March 17, 2021

expert reaction to creating human blastocyst-like structures in a dish

Two studies published in Nature report two different methods to produce human blastocyst-like structures in the lab.

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

“The blastocyst is the first embryonic stage where embryonic and extraembryonic cell types are readily detectable during development. Defects at the human blastocyst are a cause of miscarriages and 2/3 of monozygotic twinning occurs during the blastocyst stage. In humans, blastocyst research is limited as it as it requires the use of embryos donated to research following IVF. Therefore, an in vitro model of the human blastocyst may help investigate some features of blastocyst development.

It has been previously shown that mouse stem cells cultured in vitro can re-arrange and organize themselves in a cyst-like structure with extraembryonic stem cells surrounding internal embryonic stem cells (mouse blastoids) that resemble the mouse blastocyst. Now, this new work expands the findings into human and demonstrates that human blastoids form a structure that resembles the morphology of the human blastocyst.

“Human blastoids will allow a precise analysis on the interaction between the population of stem cells that compose the blastocyst (trophectoderm, hypoblast and epiblast) without the need of donated embryos. Also, blastoids may allow the study of the role of specific mutations, signalling molecules or morphogenetic processes in the blastocyst, and are useful to model implantation. However, it is important to highlight that the blastoid models cannot recapitulate what we don’t know about human pre-implantation development. On the one hand, we don’t fully understand how the human blastocysts are formed (the transition from morula to blastocyst), and blastoids may not recapitulate this process. On the other, there is a gap of knowledge on human implantation. Thus, blastoid implantation may help to generate hypothesis that will need to be validated in human embryos. In sum, blastoids may help increase our understanding on human blastocyst development but we will not replace the need to use human preimplantation embryos to solve some of the unknowns.”

Prof Martin Johnson FRS, FMedSci, Emeritus Professor of Reproductive Sciences, University of Cambridge, said:

“The papers by Liu et al. and by Wu et al. both report on the successful development of blastocyst type structures from induced pluripotent cells. The blastoids contained all three types of cell expected for a blastocyst. The generation rates were between 6 and 18%, which is low and development of the blastoids is inefficient, and varies between cell lines produced from different donors, and between experimental batches. In addition, the three lineages seem to develop at slightly different rates in single blastoids, and development of blastoids in the same dish seems unsynchronized. Spatial organization of the hypoblast-related lineage in blastoids remains to be improved. Furthermore, the blastoids contain unidentified cell populations that do not have counterparts in natural human blastocysts.  None the less the authors suggest that these blastoids will provide useful models of human development for studying.  As Liu et al. state “our data show that iBlastoids represent an accessible, scalable, and tractable model system that will be valuable for many applications in basic research and translational approaches. For example, iBlastoids provide an in vitro platform for modelling early cell fate transitions during embryogenesis. Furthermore, we expect that iBlastoids could challenge the field to refine our existing understanding of human pluripotency by allowing us to re-establish the coordinated interactions between the TE (trophoblast) and PE (hypoblast), which have remained inaccessible until now. Given that iBlastoids with specific genetic loads can be generated, this will allow studies of early developmental diseases and screening for treatments, and as such has tremendous potential for understanding infertility and early pregnancy loss. iBlastoids could also serve as an excellent platform for toxicity and viral susceptibility screens, as well as enabling gene therapy techniques. In summary, iBlastoids represent an opportunity to model, in vitro, the pre-implantation blastocyst and peri-implantation stages of human embryogenesis.” They may be right, particularly if the success rate can be improved. But the authors chose to stop the development of these blastoids before they could form a primitive streak, thereby respecting the 14 day rule which is enshrined in law in this country. This was despite the fact that the blastoids were not categorised as human embryos in the Human Fertilisation and Embryology Act, and are unlikely, based on analogy with comparably produced mouse blasotoids, to have full development potential. Clearly the authors wished for public approval of their work before crossing this line. Thus there is work for scientists to be done in explaining the limitations as well as the potential benefits of the blastoid technology.”

Dr Peter Rugg-Gunn, Group Leader at the Babraham Institute, said:

“The two studies provide an exciting advance by describing conditions to engineer human blastocyst-like structures in the laboratory. The work underscores the remarkable ability of cells to self-organise into complex structures. Impressively, even in these first experiments, defined sub-structures are formed that appear to mimic landmark events in early development, thereby opening up this process to experimental observation and study. The research provides an important new cell model to investigate human early development, which could lead to a better understanding of infertility and early pregnancy loss.

“The next steps of the research will be to optimise the conditions to improve the efficiency of forming the blastocyst-like structures. The current efficiency is low, with only about 1 in 10 attempts resulting in success, and the pace at which the structures form is asynchronous. To capitalise on the discovery, the process will need to be more controlled and less variable. It is also important to establish in future research which aspects of human early development the blastocyst-like structures are able to 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 that are required for lineage formation and development, then this will be a very informative cell model.”

‘Modelling human blastocysts by reprogramming fibroblasts into iBlastoids’ by Xiaodong Liu et al.

DOI: 10.1038/s41586-021-03372-y

and ‘Blastocyst-like structures generated from human pluripotent stem cells’ by Leqian Yu et al.

DOI: 10.1038/s41586-021-03356-y

were published in Nature at 16:00 UK time on Wednesday 17^th March.

Declared interests

Dr Teresa Rayon: I declare no conflict of interest.

Prof Martin Johnson: I have no conflicting interests

Dr Peter Rugg-Gunn: No interests to declare.

None others received