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Research, published in Cell, reports on a new mouse stem cell model to aid in the study of early development and pregnancy.
Prof Darren Griffin, Professor of Genetics, University of Kent, said:
“This is an outstanding study that will advance our understanding of early development. It is important to understand that so called ‘EPS-blastoids’ as developed in this study are not embryos. This work was done in mice, and the mouse blastoids were implanted into mouse wombs but they did not develop into mouse babies. And the purpose of this research is to investigate early embryo development – so even if human ‘blastoids’ were ever generated (which has not been done here), there is no suggestion that they would be used to try and establish pregnancies. Rather, these mouse blastoids represent an excellent model system for the study of early mammalian development and, because many more genetically identical blastoids could be produced than would ever be possible by producing embryos, we can have more confidence in results obtained. It will be interesting to discover whether similar successes in model development would be possible in other mammals such as humans – but we don’t know that yet. If human blastoids ever were generated, one of the possible benefits would be understanding the processes of early human development, information that ultimately could be used to improve IVF treatment. But for the moment, this research may help show how early mouse development progresses.”
Prof Magdalena Zernicka-Goetz, Professor of Mammalian Development and Stem Cell Biology, University of Cambridge, said:
“This is wonderful achievement and highly significant step forward. These studies in mice will help us to better understand the very beginnings of life and how a single cell can give rise to all cells that build bodies how they interact in space and time. This new work provides a model for the very earliest stages of mammalian development and is a natural link to our own work using mouse stem cells to model the stages at which the embryo implants into the womb. Importantly, these approaches in mice avoid the use of real embryos and open the way to gain greater understanding of early pregnancy.”
Prof Azim Surani, Director of Germline and Epigenetics Research, Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, said:
“A particular type of mouse pluripotent stem cell can organise and develop into structures resembling mouse blastocysts in a novel finding reported in the study by Li and colleagues.
“Blastocysts naturally develop from a single oocyte after fertlisation. Fertilised eggs then divide to form progressively smaller cells until there are ~60-100 cells, which organise to form blastocysts. These 100 cells acquire two critical fates; the outer cells give rise to the placental tissues and the inner cells to the embryo that develops into a fetus.
“This new study gives insight into our understanding of very early mouse development to blastocyst-like structures (blastoids), starting with a few stem cells. The ‘blastoids’ generated from stem cells do not, however, mimic all the events precisely as observed with the development of normally fertilized eggs. As this study shows, the development of blastoids after implantation in the mouse uterus results in only disorganised mousetissues that last very briefly. This observation suggests that there might be flaws in some of the developmental events leading to blastoids in this research. The long-term utility of the model will depend on whether or not the blastoids can develop to apparently healthy advanced stages of fetal mouse development.
“What occurs in general in human embryo development is that fertilisation of human eggs by sperm shows subsequent development of viable blastocysts in culture. Upon transfer of these blastocysts to the uterus, they can develop to term, as evidenced by the birth of millions of human babies in IVF clinics. Whether the mouse blastoids generated in this research can similarly grow into viable mouse adults will require extensive research in the future and is not certain yet.”
Prof Dusko Ilic, Professor of Stem Cell Science, King’s College London, said:
“In this work, an international group of scientists from USA, China and Spain, led by Juan Carlos Izpisua Belmonte from the Salk Institute, came a step closer to creating viable synthetic mouse embryos from cultured cells. So called ‘blastoids’ could recapitulate several key developmental processes occurring during the first several days of development. However, following implantation in mice, they could generate live, though disorganized mouse tissue.
“It is an exciting achievement at and beyond frontiers of developmental science. The use of these models is, however, strictly limited to research and understanding governance of fundamental biological processes.”
Dr Darius Widera, Associate Professor in Stem Cell Biology and Regenerative Medicine, University of Reading, said:
“Although embryonic stem cells can generate nearly every cell type in the body, they lack the ability to specialise into cells supporting the development of the embryo (extraembryonic cells). Notably, during early development, both embryonic and extraembryonic cells are required to form an early developmental structure called the ‘blastocyst’. Therefore, embryonic stem cells cannot be used as tool to understand very early development of animals and humans.
“To address this problem, several laboratories have developed sophisticated methods to isolate an even earlier stem types and to `freeze` their maturation in a dish. However, even the most advanced models of early development relied on mixing multiple cell types to generate blastocyst-like structures outside of the body.
