The blastoid project

Embryology with stem cells.

We still know very little about how early embryos develop, due to their small size (the width of a hair) and inaccessibility in the womb. Such knowledge is however vital as minor flaws at the start of pregnancy can prevent the embryo to implant in utero or contribute to diseases during adult life. Our team has discovered how to trigger the formation of synthetic blastocysts in the laboratory from trophoblast and embryonic stem cells. We believe that our research will help to understand the perfect path an early embryo must take for a healthy development.

 

A conversation between stem cells.

The early embryo is a hollow sphere formed by less than a hundred cells. It comprises an outer layer of trophoblast cells, the future placenta, and a small cluster of inner embryonic cells, the future embryo. Stem cell lines representing these inner and outer parts can be cultured independently, largely multiplied and genetically edited in the laboratory. Using microwell platforms, we assembled these two cell types in a cocktail of proteins and small molecules that triggered their conversation and self-organisation. The resulting structures, that we termed blastoids, are morphologically and transcriptionally resembling E3.5 blastocysts. 

We observed that, like blastocysts, blastoids form via inductive signals originating from the embryonic cells and driving trophectoderm development. Genetically and physically uncoupling the embryonic and trophectoderm compartments revealed that the embryonic cells maintain trophoblast stemness (proliferation, self-renewal) while fine-tuning trophoblast transcriptome and phenome to drive epithelial morphogenesis.

 

In utero implantation.

Blastoids model the state just before the conceptus implants in utero, and contains all the tissues necessary to interact with the mother (polar and mural trophectoderm). As such, blastoids can be transfered in utero to investigate the mechanisms mediating the attachment and invasion into the uterine wall. This phenomena of implantation is absolutely crucial for the development of the conceptus and often fails.

Until now, the blastoid system revealed that, all together, the embryonic inductions are necessary to maintain a trophoblast state that implants in utero and form patterned deciduae. From these initial discoveries, we concluded that, at this stage, the nascent embryo fuels the development and implantation of the trophectoderm, the future placenta.

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Understanding the mechanisms leading to fertility, infertility and sub-optimal pregnancies.

We currently use the blastoid model to investigate the flow of information occurring between the different compartments of the blastocyst and regulating its development. By understanding this molecular conversation, we aim at opening new perspectives to solve problems of infertility, contraception, or the adult diseases that are initiated by small flaws in the embryo. For example, diabetes or cardiovascular diseases.

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Five ways in which embryo models could contribute to biomedical discoveries.

On the long term, embryo models could contribute to improve health in five different ways:

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• Treating infertility. Synthetic embryos could give researchers a better understanding of implantation, and lead to better infertility treatments. It is thought that at least 40% of pregnancies fail by 20 weeks, and that 70% of those that fail do so at implantation (Norwitz et al. 2001).

• Improving IVF. Only around 20% of IVF procedures result in a birth (Chen et al. 2017). Using stem-cell models, researchers could optimize implantation and minimize cellular abnormalities, such as an aberrant number of chromosomes. As well as safeguarding the health of children conceived in vitro, this could reduce the number of procedures.

• Designing new contraceptives. Synthetic embryo work could improve drugs that prevent implantation (as the oral contraceptive pill or intrauterine devices do, in part). Women and health professionals need drugs and devices that are easier to use and that have fewer side effects. Family planning is central to sustainable, global development.

• Preventing disease. Subtle cell abnormalities during the first weeks of pregnancy, such as those caused by the use of alcohol or medications, can do damage throughout pregnancy and beyond (Cha et al. 2012). They can alter development of the placenta and restrict embryo growth, affecting the baby’s birth weight and propensity for chronic diseases (such as those of the heart) decades later (Burton et al. 2016). Entities based on stem cells could help researchers to pinpoint the genetic and epigenetic changes involved (Burton et al. 2016), and assess the effects of diets or drugs (Chen et al. 2017; Bianco-Miotto et al. 2017).

• Creating organs. Mini brains, livers, kidneys and other organoids made from stem cells are highly simplified. Initiating organ development in an environment as similar as possible to the developing embryo might enable researchers to reliably generate structures that more closely resemble mature, functional organs, for drug screens or even for transplantation.

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References:

Norwitz, E.R., Schust, D.J. & Fisher, S.J.N. Engl. J. Med.345, 1400–1408 (2001).

Chen, M. & Heilbronn, L.K.J. Dev. Orig. Health Dis. 8, 388–402 (2017).

Cha, J., Sun, X. & Dey, S.K. Nature Med. 18, 1754–1767 (2012).

Burton, G.J., Fowden, A.L. & Thornburg, K.L. Physiol. Rev. 96, 1509–1565 (2016).

Bianco-Miotto, T., Craig, J.M., Gasser, Y.P., Van Dijk, S.J. & Ozanne, S.E.J. Dev. Orig. Health Dis. 8, 513–519 (2017).

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The following pictures and others can be downloaded and used under a Wikimedia Commons license (https://commons.wikimedia.org, search for 'blastoid')