Novel protocol to differentiate iPSCs into testis-like organoids developed
Disruption to the embryonic gonads can cause disorders/differences of sex development (DSDs), a diverse group of genetic conditions affecting an alarming 1 per cent of the population.
Aberrant genetic signalling during reproductive organ development underlies most DSDs and an early genetic diagnosis can end the diagnostic odyssey, reducing cost to the health care system by eliminating the need for invasive or uninformative testing.
Research from Professor Andrew Sinclair’s team has significantly improved genetic diagnostic rates from 13 per cent to 40 per cent, and facilitated the introduction of a diagnostic sequencing panel for DSD at the Victorian Clinical Genetics Service. Yet, despite this progress, 60 per cent of patients do not receive a genetic diagnosis, and for those who do, the underlying disease mechanisms are poorly understood, limiting the clinical utility of the genetic finding. Such disease mechanisms would typically be explored using appropriate cell lines but due to the lack of human embryonic testis cell lines it has been nearly impossible to accurately study disorders of testis development.
In recent years the differentiation of induced pluripotent stem cells (iPSCs) into a wide range of tissues and organoids has delivered a powerful biological model that has radically changed the way that human disorders are studied. This technology has not been applied to the embryonic testis or to DSD. Dr Katie Ayers, Professor Melissa Little and Professor Andrew Sinclair have drawn on their expertise in gonadal biology, disease modelling and stem cell technologies to develop a novel protocol to differentiate iPSCs into testis-like organoids. This is a major step towards producing a human embryonic testis organoid as a disease model.
The team plans to continue to optimise this novel method, and to apply it to studying cells that have genetic variants found in patients with a DSD, allowing us to understand disease pathology. An organoid model that accurately recapitulates the early human embryonic testis will create a paradigm shift in the way DSD are studied, ultimately improving patient diagnosis and prognostics, clinical management and health outcomes.