Induction of fetal meiotic oocytes from embryonic stem cells in cynomolgus monkeys
Induction of fetal meiotic oocytes from embryonic stem cells in cynomolgus monkeys
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DOI：
10.15252/embj.2022112962
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发表时间：
2023-03-16
期刊：
影响因子：
11.4
通讯作者：
Saitou, Mitinori
中科院分区：
文献类型：
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作者：
Gyobu-Motani, Sayuri;Yabuta, Yukihiro;Saitou, Mitinori
人类体外卵子发生为阐明人类卵子发生机制提供了一个框架。为了建立其基准，至关重要的是使用生理学上接近人类的模型来促进体外卵子发生。在这里，我们建立了一个基础，在体外卵子发生在食蟹猴（猕猴）：携带一个活跃的和一个不活跃的X染色体（Xa和Xi，分别）的雌性胚胎干细胞分化成原始生殖细胞样细胞，在异种重建卵巢有效地发展成卵原细胞，并显着，进一步进入减数分裂卵母细胞在偶线期。这种分化需要全面的表观遗传重编程，包括Xi重编程，但Xa和Xi仍然表观遗传不对称，部分在体内观察到，不完全的Xi再激活。在人类和猴子中，多能干细胞中的Xi表观基因组作为Xi重编程决定因素发挥作用。我们进一步表明，发育途径过度激活与次优上调相关减数分裂基因阻碍体外减数分裂进程。Cy体外卵子发生与人类系统具有重要的同源性，包括瓶颈，为推进人类体外卵子发生提供了一个突出的模型。
Human in vitro oogenesis provides a framework for clarifying the mechanism of human oogenesis. To create its benchmark, it is vital to promote in vitro oogenesis using a model physiologically close to humans. Here, we establish a foundation for in vitro oogenesis in cynomolgus (cy) monkeys (Macaca fascicularis): cy female embryonic stem cells harboring one active and one inactive X chromosome (Xa and Xi, respectively) differentiate robustly into primordial germ cell-like cells, which in xenogeneic reconstituted ovaries develop efficiently into oogonia and, remarkably, further into meiotic oocytes at the zygotene stage. This differentiation entails comprehensive epigenetic reprogramming, including Xi reprogramming, yet Xa and Xi remain epigenetically asymmetric with, as partly observed in vivo, incomplete Xi reactivation. In humans and monkeys, the Xi epigenome in pluripotent stem cells functions as an Xi-reprogramming determinant. We further show that developmental pathway over-activations with suboptimal up-regulation of relevant meiotic genes impede in vitro meiotic progression. Cy in vitro oogenesis exhibits critical homology with the human system, including with respect to bottlenecks, providing a salient model for advancing human in vitro oogenesis.