Programmable stem-cell-based embryo models created using epigenome editing

A programmable stem cell model, with the ability to mimic early stages of mammalian development, has been created using an engineering biology technique.

Researchers from the University of California, Santa Cruz, aimed to create a reproducible and customisable mouse embryo model to complement and improve existing approaches. Stem-cell-based embryo models (SCBEMs) are cell aggregates that resemble embryos in the early stages of development, allowing scientists to study how cells interact between them (see BioNews 1219, 1204, 1124, 1091, 1088 and 1020). Three types of cells are needed to model the early mouse embryo in its entirety – cells that will form the embryo itself, cells that will generate the placenta, and cells that will give rise to the yolk sac.

'We as scientists are interested in recreating and repurposing natural phenomena, such as formation of an embryo, in the dish to enable studies that are otherwise challenging to do with natural systems', said Dr Ali Shariati, principal investigator and senior author of the paper published in Cell Stem Cell.

In order to create SCBEMs, scientists need to generate the required cell types prior to or during cell aggregation. Other methods depend on media optimisation, require overexpressing genes or use cell lines derived from embryos.

This particular study used CRISPR activation, an epigenome editing technique that does not alter DNA sequences but rather enhances gene expression. By activating factors known for their role in development, the researchers were able to generate the three cell types they needed from embryonic stem cells. These cells were able to form an aggregate that, after a few days, resembled a day 5-6 mouse embryo.

'These cells co-develop together, just like they would in an actual embryo, and establish that history of being neighbours,' Dr Shariati said. 'We do not change their genome or expose them to specific signalling molecules, but rather activate the existing genes'.

Epigenetic changes have been known to occur during early development, affecting factors involved in determining the identity of cell types. However, epigenetics had not been explored in this way in SCBEMs before now. The new study shows that editing epigenomes is sufficient to allow stem cells to self-organise into reproducible SCBEMs.

Beyond just making a model that mimics an embryo, this editing technique allowed researchers to understand the role of other factors during this crucial stage of development. The system is also programmable, meaning that it gives scientists the ability to control the expression of certain genes in a specific cell type only. The precision of the approach could show how certain genes affect a lineage, while also affecting neighbouring cells.

'We want to know how cells organise themselves into an embryo-like model, and what could go wrong when there are pathological conditions that prevent an embryo from successfully developing,' explained Dr Shariati, whose team is interested in using this technique in other mammalian species.

This embryo model offers the potential to test a large number of genes, and identify whether and when expression of these genes is crucial for successful development.

Read the Code of Practice for the Generation and Use of Human Stem-Cell-Based Embryo Models, published jointly by Cambridge Reproduction and PET.