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expert reaction to study reporting the development of embryo-like structures derived from mouse stem cells

A new study, published in Nature, reports the development of embryo-like structures -“blastoids” – derived from mouse stem cells.

 

Prof Robin Lovell-Badge FMedSci FRS, Group Leader, The Francis Crick Institute, said:

“When mouse trophoblast stem cells were first generated almost 20 years ago it was speculated whether they could be combined with embryonic stem cells, which had been derived about 18 years before this, to form blastocysts – early embryos shortly before implantation. I imagine that many attempts to do this failed. The present authors have succeeded in finding conditions where this will happen, initially at a very low frequency, but by various refinements they improve this sufficiently to make it a potentially useful system to ask some questions about the interactions between the outer trophectoderm layer than normally goes on to make the placenta and the inner cells that would normally make the embryo proper. Not surprisingly, the authors show that signaling is required between the two components for each to develop properly. Perhaps the part of the work that will generate the most excitement is the ability of these “blastoids” to induce a response in the uterus of mice that mimics implantation of normal blastocysts. That the resulting embryo-like structures fail shortly after this is again not a surprise as a third cell type that should be present in late stage blastocysts, and which gives extraembryonic endoderm that has a vital role in patterning the embryo as well as forming the yolk sac, is generated very poorly by embryonic stem cells compared to the inner cell mass of a normal blastocyst. A third stem cell type, so called XEN cells, which corresponds to extraembryonic endoderm, that can also be derived from mouse blastocysts, could perhaps be combined with the other two to make embryo-like structures that will develop further than those described here.

“However, the prospects for obtaining human embryo-like structures in this way is currently very remote. This may require using naïve human embryonic stem cells corresponding to an earlier stage than most such cell lines that are in use, and the conditions in which these are maintained may not be compatible with embryo-like development. But even more critically, no one has yet succeeded in deriving bone-fide stem cells corresponding to either human human trophectoderm or extraembryonic endoderm cells. This is a pity for basic research because it would be very useful to have a limitless supply of human blastocyst-like stage embryos to understand the relevant cell-cell interactions required to make normal embryos and to study mechanisms of implantation. However, it may come as a relief to others that such a method of producing many genetically identical human embryo-like structures that might be capable of implantation is not feasible – even if it would be illegal to implant them into women, as is clearly the situation in the UK.”

 

Dr Teresa Rayon, Postdoctoral Training Fellow, The Francis Crick Institute, said:

“In the paper, the authors co-culture two different stem cell populations (embryonic and extraembryonic stem cells), and show that their system allows the cells to re-arrange and organized themselves in a cyst-like structure with extraembryonic stem cells surrounding internal embryonic stem cells (blastoids). This structure resembles the morphology of the embryo were the cells were derived from (the blastocyst). The next step in embryo development after blastocyst formation, is the implantation of the embryo in the uterus. Rivron et al. show that the blastoid culture system recapitulates some aspects of uterine implantation. However, blastoids didn’t fully support embryonic development.

“The co-culture of these two cell types together had been previously characterized, however it is the first time that the cells form a blastocyst-like shape in culture. Blastoids offer a new culture system to study early murine development, allowing for a precise analysis on the interaction between the two population of stem cells. In addition, it could be seen as an alternative approach to reduce the number of animals used to study pre-implantation development. However, it is important to mention that we still don’t fully understand the mechanisms of implantation and the stem cell properties that allow for correct embryonic development, and we will need to continue using mouse models to understand how does this happen.”

 

Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London (KCL), said:

In this remarkable work, combining a specific number of mouse embryonic and trophoblast stem cells, the scientists from the Netherlands, were able to create in vitro blastocyst-like formations or blastoids, mimicking the stage of embryo development at which the embryo implants into the uterine wall. When transplanted into uterus of mice, blastoids were capable of inducing the changes in the endometrium observed during pregnancy.

