11 April

Thesis defense Javier Frías Aldeguer: Early differentiation in embryo development

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Javier Frías Aldeguer from the research group of Nicolas Rivron (Maastricht University and Hubrecht Institute) successfully defended his thesis “Early differentiation dynamics of the trophoblastic lineage and its cross-communication with the embryo” on the 11th of April. His PhD project was a collaboration with Clemens van Blitterswijk (Maastricht University) and the group of Niels Geijsen (Hubrecht Institute). During his PhD, Frías Aldeguer studied the first differentiation event in the embryo, during which the first extra embryonic tissue is formed, which will later form the placenta.

Human reproduction is relatively inefficient: only around 30% of conceptions lead to a baby being born.  One of the main factors involved in this is the delicate process of implantation of the embryo in the uterus. At the moment of implantation, the embryo consists of an outer layer, called the trophectoderm and a group of cells within this outer layer, called the inner cell mass. The outer layer, the trophectoderm, is the main mediator of implantation. If something goes wrong during implantation, it is often due to defects in the trophectoderm.

Early embryogenesis
After fertilization in the mouse, the one-celled embryo divides multiple times to form a group of 16 identical cells. Next, the first differentiation takes place; the cells on the outside of the embryo will form the trophectoderm, while the cells on the inside of the embryo will form the inner cell mass. Subsequently a cavity is formed, and at that point the embryo is called the blastocyst (Figure). This is the structure that will implant in the uterus and continue developing there. The trophectoderm will later form the placenta, while the inner cell mass is responsible for forming the embryo itself and the other extra embryonic tissues. Studying this first differentiation process and the correct formation of the trophectoderm is difficult, because it takes place within the female reproductive organ, it is hard to retrieving large numbers of embryos, and genetic modification to study gene function is time consuming and challenging to achieve.

Early embryonic development, from the fertilized egg (left) to the blastocyst (right), consisting of the trophectoderm (green) and the inner cell mass (red)

Stem cells
To overcome some of the difficulties around studying early embryogenesis, researchers have cultured cell lines in the lab that resemble the two earliest types of cells. Trophoblast stem cells resemble the cells in the trophectoderm, while embryonic stem cells resemble the cells in the inner cell mass. However, studying these cells separately will not elucidate the interaction between these cells in the early embryo that lead to the proper formation of both tissues.

Blastoids
Because more complex models were needed to study early embryogenesis and trophoblast formation, Frías Aldeguer and his colleagues developed a method to generate blastocyst like structures, called blastoids, by combining trophoblast stem cells and embryonic stem cells in a dish. These blastoids strongly resemble the blastocysts that are formed during early embryonic development, both functionally and visually (Figure). The blastoids are able to implant into the uterus of mice, but are not yet able to develop much longer within the uterus.

Blastoids (left) are visually highly similar to blastocysts (right)

Future applications
The blastoids that were developed by Frías Aldeguer and his colleagues can be used to study many aspects of early embryogenesis. The developmental processes involved in forming the first two cell types can be studied in detail and we can gain more insight into the factors important for successful implantation. In addition, the blastoids may be used for toxicological studies to find out which substances are toxic to an early embryo, which might be beneficial, and why. A main advantage of using blastoids is that they be generated in large numbers, which allows for the large-scale screening of genes involved in early development and large-scale toxological studies. In the future, this research will hopefully lead to advances in reproductive biology and help increase the chances of a successful pregnancy, for instance for couples going through the IVF procedure.

 

The PhD project of Javier Frías Aldeguer was a collaboration between researchers from the MERLN institute in Maastricht and the Hubrecht Institute in Utrecht. The field of artificial embryology is a new and exciting field, in which such collaborations are key to the development of new models and protocols. Frías Aldeguer and his collaborators were able to develop new protocols to improve the culture of embryo-like structures called blastoids, which will be valuable tools to further study embryonic development in the future.

 

 

Nicolas Rivron is group leader at the Hubrecht Institute in Utrecht and the MERLN Institute in Maastricht, the Netherlands.

 

Clemens van Blitterswijk is professor of Tissue Engineering and former director of the MERLN Institute in Maastricht, the Netherlands.

 

 

Niels Geijsen is group leader at the Hubrecht Institute and professor of Regenerative Medicine at Utrecht University.