Researchers have developed a model of human development in the lab that more closely mimics the very first steps of embryo development from a mass of homogenous stem cells into distinct cell types, according to a study published today in eLife. The authors hope this development will find future applications in creating more authentic organoids for drug testing, disease modeling, and potentially even transplantation.
The research was done by scientists at the Gladstone Institute looking to create a system that more closely resembles the natural morphogenesis path taken by cells. Natural morphogenesis involves interactions of asymmetric cell populations, leading to development of distinct cell types and organs. Previous methods have lacked control over cell-type co-emergence and have been unable to perturb specific cell types.
To circumvent these issues, the researchers used a variation of CRISPR genome editing to temporarily silence two different genes in pluripotent stem cells. The first gene, called CDH1, acts to help stick cells stick together—silencing this gene caused cells to clump together in small islands, surrounded by clusters of unaltered cells. This type of segregation is known to occur many times during development.
The second gene silenced, called ROCK1, changes how flexible the cell is. Stiffer cells are known to exert more pulling force on neighboring cells—silencing the ROCK1 gene caused unaltered genes to be stiffer and pull into the center with the softer cells being pushed to the side, creating a ring. Ring pattern emergence is involved in many aspects of development, including in limb formation.
Beyond immediate effects to the edited cells, silencing of these genes led to changes in the cells’ future identities and had effects on unedited neighboring cells as well.
"If cells remain homogenous, you can't get tissues to form," said Gladstone Senior Investigator Todd McDevitt, Ph.D. "An event that breaks the symmetry needs to occur to create the diverse array of cell types needed to form functioning tissues and organs. We had observed this before, but we didn't know how to control it in an experimental study until now."
The new knowledge could eventually be applied to create better organoids for the study of embryo formation, development of congenital effects, and the formation of complex human tissues.