Developing human gonad organoids to promote germ cell differentiation

摘要 生殖细胞对我们物种的繁殖是必不可少的。破坏正常生殖细胞 分化和功能可导致子代不孕和遗传性疾病 受影响的个体。然而，管理形成和发展的许多机制 生殖细胞的功能仍然知之甚少。我们的长期目标是识别和 描述调节生殖细胞特定过程的途径。然而，对其的研究 人类配子发生在很大程度上仍然不切实际，因为这一过程的特定步骤 在实验上仍然是无法接近的。此外，人类与人类之间还有一些关键的区别 生殖细胞和其他哺乳动物的生殖细胞，包括小鼠和大鼠，限制了 用于研究和操纵人类配子发生的特定方面的动物模型。 为了克服这些障碍，我们建议设计一种具有变革性和可扩展性的 用于重建人类配子发生的体外平台。为了实现这个目标，我们 寻求开发驱动人类诱导多能干细胞(IPS)的新方法 分化为人类女性性腺中发现的每一种细胞类型的细胞。基座 来自实验模型的证据，我们预计混合iPS细胞来源的生殖细胞 与iPS细胞的适当组合可促进体细胞来源的支持细胞 配子发生过程中的进一步步骤。成功地完成这项提案 将给人类生殖研究带来革命性的变化，并为 开发治疗不孕不育和预防广泛遗传疾病的新疗法。

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.