12 September 2019

Embryos in a biochip

Microfluidics helped to grow two-week-old embryos from stem cells

Polina Loseva, N+1

Scientists have created a microfluidic system that allows you to reproduce early human development. The stem cells were immersed in a gel and washed with a solution with signaling substances. As a result, embryos were obtained that correspond to the first stages of development after implantation: they had the first germ shells and the precursors of stem cells were formed. The work was published in the journal Nature (Zheng et al., Controlled modeling of human epiblast and amnion development using stem cells).

After the first two weeks of development, the human embryo is implanted into the uterine wall and loses its independence: further events in the life of its cells are closely related to signals from the maternal organism. It is at this moment that the main event in human development takes place – gastrulation. This is the process during which the future organism turns from one layer of cells into two, and then into three. At the same time, a plan of the structure of the embryo is formed: the dorsal and abdominal sides are formed, as well as the future head and tail. 

At the same time, the first beginnings of the nervous system arise – a group of progenitor cells, from which the neural tube and all its derivatives are later formed. This, in particular, is connected with the "14-day rule" – a ban on the cultivation of embryos in the laboratory for longer than this period. It is believed that this prohibition excludes the possibility that the embryo will feel any pain from the manipulations that are performed with it.

The "14–day rule", on the one hand, and the impossibility of development outside the mother's body, on the other, severely limit human embryologists in their work. Everything we know about the post-implantation period of the life of human embryos has either been studied on abortive material (but often these are non-viable embryos), or tested on mice (whose development does not completely repeat human development), or modeled on individual cell cultures, which does not allow us to draw conclusions about the state of the embryo as a whole on one or another stages. 

Yi Zheng from the University of Michigan and his colleagues built a model of human embryos using a microfluidic device. As a cellular basis, scientists took human pluripotent stem cells – these are embryonic stem cells that are obtained directly from early embryos, and induced pluripotent cells that are obtained from adult cells, reprogramming them into the embryonic state. The researchers placed pluripotent cells on a gel base, where, as the gel solidified, they formed balls. Then, through adjacent channels, scientists injected morphogens into the solution – signaling substances that affect cell fate. From time to time, researchers stained groups of cells with characteristic markers to determine which cell populations make up the germ ball.


The scheme of the experiment: microfluidic device, formed cell balls, differentiation towards the front and back of the body (figure from the article in Nature).

Under the influence of morphogens, the homogeneous cell mass in the balls was divided into two types: epiblast cells, from which the body's own tissues can form, and amnion cells – the first of the germ membranes. Then the epiblast cells continued to specialize: gastrulation began and even primary germ cells were formed – the very ones that should give rise to the actual human germ cells. At the same time, a dorso-ventral axis was formed in each ball, that is, it became clear where the future back was and where the stomach was, but the anterior-posterior axis was not formed. Each embryo was entirely similar either to the front part of the organism or to the back. 

Thus, the researchers were able to reproduce the events occurring in the embryo during implantation. This model can be used further – for example, to study the mechanisms of miscarriages. At the same time, the new method does not cause ethical doubts – after all, you can not use cells from real embryos – and allows you to bypass the "14-day rule", because these model structures do not fully reproduce a living embryo.

The "14–day rule" also applies in experimental embryology: for example, in Spain and China, chimeric embryos of monkeys and humans are now being created - but they are also allowed to grow them no longer than this period. 

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