New human ovaroid model offers insight into infertility and differences in sex development

A new model of tiny human ovary organoids, or ovaroids, has been developed from stem cells, according to research presented at the first Joint Congress between the European Society of Paediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE). This achievement may help to understand and develop treatments for conditions in which these organs do not develop or function properly, including differences in sex development and infertility.

During human embryo development, sex determination occurs at a very early stage, making the process difficult to study and understand. Typically, gonads begin to form at about four weeks, and the decision to become testes or ovaries happens at about six weeks. Sometimes, however, there is a mismatch between an individual's sex chromosomes and gonadal or anatomical sex - a group of rare conditions known as differences in sex development (DSDs). 

While these conditions are rare - about 1 in 4,500 - milder forms occur in about 1 in 200 people. DSDs are often detected prenatally or in infancy, though some do not become evident until puberty or later. In the past 15 years, a growing number of genes have been implicated in atypical gonad development, but approximately 50% of children with DSDs due to atypical gonad formation still lack a definitive genetic diagnosis. 

To understand gonad development and disease, researchers from the Institut Pasteur in Paris differentiated human induced pluripotent stem cells (hiPSCs) into granulosa-like cells - an ovarian somatic cell type which helps eggs grow and mature - and primordial germ cell-like cells. Next, they combined the two cell populations to form the human ovaroids that replicate key structural and functional aspects of ovarian follicles. 

While other ovaroid models exist, this is the first time for granulosa-like cells and primordial germ cell-like cells to be generated together, without introducing exogenous transcription factors, to produce organoids.

Transcription factors are proteins that bind to specific DNA sequences and turn nearby genes on or off, so using external ones can override the innate genetic programme of the cells, which makes the derived populations unsuitable for disease modelling."

Dr. Anu Bashamboo, senior author 

Previously, researchers from the Institut Pasteur, along with collaborators from the Francis Crick Institute, developed somatic cells of the testes - specifically Sertoli cells which are commonly affected in DSDs - from hiPSCs. The team grew somatic gonadal cells with male chromosomes (XY), carrying a genetic variant of a specific gene associated with atypical testis development. As a result, these cells were unable to form three-dimensional tubular structures that resemble the testis cords, leading to a dysgenetic gonad that mimics DSDs.

"By creating human-specific, lab-grown models of both testicular and ovarian development using induced pluripotent stem cells (hiPSCs), the research overcomes key limitations in the field -particularly the lack of suitable animal models due to poor conservation of developmental genes and mechanisms across species - and provides a powerful platform for studying gene function in a controlled environment,' said Dr. Bashamboo.

"Our work more broadly contributes a scalable, human-relevant model system to developmental biology, reproductive medicine and genetic diagnostics. It bridges the gap between basic science and clinical application, offering tools that could improve diagnostic yields and support the development of targeted treatments for individuals with DSDs and related reproductive disorders, including infertility and certain types of ovarian tumours" said Dr. Bashamboo.

Dr. Bashamboo added: "Our model also opens up new possibilities for screening drugs and environmental toxins affecting human gonads, personalized medicine and future therapeutic interventions."