Developing human gonad organoids to promote germ cell differentiation

总结 生殖细胞对我们物种的繁衍至关重要。正常生殖细胞破坏 分化和功能可能导致不育和遗传疾病的后代， 受影响的个人。然而，许多控制形成的机制和 生殖细胞的功能仍然知之甚少。我们的长期目标是识别和 表征调节生殖细胞特异性过程的途径。然而，研究 人类配子发生在很大程度上仍然是不切实际的，因为该过程的特定步骤 仍然无法通过实验获得。此外，人与人之间存在关键差异。 生殖细胞和包括小鼠和大鼠在内的其他哺乳动物的生殖细胞，限制了 研究和操纵人类配子发生特定方面的动物模型。 为了克服这些障碍，我们建议设计一个变革性和可扩展的 用于重建人类配子发生体外平台。为了实现这一目标，我们 寻求开发用于驱动人类诱导多能干细胞（iPS）的新方法 细胞分化成人类女性生殖腺内的每一种细胞类型。基于 从实验模型的证据，我们预计混合iPS细胞衍生的生殖细胞 与iPS细胞衍生的体细胞支持细胞的适当组合将促进 配子形成过程中的进一步步骤。成功完成这一提案 将彻底改变人类生殖的研究，并提供一个可扩展的平台， 开发新的治疗不孕症和预防广泛的遗传疾病的疗法。

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.