The science behind the blastocyst and the iBlastoid

Left to right: Jia Tan, Jose Polo, Xiaodong (Ethan) Liu. Photo credit: Monash University

It was an unexpected event that led to what researchers call one of the greatest advances in our understanding of early-stage embryos known as the blastocyst: the tiny ball of cells that has the potential to become an embryo and eventually an embryo Human.

The research was just published in Nature.

Two years ago, an international team of scientists led by Professor Jose Polo of Monash University investigated how induced pluripotent stem cells (iPS cells), a type of cell similar to embryonic stem cells but derived from skin or blood cells, can be in any other reprogrammed human cell.

But Polo’s team noticed something that other groups had missed: when they reprogrammed the cells, not everyone did as they were told.

Some – about two percent – appeared to activate a library of unexpected genes. Using single cell transcriptomics, a technique used to study gene expression in individual cells, Polo discovered that the cells activate genes that were expected in the early days of embryogenesis – the time a sperm fertilized an egg.

In a flat Petri dish, the cells did little more than flash these unexpected genes. But cells are not isolated entities in the body; They work together to form complex structures and send signals to one another. Polo’s team wondered what would happen if they had the chance to chat.

So they took these cells, which had grown on a flat-topped petri dish, and placed them on an AggreWell microtiter plate. Often used in stem cell research, these structures look like an inverted pyramid, with cells in solution grouped at the bottom of the borehole. Then the team left to interact.

“We found that six days later the cells had become spheres of organized cells, and we asked ourselves, what are these spheres?” Polo says.

To get an answer, the team needed molecular data – they needed to know which genes and proteins were active in which cells. They solved this with microscopy and examined biomarkers. They also used some sophisticated genomic approaches (called single cell transcriptomics) to study this.

You also had to consider cellular architecture: you had to see and analyze the structural appearance, shape, and location of the cells. They did the same with microscopy. To understand how the cells behaved, they carried out a series of complex analyzes.

With the results in, the team named the cell balls iBlastoids. And while they resemble an early-stage IVF embryo, they are by no means identical. One of the three cell types in the blastocyst, known as the “primitive endoderm” (the layer that becomes the yolk sac), was not well defined in the iBlastoids.

“This discovery is still very important. Even if they’re a model and not exactly the right thing, they provide valuable data to help figure out why miscarriages occur and potentially point to causes of infertility, ”says Polo.

For now, all we know about the earliest stages of human development is studying IVF embryos donated to science. According to Polo, with this discovery, researchers can not only learn the role of a gene or mutation in the implantation phase, but also better understand how toxins and drugs affect the first stage of human development.

While the International Society for Stem Cell Research (ISSCR) expects to publish an update of its guidelines for stem cell research and clinical translation later this year, the existing guidelines published in 2016 recommend that this is an area of ​​research that is only permitted after appropriate review and review is a need for a convincing scientific justification. (For more information on the ethical considerations of this work, see “Ethics and Embryos”.)

How blastocysts differ from iBlastoids. A) The biological growth and cell division of a blastocyst from a fertilized egg. B) In vitro growth of an iBlastoid made from skin cells. Photo credit: Monash Biomedicine Discovery Institute.

The work of the Polo team is based on the discovery by Nobel Prize winner Shinya Yamanaka, who showed in 2007 that it is possible to convert ordinary adult skin cells into cells that, like embryonic stem cells (which can develop into any of the more than 200 cell types) of the adult bodies, as long as they are intended) can develop into any cell in the human body.

In 2007 (in 2006 in mice), Yamanaka discovered that by adding just four factors to human adult skin cells, he could make the cells become like embryonic stem cells. He called them induced pluripotent stem cells or iPS cells.

Since that discovery, iPS cells have become an important tool for modeling the shape of various organs in the body, studying human diseases, and screening drugs. Until the discovery of the Polo team – and the discovery of a second group of researchers, which was also published in Nature on Thursday, but using a different method – it was not clear whether iPS cells were capable of causing human blastocysts to develop model.

Previous studies in mice had built blastoids using stem cells, and other researchers had used stem cells to model other aspects of post-implantation. However, this is the first time an integrated model of the earliest stage in human cells has been created.

Professor Megan Munsie, assistant director of the Center for Stem Cell Systems at the University of Melbourne, says that while the results build on previous, similar research, they are an invaluable step in understanding the role of infertility, miscarriages and even the effects of other drugs on early human development.

“It’s amazing that these cells can assemble themselves and replicate what looks like this early stage of human development,” she says.

And while this is a valuable first step, replicating the results on a larger and more consistent scale is another matter, Munsie says.

“Yes, we did, but the question now is: How reliable is that as a model? Much more needs to be done to understand the limitations of this technology.

“Both articles talk about the inefficiency of their approach: while you can glue these cells together, only some of them form the blastoids, and we don’t yet know why it happened or how it happened. Once we figure that out, we can look for other uses. “

Dr. Peter Rugg-Gunn, group leader at the Babraham Institute in Cambridge, UK, says that both studies “represent an exciting advance in describing the conditions for the construction of human blastocyst-like structures in the laboratory … the next steps in the research will be to optimize the conditions, to improve the efficiency of the formation of the blastocyst-like structures ”.

Currently, only one in ten attempts to create these structures is successful, and the rate at which they are formed is inconsistent.

“To benefit from the discovery, the process needs to be more controlled and less variable,” says Rugg-Gunn, adding that it is also “important to determine in future research which aspects of early human development the blastocyst-like structures can recapitulate.

“If the structures can shed light on how the cell types in a blastocyst communicate with each other, and also help identify the key factors required for lineage formation and development, then this is a very informative cell model.”

Human skin cells are reprogrammed through a cocktail of reprogramming factors (RF). During reprogramming, these are then placed in V-shaped microtiter plates where they gradually develop into a blastocyst-like 3D cell structure called an iBlastoid. Photo credit: Monash BDI.

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