Human embryo development and early organ formation remain underexplored topics due to ethical issues surrounding the use of embryos for research, as well as the limited availability of materials for their study.
Now, Chinese researchers have succeeded in developing structures similar to macaque embryos from embryonic stem cells for the first time. In addition, they have managed to implant themselves in the uterus of female macaques and develop a hormonal response similar to that of a pregnancy, although they have only survived for about a week. According to the authors, whose research is published in “Cell Stem Cell”, these models could serve to improve knowledge about embryonic development and to investigate the causes of some early abortions.
But, as Antonio Urries, director of the Assisted Reproduction Unit of the Quirónsalud Hospital in Zaragoza and president of the Association for the Study of Reproductive Biology (ASEBIR), warns, these are not embryos per se, “but” embryoid structures »capable of behaving like an embryo in its first days of development».
And, as the researchers stress, the study has not resulted in the birth of any macaque babies. Because, as Luís Montoliu, a researcher at the National Center for Biotechnology (CNB-CSIC) and at CIBERER-ISCIII, points out, in statements to the Science Media Centre, it is about «an experiment that cannot be performed on humans, due to the associated technical, legal, and ethical limitations», although he acknowledges that studies like this one, carried out in macaques, gradually bring us closer to this possibility. “The birth of non-human primates derived entirely from embryonic pluripotent stem cells grown in the laboratory is getting closer and closer without the need to go through the fertilization of an egg by a sperm, as has been possible for years in mice.”
Graphic explaining the process of making embryo-like structures from monkey embryonic stem cells
At the moment, acknowledges study author Zhen Liu, from the Chinese Academy of Sciences (CAS) in Shanghai, “the molecular mechanisms of human embryogenesis and organogenesis are not very clear.” And because monkeys are evolutionarily closely related to humans, “we hope that studying these models will deepen our understanding of human embryonic development, even shed light on some of the causes of early miscarriage.”
The work, points out Alfonso Martínez Arias, ICREA research professor and researcher in Bioengineering Systems-MELIS at Pompeu Fabra University, is a further step in the characterization of these development models based on embryonic stem cells and there will be others. Its value, he points out to SMC, will depend on two things: “reproducibility and the demonstration of its scientific value in providing new knowledge. The latter is, for the moment, far away. Macaques and humans are different, even in the way that blastocysts implant.”
Martínez Arias sees this work as an proof of concept that it will be a challenge to reproduce due to the cost of the research – working with primates is not easy or affordable – “but it is clearly evidence that blastoids will be, are, a useful tool to study the first steps of uterine implantation, which affect many aspects of infertility.”
What the Chinese researchers have achieved is to engineer an embryo-like system that can be induced and cultured indefinitely, explains co-author Quian Sun. “It provides new tools and insights for the further exploration of primate embryos and reproductive health.”
The birth of non-human primates derived from embryonic cells grown in the laboratory is getting closer
Luis Montoliu
CNB-CSIC and CIBERER-ISCIII
The researchers started with macaque embryonic stem cells, which they exposed to a series of growth factors in cell culture. These factors induced stem cells to form embryo-like structures for the first time using non-human primate cells.
They then saw that the embryonic structures, also called blastoidespresented a morphology similar to that of natural blastocysts.
Martínez Arias explains that from a structural point of view (genes expressed by their cells), blastoids are almost identical to their natural counterparts, blastocysts. «What the blastocyst does is implant itself in the uterus and, once well established, begin the construction of the organism with the process of gastrulation: the generation of the seeds of each tissue and organ while they are arranged in space. Until now there was no evidence that blastoids could implant correctly and initiate embryo development. In the case of humans, for obvious ethical reasonss».
In research, as the blastoids developed in vitro, they formed amnion- and yolk-sac-like structures. In addition, they also began to form the types of cells that would eventually make up the three germ layers of the body.
Implanted in the uterus
The blasts were then transferred to the uteri of 8 female monkeys; in 3 of the 8, the structures were implanted. This implantation resulted in the release of progesterone and chorionic gonadotropin, hormones normally associated with pregnancy. The blastoids also formed early gestation sacs, fluid-filled structures that develop early in pregnancy to enclose an embryo and amniotic fluid. However, they did not form fetuses and the structures disappeared after a week.
The researchers acknowledge the ethical concerns surrounding this type of research, but stress that many differences remain between these embryo-like structures and natural blastocysts. And what is more important, the embryonic structures do not have full potential for development.
Urries recalls that despite the fact that these types of embryoid structures have already been successfully generated in humans with morphology and structures similar to natural embryos, their cultivation beyond day 14 or their implantation in the uterus of a woman is not allowed. due to ethical issues.
The technique has great potential for the future and very promising applicability in humans.
Anthony Urries
Director of the Assisted Reproduction Unit of the Quirónsalud Hospital in Zaragoza and president of ASEBIR
For this reason, he points out to SMC, “being able to do this type of research in a species so closely related to ours as the macaque monkeys is a ideal model for the study in detail of the first phases of organ development as vital to mammals as are the heart, brain or neural tube».
On the other hand, he continues, “it can help us delve into certain implantation mechanisms and understand why pregnancies fail, detecting those anomalies that can cause abortions. Likewise, it can guide us in the development of “synthetic” organs and tissues for transplants and discover the origin of some diseases”.
And, he adds, although it has the limitations of being a technique in a very preliminary phase, the result of a very complicated and inefficient process (around 25%), it has “great potential for the future and very hopeful applicability in humans.”
In future work, the researchers plan to focus on further developing the embryo-like structure culture system from monkey cells. «This will provide us with a useful model for future studies.says co-author Fan Zhou of Tsinghua University. “Further application of monkey blasts may help dissect the molecular mechanisms of primate embryonic development.”