How, why, and what the future holds when it comes to making embryos in the lab

How, why, and what the future holds when it comes to making embryos in the lab ...

The ability to make an embryo from other cells than sperm and egg cells and then growing them outside the uterus is a field of research that has significantly evolved in the last five years. How long will we have to get to the truth about human embryology?

Researchers announced that they have been culturing a mouse embryo model made entirely out of embryonic stem cells and without the use of a sperm and egg, or a uterus, for 8.5 days, which was comparable to previous experiments.

The structures and cell activity in these embryo models were 95% similar to those in real mouse embryos and were functional, according to genetic analysis. This suggests that these embryo models were sufficiently similar to natural embryos that they might be examined to understand how they operate.

Researchers studying mouse and human embryos can provide insight into the mechanisms that enable them to divide, implant, and develop. However, being able to construct them entirely from scratch allows researchers to avoid costly and unjustifiable experiments on embryos, as well as helps them verify if their assumptions about how they work are correct.

A paper published recently in Cell outlines the contributions of researchers at the Weizmann Institute of Science in Rehovot, Israel.

This is the latest step in a long line of incremental steps to create an embryo from scratch in the lab in recent years.

The first embryo to be born from stem cells

The Prof. Hannas team had already published in Nature publications on one particularly important piece of the puzzle last year, when they presented the methods they used to grow embryos outside of the uterus.

The method they developed relies on bottles filled with substances that act as a cell culture, which can rotate or remain static at different stages of development.

Prof. Hanna wrote in an email to Medical News Today that since we know how to help [natural mouse embryos] expand outside the uterus (device and conditions), we may finally test whether and which stem cells can generate an embryo ab initio [from the start] only from stem cells.

We couldnt do it before, for what reason would you want to grow a synthetic embryo if you don't know how to grow a natural embryo? Low and behold, the same device, the same media conditions, and the same parameters allowed aggregates of 27 pluripotent stem cells to reach day 8.5-stage embryos when placed in this device after 8 days.

Prof. Jacob Hanna

The device and the media were critical. These embryos are whole embryos, and they have [a] yolk sac and placenta, but we did use placenta stem cells and yolk sac stem cells, but demonstrated that everything can be made exclusively from naive pluripotent embryonic stem cells or induced pluripotent stem cell lines that are routinely expanded in labs across the world.

This was remarkable because previously, scientists had created embryo models that began to form the placenta, egg yolk, and amnion using a mixture of embryonic stem cells and stem cells taken from the trophoblast layer, which is normally formed in embryos.

The failure rate in this latest set of experiments was high, with just 50 of 10,000 cell mixtures forming first into spheres and then into more egg-shaped structures, such as an embryo.

These embryo models began to develop the structures that would support a pregnancy, but at the end of their 8.5 days of growth, they had established a beating heart, blood stem cell circulation, a head region with folds, a neural tube, and the beginnings of a gut tube.

In embryo research, a race is on.

The University of Cambridge lab of Prof. Magdalena Zernicka-Goetz published two papers on a preprint server the same week as the Cell study was published.

This paper explains how Cambridge researchers had observed similar organ structures begin to form in their own research using embryo models.

Prof. Zernicka-Goetz told MNT in an interview that these papers would be published in peer-reviewed journals in the coming weeks, and that their final versions are currently under embargo.

So, as a step by step [process], our paper will demonstrate even further developments, she said.

Prof. Zernicka-Goetz and others' research have all been supported by this latest finding, according to Prof. David Glover, her husband.

Profs. Glover and Zernicka-Goetz have teams at Cambridge and CalTech. They have jointly carried out research and appear as co-authors on one of the papers scheduled to be published soon.

In an interview with MNT, he explains why you need to go back to the Magdas paper published in 2017, [whose] senior author was Sarah Harrison, which establishes the principle of being able to construct an embryo-like structure using a mixture of extraembryonic cells and embryonic cells.

Extraembryonic cells include vital components that make extraembryonic tissues, which are essential to embryo survival. Placenta, yolk sac, and amnion are three examples of extraembryonic tissues.

Prof. Glover believes that being able to develop embryo models that show the start of development of these tissues is essential. They also aid in the development of the embryo model and its self-assemble, much like a naturally developing embryo would.

Because our own embryos develop inside the womb, they require extraembryonic tissues to develop properly. And those extraembryonic tissues have two functions, according to the speaker. They provide a structural basis, they provide a yolk sac, and they provide the placenta.

But before they get to that stage, they also provide signals to the embryo that it may properly develop. And if you don't have those signals, then the embryo will not develop properly, according to the researcher.

Prof. Glover claims that these particular models are just one form of embryo model currently being developed.

Researchers have also developed other models, such as blastoids, which attempt to recreate the embryo's pre-implantation blastocyst stage, and gastruloids, which do not have any extraembryonic tissues, and as a result, do not have a brain region.

Investigating the preimplantation stage

The Dr. Nicholas Rivrons lab at the Austrian Academy of Sciences in Vienna, Austria, has been developing embryo models to better understand the stages of preimplantation.

A 2018 key paper by his group was published in Nature. It explains how they created mouse embryo models based on embryonic stem cells and stem cells from the trophoblast layer, which could be implanted into the uterus of a mouse for a few days.

The same team published another paper in Nature in December 2021. This time, they described how they had made embryo models to the blastocyst stage from human pluripotent stem cells, which they had induced to differentiate into different types of cells.

Dr. Rivron said, "We need to investigate how those embryos may be combined with the uterine cells in order to understand the processes of implantation into the uterus" and how this may enhance our knowledge on numerous health issues including family planning, fertility decline, and the origin of illnesses.

According to Dr. Rivron, the embryo models described in the most recent paper demonstrated they were self-organized to form certain structures that would eventually form the placenta.

The main limitation is the placenta. The placenta is critical, according to him, because it contains essential nutrients and oxygen to the embryo, which is necessary for it to grow and develop further.

What distance can researchers go?

The most recent study demonstrated that the very early stages of organogenesis could be observed in these model embryos.

This has traditionally been difficult to observe, since it usually occurs in the uterus. However, by establishing a procedure to develop these embryo models in the lab, the differentiation of the cells, the genetic control of this differentiation, and the environment required for typical development can all be investigated.

The most recent paper utilized mouse embryonic stem cells to construct the model embryos, which will need ethical approval. By contrast, human embryo research is highly regulated.

The International Society for Stem Cell Research (ISSCR) releases recommendations for this regulation approximately every five years, with the most recent set of guidelines released last year. This article emphasized the possibility of using stem cell embryo models alongside human cells in chimeric embryo models.

Dr. Rivron suggested that while it might be technically feasible to use embryonic organs, this may not be necessary or even ethically acceptable.

Instead, he focused on the development of organoids, stem cell-derived models of organ tissues that may be used to investigate cellular behavior and, perhaps, the development of organs.

In the same week as the latest article on embryo models, a paper describing Harvard Unversity's bioengineered human heart structures appeared in Science.

Dr. Rivron contributed to the latest set of ISSCR guidelines and told MNT that if you want to study organogenesis or create organs, the political principle is that you must use, morally, the least problematic method of examining them, and organoids provide a way to do this.

In the previous five years, the development of organoids and embryo models has progressed in unprecedented speed, and their main elements, as well as new genomic techniques we can use to understand and recreate mammalian structures, are similar.

In the years to come, it will be interesting to see how the disciplines intersect, as this will give us an even greater set of tools to unlock our black box of development.

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