Artificial embryo made from stem cells offers unprecedented look at early pregnancy

The artificial mouse embryos mimic real ones so well that when placed inside the uterus, they implant and initiate pregnancy.

In the earliest stages of pregnancy, developments that influence everything from whether the embryo will implant to the child's potential diseases later in life are hidden from researchers’ view. Now, a new study offers a window into that black box. Researchers have found a way to grow artificial mouse blastocysts, an early embryo structure, in the lab by combining stem cells in a dish. The artificial embryos, called blastoids, resemble natural ones so closely that when transferred into a mouse’s uterus, they implant and initiate pregnancy. Because they can easily be produced in large numbers, blastoids can serve as new models for drug development, hopefully leading to treatments for infertility and early interventions for adult diseases. We spoke with Nicolas Rivron, who led the study, to learn more.

ResearchGate: What is a blastocyst?

Nicolas Rivron: A blastocyst is an early mammalian embryo, before it implants in utero. It’s a hollow sphere formed by less than a hundred cells and consists of an outer layer of cells, the future placenta, and a small cluster of inner cells, the future embryo. It thus contains all the stem cells that are going to form the whole embryo and the whole placenta.

RG: What did your study accomplish?  

Rivron: Other labs have previously shown that stem cell lines representing these inner and outer parts can be cultured independently and multiplied in the laboratory. By combining these mouse stem cells, we have now succeeded in creating embryo structures in the laboratory. The artificial embryos are so similar to natural embryos that they nest successfully in the womb and start a pregnancy.

A representation of a blastoid, which is a synthetic embryo formed in the lab, from stem cells. The green cells are the trophoblast stem cells (the future placenta), whereas the red cells are the embryonic stem cells (the future embryo). Credit: Nicolas Rivron

RG: Why is this significant?  

Rivron: This completely new method allows us to understand the hidden processes at the start of life, to find solutions for fertility issues, and to develop new drugs without laboratory animal research. At present, very little is known about the development of stem cells during that first period of pregnancy. Early embryos are not only miniscule – the diameter of a hair – but are also virtually inaccessible in the womb. These artificial embryos can be formed in large numbers and studied in detail, allowing researchers to deeply understand the process of early embryonic development. This knowledge is of vital importance because small abnormalities at the beginning of pregnancy can have major consequences: they can prevent the implantation of the embryo, or they can contribute to the development of diseases much later in life.

RG: How did you create the artificial embryos?

Rivron: To promote the self-organization of the stem cells, we first grew embryonic and trophoblast stem cells from mice independently in the lab. The embryonic stem cells can form the whole embryo, and trophoblast stem cells can form the whole placenta. By combining them at a specific ratio and stimulating them with a cocktail of molecules, we initiated their communication and triggered them to self-organize. This creates an embryo-like structure that closely resembles a natural early embryo.

RG: Could they develop into a mature embryo?

Rivron: At the moment, we know that they can implant into the uterus, multiply, and differentiate to produce cell types that are known to appear early during pregnancy. For example, the trophoblast cells attract the blood vessels of the mother, fuse with them, and establish the first connection that irrigate the embryo with the mother’s blood. However, we did not form a full mouse at this time. We’re currently pursuing avenues of research to understand these early processes and further stimulate development.

Two blastoids. Credit: Nicolas Rivron

RG: How are these blastoids different from artificial embryos previously created from stem cells?

Rivron: The formation of post-implantation embryo models, known as Gastruloids, in the last few years was a breakthrough pioneered by Susanne van den Brink and Alfonso Martinez Arias. Sarah Harrison and Magdalena Zernicka-Goetz also did beautiful work by adding a type of extra-embryonic trophoblast tissue. These model embryos mimic a stage at which the embryo has already implanted. They do not form all the embryonic tissues. For example, they were missing the tissues that mediate the attachment to the uterus (trophectoderm) and those that later support the embryo.

What we formed are very early pre-implantation embryos that include these extra-embryonic tissues, like the trophectoderm that promotes the attachment to the uterine wall of the mother. The blastoid is thus an earlier stage embryo model that formed the tissues required to implant in utero.

RG: How could blastoids be used for research in the future?

Rivron: We are interested in understanding how the blastocyst forms and implants in utero. Because they are formed with stem cells that can be multiplied and (genetically) modified in the lab, blastoids can be made in very large numbers and studied in great detail. Blastoids thus make it possible to run genetic or drug screens, and to generate enough material for deep (epi)genetic analysis.

Lately, epidemiologists have discovered that very minor flaws that occur at this early stage of development have huge, persisting consequences. They can prevent the blastocyst from implanting or lead to sub-optimal development of the placenta and fetus, which increases the appearance of chronic disease (e.g. cardiovascular diseases) later in life. Setting up a perfect path for the embryo to develop has very important and long-term consequences, and is a tremendous lever to prevent global health problems. For the first time, we can study these phenomena in great detail and run drug screens to find medicines that could prevent infertility, find better contraceptives, or limit the appearance of epigenetic marks that appear in the blastocyst and lead to diseases during adult life.