of Science (IMBA) said: “We know nearly nothing about the first weeks of human pregnancy, and this is because it happens well hidden in the womb.”

Human blastoid fluorescently labeled for markers of the epiblast (yellow), trophectoderm (cyan), and primitive endoderm (magenta).
Rivron and colleagues reported the generation of human blastocyst-like structures (blastoids) from human pluripotent stem cells. They found that naive human pluripotent stem cells, inhibited for specific pathways, efficiently form blastoids that mature into the form that acquires the ability to attach to hormonally-stimulated endometrial cells, as seen during implantation. They identified a trio of signaling pathways that, when inhibited, enabled the formation of blastoids that efficiently emulated normal blastocyst development (greater than 70% efficiency) and formed the right cells (greater than 97% efficiency).

The human blastoids attached specifically to hormonally-stimulated endometrial cells in vitro, which allowed them to recapitulate aspects of peri-implantation development. The blastoids were cultured for up to 13 days, at which point they contained about 300 cells. Given the high efficiency and the potential scalability of the model, the authors suggest that this approach offers a new tool for investigating human implantation and development.

A blastoid constitutes of three main cell types formed before implantation: 1) epiblasts, which would go on to form the embryo, 2) trophoblasts, which would form the placenta, and 3) hypoblasts, which would form the yolk sac.

Several human blastoids in culture with scale bars for magnification. [©Rivron/Nature/IMBA]
Using this model, researchers have discovered molecules that could be candidates for contraceptives or fertility enhancers. Being able to recapitulate in a dish what human embryos normally do hidden within the womb opens avenues for improving in vitro fertilization (IVF) procedures and developing better contraceptives.

Using SC144, a molecule with FDA approval, the team found a promising pathway for a new generation of non-hormonal contraceptives. These birth control pills could be taken only if necessary, removing the burden and stress associated with medications that need to be taken daily. The need for only an occasional dose might also result in significantly fewer side effects compared to a daily hormonal pill.

Using blastoids, the researchers discovered that the epiblasts send important molecular signals to the trophoblasts, instructing one side of the blastoid to become “sticky.” If the blastoids are deposited onto cultured cells of the human uterus lining, they land, position themselves on their sticky side, and attach to the cultured cells of the uterus lining, replicating the events that occur at the very onset of pregnancy. The researchers discovered that SC144 inhibits this attachment, pointing the way towards a new generation of contraceptives by preventing implantation.

Beyond contraception, the blastoids are being used to discover a new effect of a natural molecule, LPA. This molecule strongly improves the self-organization of the stem cells and might thus be used to boost the formation of natural embryos during IVF procedures. The hope is to test this molecule in IVF procedures in the future.

IMBA September 2021
The Rivron lab, Institute of Molecular Biotechnology at the Austrian Academy of Science

“We hope we can use such molecules to improve the number and quality of IVF embryos, and the chance of becoming pregnant,” noted Rivron. “Our goal is to empower women by allowing them to better control their fertility, whether they wish to prevent pregnancy or enhance their chances of having a child.”

Importantly, blastoids can be formed from adult human stem cells and thus provide a powerful scientific and ethical alternative to the use of fertilized human eggs for research. Rivron noted, “By using blastoids we speed up research and make it more ethical.” He added, “It is clear that scientific and biomedical knowledge will skyrocket with such realistic in vitro models for early pregnancy.”

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