“Although blastoids did not lead to development of mouse embryos, they deciphered the signalling molecules essential for crosstalk between embryonic and placental compartments to trigger implantation. This is for the first time that scientists were able to shed a light on molecular mechanisms of implantation and these findings may help us to understand more about some aspects of infertility and improve outcome of assisted reproduction.”

 

Dr Harry Leitch, Group Head at MRC London Institute of Medical Sciences (LMS) and Honorary Clinical Lecturer at Imperial College London, said:

This is a novel piece of work that increases our understanding of how different cell types interact in the early embryo. It appears to be the most successful attempt so far reported to ‘build’ an early embryo exclusively from cultured stem cell lines. The fact that these ‘blastoid’ structures cannot successfully progress onwards in development however tells us that we are some way short of bypassing normal development, including the need for sperm and eggs. Perhaps the most likely reason is the failure to make fully functional extra-embryonic cells (placental precursors), which fits with evidence from previous stem cell studies. This may nevertheless prove a valuable tool to improve our understanding of the early mouse embryo, and it will be interesting to see if improvements to the protocol could allow more advanced development of these mouse ‘blastoids’ – which would certainly be a provocative finding. An obvious question is whether similar results could be obtained with human cells? However, we are yet to produce human stem cell lines with properties similar to the mouse cells used in this study. This remains a major challenge for the human stem cell field, and would be a major hurdle to overcome for future researchers should they wish to try and build similar, reconstructed, human embryos.”

 

Prof Magdalena Zernicka-Goetz, Professor of Mammalian Development and Stem Cell Biology, University of Cambridge, said:

For many years we have been able to generate transgenic mice through incorporating ES cells into blastocysts where they become part of a chimeric organism.  Might it be possible then to construct an entire artificial blastocyst that could be propagated in this way? The difficulty is that the blastocyst comprises three tissue types – the pluripotent epiblast, from which ES cells are derived, that will generate the foetus and two extra-embryonic tissues, the primitive endoderm that will form the yolk sac and the trophectoderm that will make the placenta. Could then, these cell types be combined together in vitro to make a blastocyst?

“This study presents an important step towards generating such blastocyst-like structures by combining together trophoblast stem (TS) cells and ES cells. The resulting structures look like blastocysts and are undertaking some events seen in blastocysts before they mature. This is an excellent beginning. However, these blastocyst-like structures do not continue to develop and undertake the events of post-implantation development.

“Why might this be? One possibility is that the structure are built from only two stem cell types, ES and TS cells,  and it is uncertain that the ES cells are capable of generating primitive endoderm (PE) cells of sufficient quality to support development. In this sense, these pre-implantation structures are similar to pervious study from our lab (Magdalena Zernicka-Goetz) laboratory at the University of Cambridge that also combined ES and TS cells together but to make structures that strongly resemble the embryo slightly older, at the time that it is undergoing post-implantation development.  This previous study cultured the ES + TS in a gel of extra-cellular matrix that partially substitutes for some of the functions of the PE-derived visceralendoderm.  This enables the resulting “ET embryos” to develop to form two well defined abutting embryonic and extra-embryonic compartments;  to establish signalling between the two compartments; to undertake pro-amniotic cavity formation, and to establish gene expression patterns defining the onset of mesoderm and primordial germ cell formation.

“The next big challenge, therefore, in making synthetic blastocysts with greater developmental potential will be to incorporate functional PE into the structures because this might appear critical for undertaking the first steps of post-implantation development.”

 

* ‘Blastocyst-like structures generated solely from stem cells’ by Nicolas C. Rivron et al. published in Nature on Wednesday 2 May.

 

Declared interests

Prof Robin Lovell-Badge: “I have no conflicts of interest to declare.”

Dr Teresa Rayon: “I declare I don’t have a personal interest in this story, other that it being scientifically accurate for the general public.”

Dr Dusko Ilic: “I declare no conflict of interest.”

None others received.

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