T.To better understand the earliest stages of human growth, researchers can examine donated embryos or human embryonic stem cells, both of which are limited in availability, or use animal models to answer their questions. In two studies published in nature Today (March 17th) the authors present an additional option: the human blastoid, a blastocyst-like three-dimensional model system that summarizes many events in the first 10 days of human development – and does not require any starting material from a human embryo.
These articles “are great news,” says Marta Shahbazi, a developmental biologist at the Medical Research Council’s Molecular Biology Laboratory in England who was not involved in the work. “Studying human development is a big challenge because. . . Access to human embryos is very difficult, so developing a stem cell model is a great way to help advance the field. ”
A blastocyst is a human embryo that grows about five or six days after fertilization and prepares for implantation in the uterine wall. It consists of an outer spherical layer called the trophectoderm, made up of cells known as trophoblasts, which are the precursors of the placenta. Inside the sphere there is a characteristic cavity that contains the so-called inner cell mass. This group of cells contains three embryonic cell types – the ectoderm, the mesoderm, and the endoderm – that eventually divide to fill the cavity. These tissues have the potential to make all cells in the body and are the cells from which researchers derive human embryonic stem cells.
“The early human development stage near implantation is key to understanding developmental disorders and pregnancy loss,” says Jun Wu of the University of Texas Southwestern Medical Center, “but especially at this stage.” . . It’s essentially a black box. “
To generate an alternative to human embryos for research and to break this black box, Wu and colleagues previously created blastoids from mouse stem cells and showed that they can form some, but not all, embryonic structures when implanted in a surrogate woman. To make a human blastoid, they subjected both human embryonic stem cell lines registered with the National Institutes of Health and induced pluripotent stem cell lines to culture conditions designed to induce the cells to form a blastocyst-like structure. In about 10 to 20 percent of cases, their strategy resulted in blastoids, which they found to have similar gene expression patterns as blastocysts, to be able to generate stem cells from the inner cell mass-like cells and, with additional cultivation, to form peri-implant embryo-like structures and on Attach plastic trays.
What was completely surprising is that when you put them together, they organize themselves. They seem to talk to each other in ways that we need to investigate.
– Jose Polo, Monash University
As they describe in their study, the researchers also treated the blastoids with four different inhibitors of human blastocyst-specific isoforms of the enzyme protein kinase C. The team found that some of these isoforms are important for creating cavities in the blastoids, which is what on it indicates that the enzyme may play a specific role in cavitation in human blastocysts.
In the other study, a research team led by Jose Polo, a developmental biologist at Monash University in Australia, began a previously published protocol for reprogramming human fibroblasts into trophoblast stem cells. They noticed that after about three weeks in culture, the cells differentiated into cells that looked like all three cell types found in a very early human embryo. When they transferred groups of these cells from their flat culture dishes to a three-dimensional culture system, different types of structures were formed. Between about 6 and 18 percent of these 3-D units had an internal cavity with an adjacent cell clump that produced multiple markers of pluripotency, as the internal cell mass does in a blastocyst. In contrast, the outer cells surrounding the cavity looked more like trophoblast cells.
“What was completely surprising is that when you put them together they organize themselves,” says Polo. “They seem to be talking to each other in a way that we need to investigate.”
Blastoids “clearly have morphological and gene expression patterns that resemble some aspects of the blastocyst,” says Janet Rossant, a stem cell biologist at the University of Toronto and Hospital for Sick Children Who Did Not Participate in the work. The blastoid strategy has some limitations: the primitive endoderm does not seem to form very well, there are other cell types in the mixes that are not well defined, and the efficiency of making the blastoids is quite low.
“Neither paper claims they are perfect,” says Rossant, “but the potential.” [is] There it will be investigated how the trophectoderm – while the embryos are developing – can signal the inner cell mass to really promote the rest of the development. You will have access to blastocyst development, initial implantation, how the trophoblast works, and perhaps a little understanding of how the embryo and the extra embryonic lines need to talk to each other for normal development. “A next step, according to Rossant, is to improve the strategy by making it more robust, efficient, and reproducible.
In the future, blastoids could be created in large quantities to study infertility issues, implantation, and the effect of chemicals or pathogens on early development without using actual human embryos, says Polo, since you could start with adult fibroblasts.
All experts agree that with the bright future of the strategy in mind, the ethical implications of creating groups of cells that resemble very early embryos must be considered. “These blastoid models are an exciting milestone for this emerging field,” explains Sophie Petropoulos, developmental biologist at the University of Montréal who did not participate in either study The scientist. “Political questions and guidelines for ethical behavior regarding 3D embryo models [are] Not exactly defined at the moment, ”she adds. “This model is a cause for concern and a lengthy discussion.”
X. Liu et al., “Modeling Human Blastocysts by Reprogramming Fibroblasts in iBlastoids”, nature, doi: 10.1038 / s41586-021-03372-y, 2021.
L. Yu et al., “Blastocyst-Like Structures Generated from Human Pluripotent Stem Cells”. nature, doi: 10.1038 / s41586-021-03356-y, 2021.