“In their current study, Juan Carlos Izpisua Belmonte and colleagues developed a very elegant and simple method to generate mouse blastocyst-like aggregates in a dish starting with a single cell type. Using a 3D cell culture technique and appropriate cell culture medium in combination with biochemical cues, the authors were able to produce a self-assembling, mouse blastocyst-like structures from an early stem cell type. This study clearly shows that these ‘blastoids’ show many molecular and functional characteristics of their early natural counterparts.
“This an extremely important study which could contribute to our knowledge of early embryonic development. This was previously limited by the lack of appropriate experimental models. However, although very promising and methodologically sounds, the study also has its limitations.
“Firstly, the efficacy of the method appears to be relatively low. Moreover, upon implantation in mice, the tissues generated from the blastoids were partly disorganised. This suggest that the model requires further refinement. Secondly, the authors used mouse cells to generate the ‘blastoids’. Despite all similarities, human and murine development differ. Therefore, it remains to be seen if the model can reveal anything about human development. Nevertheless, this research could one day pave the way for development of human ‘blastoid’-models of early development for purposes of scientific research and investigation, which could have an even greater impact – but we are a way off that yet.”
Dr Harry Leitch, stem cell biologist and group leader at the MRC London Institute of Medical Sciences, and Academic Clinical Lecturer in Clinical Genetics at Imperial College London, said:
“This is an interesting research study which builds on previous work from many labs demonstrating that cultured mouse stem cells can be manipulated to form structures that resemble mouse blastocysts. Importantly, these structures are not themselves embryos and the authors demonstrate this by showing that they cannot implant normally or undergo the kind of ordered, organised development that an embryo does.
“We have known for some time that adult cells can be reprogrammed to stem cells that represent an earlier stage of development, and this new research shows that such reprogrammed cells can also form these ‘blastoid’ structures, in mice. However, we already know that reprogrammed cells have great translational potential in regenerative medicine, and indeed there are clinical trials ongoing using these more established technologies.
“This new approach is currently a research tool and it remains an open question whether it will ever make an impact in the clinic. I would caution against interpreting the current study as showing that embryos can be made from adult tissues – this has the potential to raise undue ethical concerns, the structures made are not embryos, and the research is in mice not humans. In reality, this study reports incremental findings in a pre-existing model system, and makes a valuable contribution to ongoing research in the field.”
Prof Alfonso Martinez Arias, Group Leader of the Martinez Arias Group, Department of Genetics, University of Cambridge, said:
“The work in mice is an interesting further development from earlier work1 from The Hubrecht institute which developed the idea of blastoids, as well as the term. So, this isn’t entirely new.
“There are differences, though, and these are important. The work from the Hubrecht never obtained the three cell types with enough frequency and their blastoids never implanted properly. In this work, they obtained mouse blastoids with the three cell types, and they implanted in mouse wombs. It is also interesting that they do it from one cell and with iPSCs (induced pluripotent stem cells). So, the work is an extension (or further elaboration) from published work, but an important one.
“However, while the press release is correct in that this may contribute to understanding early development and pregnancy, they do not show that the implanted structures go to term in mice or even that they develop into anything as recognisable as a mouse embryo. This is intriguing as it raises questions about why, suggesting that there is something not quite right with the specification of the embryonic lineage under these conditions. In order to live up to the opening statement of helping inform issues around health problems, they would need to show that these contraptions develop beyond the stages that they show here. Importantly, given the abnormal development of the implanted mouse blastoids it is not clear how they could study pregnancy when their system does not develop normally.
“It is an interesting advance, but its needs to be emphasised that it is done in mice and that not all claims in the press release are backed up by evidence. For this to happen similar work would have to be done with human cells and, at the moment there is no clear prospect of this being possible. This is an area where there is a need to emphasise the limitations of the observations. If we don’t we shall be using hype to play with hopes.”
1 https://www.nature.com/articles/s41586-018-0051-0
‘Generation of blastocyst-like structures from mouse embryonic and adult cell cultures’ by Ronghui Li et al. was published in Cell at 16:00 UK time on Thursday 17 October 2019.
DOI: 10.1016/j.cell.2019.09.029
Declared interests
Prof Darren Griffin: “No COI.”
Prof Magdalena Zernicka-Goetz: “No conflict to declare.”
Prof Azim Surani: “I have no conflict of interest.”
Prof Dusko Ilic: “I declare no conflict of interest.”
Dr Darius Widera: “I declare that I do not have any competing interests.”
Dr Harry Leitch: “No conflicts of interest.”
Prof Alfonso Martinez Arias: “AMA uses Pluripotent Stem Cells to study mammalian development but has no competing interest in the area of preimplantation development.”