Generation of offspring-producing 3D ovarian organoids derived from female germline stem cells and their application in toxicological detection
Generation of offspring-producing 3D ovarian organoids derived from female germline stem cells and their application in toxicological detection
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DOI：
10.1016/j.biomaterials.2021.121213
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发表时间：
2021-10-26
期刊：
影响因子：
14
通讯作者：
Wu, Ji
中科院分区：
文献类型：
--
作者：
Li, Xiaoyong;Zheng, Man;Wu, Ji
能够产生后代的卵母细胞的体外生产在生殖医学中具有令人兴奋的潜在应用。在这里，我们使用三维培养系统生成并表征了源自女性生殖干细胞的卵巢类器官模型。我们证明该模型产生了正常的后代并检测到了药物毒性。卵巢类器官可以产生卵母细胞并表现出内分泌功能。卵巢类器官的单细胞分析鉴定了六种卵巢细胞谱系，例如生殖细胞、颗粒细胞和卵泡膜细胞，并产生了每种细胞类型的基因表达特征。对生殖细胞簇减数分裂相关基因表达模式的研究和基因个体发育分析表明，卵巢类器官中维持着生殖细胞群。此外，流式细胞术分析证实，类器官上可以维持生殖细胞群，并表明抗坏血酸处理对类器官上生殖细胞群的维持具有有益作用。此外，我们证明了从卵巢类器官衍生的卵母细胞成功产生后代。最后，我们证明卵巢类器官具有药物毒理学检测的潜力。例如，我们发现盐霉素通过诱导细胞凋亡来损害卵巢类器官的形成和生殖细胞群的维持。这些结果表明，雌性生殖干细胞衍生的卵巢类器官代表了产生可产生后代的卵母细胞的有价值的模型系统，并为药物筛选和毒理学检测提供了新的模型。
In vitro production of oocytes capable of producing offspring has exciting potential applications in reproductive medicine. Here, we generated and characterized an ovarian organoid model derived from female germline stem cells using a three-dimensional culture system. We show that this model generated normal offspring and detected drug toxicity. The ovarian organoids could produce oocytes and exhibited endocrine functions. Single-cell analysis of ovarian organoids identified six ovarian cell lineages, such as germ, granulosa and theca cells, and produced gene-expression signatures for each cell type. Investigation of the expression patterns of genes related to meiosis and gene ontogeny analysis for germ cell clusters showed that a germ cell population was maintained in the ovarian organoids. Moreover, flow cytometric analysis confirmed that the population of germ cells could be maintained on the organoids and showed that ascorbic acid treatment had a beneficial effect of germ cell population maintenance on the organoids. Furthermore, we demonstrated the successful production of offspring from oocytes derived from ovarian organoids. Finally, we showed the ovarian organoids had the potential to drug toxicological detection. For example, we found that salinomycin impaired the formation of ovarian organoids and germ cell population maintenance by inducing apoptosis. These results indicate that the female germline stem cell-derived ovarian organoids represent a valuable model system for generating oocytes that can yield offspring, and provide a novel model for drug screening and toxicological detection.