Researchers at the Francis Crick Institute, in collaboration with the lab of Anu Bashamboo at the Pasteur Institute and Bar-Ilan University, have developed a stem cell model for studying the earliest stages of sex determination, which could help uncover why some people are born without a clearly identifiable sex at birth, as well as the development of future fertility treatments.
During human embryo development, sex determination happens at a very early stage, which makes the process difficult to study and understand. Typically, gonads begin to form at about 4 weeks and the decision to become a testis or ovary occurs at about 6 weeks.
Very little is known about what happens when an individual’s genetic makeup doesn’t match their physical sex. There is a spectrum of conditions termed differences of sex development (DSDs), which occur in 1 in 4,500 newborns. An example of this is that some genetic variations can lead to partial ovary or testis formation, but this is very unpredictable.
In their study, published in Science Advances today, the research team created a model of early gonad development, using induced pluripotent stem cells, which can be directed to become any cell type in the body. From these, they grew somatic gonadal cells that go on to become the precursors to either ovaries or testes.
Combined with genome editing techniques, the new model allows researchers to study the roles of a range of different genes thought to be involved in sex determination and gonad development.
Using their model, they grew somatic gonadal cells with male chromosomes (XY) but with a variant of a specific gene associated with the development of ovaries. They observed that these cells were unable to go on to form so-called testis cords, which are the forerunners of the seminiferous tubules found in postnatal testes. The inability to make such cords led to a gonad appearance which was closer to an ovary.
Nitzan Gonen, first author on the study and now the head of the Sex Determination Laboratory at Bar-Ilan University said: “Our model allows us to see the transformations associated with the earliest stages of sex differentiation, and how various genetic changes can impact different parts of this process.”
“This in vitro cellular system of the gonads will be imperative for better understanding cases of DSDs, many of which remain unexplained to date at the genetic and mechanistic level.”
Robin Lovell-Badge, head of the Crick’s Stem Cell Biology and Developmental Genetics Laboratory, said: “Being able to understand the reasons behind differences in sex development is often very valuable to the individual affected and to their family. Additionally, it is often important when deciding on possible clinical treatments. For example, to potentially preserve, maintain or restore fertility.
“There is also a lot of interest in growing functional sperm or eggs from induced pluripotent stem cells, and this technique could help by providing the option to co-culture these with the relevant somatic gonadal cells. In the future, this might be a fertility treatment option for infertile men or women left unable to conceive due to cancer treatments.”