In our recently published paper1, we showed that mouse stem cells self-organize into blastocyst-like structures, that we termed blastoids. Because blastoids can be generated in large numbers, can be finely manipulated, and implant in ut
In our recently published paper1, we showed that mouse stem cells self-organize into blastocyst-like structures, that we termed blastoids. Because blastoids can be generated in large numbers, can be finely manipulated, and implant in utero, they are a powerful tool to investigate the principles of pre- and post-implantation development. Here is the backstory of our discovery and why we think it is important for science and medicine.
Nature | doi:10.1038/s41586-018-0051-0
The early mammalian embryo, known as the blastocyst, combines the simple and esthetic design of an outer cyst (the future placenta) englobing an inner cell cluster (the future embryo) with the powerful potential to form the whole organism (both embryonic and extra-embryonic). But blastocysts are also few, small, with a small number of cells (<100), and are difficult to physically and genetically manipulate2. Many of its operating principles therefore remain unknown.
Stem cell-based embryology.
Stem cells have the intrinsic capacity to self-organize in vitro, as shown with post-implantation models known as gastruloids3-5 or with organoids. Here, we created the first version of a pre-implantation blastocyst model by promoting the self-organization of mouse embryonic (ESCs) and trophoblast stem cells (TSCs).
The reductionist approach of forming entities ‘from the bottom up’ allows to modulate and reveal previously unnoticed principles of development. In addition, blastoids have technical advantages as compared to blastocysts. Large number of genetically similar structures can be generated, thus opening possibilities for high-throughput screens and for biochemistry-based assays. Also, sub-populations can be rapidly and efficiently fine-tuned. For instance, the trophoblast and embryonic compartments can be physically and genetically modified independently one from another (e.g. dosing/mixing of different genotypes)1, 2.
Altogether, blastoids are models to study the genetically-encoded principles of self-organization, and to generate novel hypotheses on development, which complement the classical ‘top-down’ approach (e.g. observing genetically modified blastocysts). In the future, blastoids, which comprise the cell types necessary to form the whole organism and which can be transferred in utero, might form a full organism solely from stem cells.
Pulling forces to initiate the project.
As an undergraduate in France, I studied a range of physics and engineering-related topics such as polymer physics and fluid dynamics, which are statistical and modelling sciences. However, what grasped my imagination was the experimental concept of tissue engineering as proposed by Linda Griffith and Robert Langer6. I applied it during my PhD (2006-2010) by studying the self-organization of pre-vascularized engineered tissues (Prof. Clemens van Blitterswijk, University of Twente, The Netherlands). At the end of it, Clemens van Blitterswijk gave me the freedom to work independently, and to hire two PhD students. A great opportunity to develop new ideas, and at an interesting time: the laboratories of Hans Clevers (Hubrecht Institute) and of Yoshiki Sasai (CDB RIKEN) had just shown that stem cells can form organoids. These discoveries perfectly balanced self-organization and developmental biology.
As I wanted to model the embryo, the blastocyst appeared as a lucid choice in light of the available ESCs and TSCs types. The necessity to gain knowledge on blastocysts stem cells led me to ask Niels Geijsen to become a guest at the Hubrecht Institute for developmental biology and stem cell research (Utrecht, The Netherlands). I obtained an additional grant (“Modulating trophectoderm pluripotency and placental development in artificial blastocysts”, ZonMw project number 116005008), hired two great PhD students Erik Vrij (2011) and Javier Frias Aldeguer (2012), and started pipetting ESCs and TSCs, while finalizing the publication of my PhDs’ papers (2012)7,8. Erik focused on developing high-content imaging to quantify the phenotypes, while Javier took a deep dive into the relatively unexplored biology of TSCs.
It took us years of intense, stressful and risky work, and we had to run less uncertain projects to maintain a reasonable output, but the team progressively gained expertise and developed efficient, robust experimental pipelines.
How did it come to work?
Self-organization relies on setting up the right boundary conditions to trigger the process. Once initiated, the stem cells remember where they come from, and unleash their intrinsic potential. Two elements were 