July 20, 2023

expert reaction to a paper on a stem-cell derived embryo model

A study published in Cell models post-implantation stages of human development into early organogenesis with a stem-cell derived embryo model.

Prof Magdalena Żernicka-Goetz FMedSci, Professor of Development and Stem Cells at the University of Cambridge and a Bren Professor of Biology and Biological Engineering at the California Institute of Technology, said:

“This is an exciting paper that adds to a recent flurry of publications describing stem cell models of the human embryo around the time of gastrulation. It builds upon a principle my lab first established with mouse embryo models, that by combining embryonic stem cells with extra-embryonic stem cell types, the embryonic stem cells are guided accurately to develop like natural embryos. Whereas our own most recent paper applied these principles to model the human embryo using wild-type embryonic stem cells together with ones genetically manipulated to form both extra-embryonic stem cell types, the Jun Wu paper exploits the ability of so-called “extended pluripotent stem cells” to generate embryonic stem cells and just one of the two extra-embryonic tissues.  These organise into beautifully compartmentalised structures that recapitulate many of the events around gastrulation.  As they lack trophectoderm stem cells, they would be unable to make the placenta and so unable to generate viable embryos. The new work adds to a growing number of systems that we now have to model these enigmatic stages of human development. Exciting times for developmental and stem cell biology!”

Prof Alfonso Martinez Arias, ICREA Senior Research Professor, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), said:

“This is one of a number of manuscripts on human perigastrulation structures that have been reported recently derived from human pluripotent stem cells over the past few weeks; six to my count. These structures, called ‘stem cell embryo models’ aim to reproduce the early stages of  human development with the idea of creating an experimental system that would allow the study of these early stages of development which, otherwise, are inaccessible. The term gastruloid was coined a few years ago to represent structures that mimic the process or the outcomes of gastrulation. Of the six models presented lately, and from the embryo point of view, this is probably the most advanced one.

“During implantation the cells that will give rise to the human embryo become ensnared into several membranes derived from the extraembryonic lineages, notably the trophoblast that will give rise to the placenta and the so called primitive endoderm that gives rise to a transient feeding organ: the yolk sac.

“Previous studies from the group of Jianping Fu in the University of Michigan had shown that human pluripotent stem cells can be gauged to self-organized into structures resembling embryos at the onset of gastrulation but then collapse. In this work, the authors manage to coax stem cells to organize themselves into embryonic and primitive endoderm cells in a manner that maintains some integrity of the embryonic cells at onset of gastrulation and allow the process to proceed for a while.

“I found the result very convincing, the structures interpretable and the experiments well documented. The model represents a real advance. The model is not simple to achieve and still lacks the trophoblast but the results suggest that while the primitive endoderm is necessary to pattern the embryo, the role of the epiblast is likely to have more to do with the connection to the maternal tissues and probably an important but fine tuning of the pattern in the embryo. The term gastruloid is appropriate as the system proceeds through the early stages of gastrulation.

“Much of the usefulness of these structures will depend on the ease with which they are and can be generated, though going by the results looks as if this will be made easier with time.

“An important aspect of this field is the ethical issues associated with these structures. The ISSCR has suggested a division between structures with a full complement of extraembryonic and embryonic membranes that have the same full potential of a natural structure, and non-integrated which lack some of these and for which regulation might be more lax. The structures reported here while not fully integrated, appear to be in between by virtue of how far they develop and the fact that they have two of the three cell types required for a full structure. Their ethical status will have to be discussed. Nevertheless, impressive and useful as they are, these structures are not embryos and, in comparison, have several abnormalities.

“Given the deluge of structures reported over the last few days, it is probably important to provide some perspective. Importantly the rapid developments in this area of research means that ongoing discussions on the regulation of this type of research should gather pace. People should be careful with not using the term ‘embryo model’ for structures that either don’t resemble nor have the potential to look like natural structures. Now, the publication of the work of several laboratories make clear that only two of the reports deserve this accolade: this one and the one in preprint form from Israel. Others simply represent aggregates of cells organized to different degrees and these might not raise ethical concerns.

“An important conclusion that can be drawn from the comparison of all these models is that if the embryonic cells are embedded in abnormally patterned and organized trophoblast and primitive endoderm, their development will be abnormal (several of the published works) but if they are embedded in the right environment that potential that they have on their own, will thrive, as in the case of this work and that of the Israeli group. This highlights the importance of interactions between embryonic and extraembryonic tissues for the development of the embryo.”

‘Modeling post-implantation stages of human development into early organogenesis with stem- cell-derived peri-gastruloids’ by Lizhong Liu et al. was  published in Cell at 16:00 UK time on Thursday 20 July.

DOI: https://doi.org/10.1016/j.cell.2023.07.018

Declared interests

Prof Magdalena Żernicka-Goetz: “I have patents on generating human and mouse embryo-like models from stem cells.”

Prof Alfonso Martinez Arias: “I have a patent on a human stem cell embryo model for gastrulation and coined the term gastruloid.

For all other experts, no reply to our request for DOIs was received.”