Developing human gonad organoids to promote germ cell differentiation

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Summary Germ cells are essential for the propagation of our species. Disruption of normal germ cell differentiation and function can result in infertility and genetic disorders in the progeny of affected individuals. However, many of the mechanisms that govern the formation and function of germ cells remain poorly understood. Our long-term goal is to identify and characterize pathways that regulate germ cell specific processes. However, the study of human gametogenesis remains largely impractical because specific steps of the process remain experimentally inaccessible. In addition, there are key differences between human germ cells and those of other mammals including mice and rats, limiting the usefulness of animal models for studying and manipulating specific aspects of human gametogenesis. To overcome these obstacles, we propose to engineer a transformative and scalable in vitro platform for reconstituting human gametogenesis. Towards this goal, we seek to develop novel methods for driving human induced pluripotent stem (iPS) cells to differentiate into every cell type found within human female gonads. Based of evidence from experimental models, we anticipate mixing iPS cell-derived germ cells with the appropriate combination of iPS cell-derived somatic support cells will promote further steps in the process of gametogenesis. The successful completion of this proposal will revolutionize the study of human reproduction and provide a scalable platform for developing new therapies to treat infertility and prevent a broad range of genetic disorders.