In vitro reconstitution of the whole male germ-cell development from mouse pluripotent stem cells
In vitro reconstitution of the whole male germ-cell development from mouse pluripotent stem cells
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DOI：
10.1016/j.stem.2021.08.005
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发表时间：
2021-12-02
期刊：
影响因子：
23.9
通讯作者：
Saitou, Mitinori
中科院分区：
文献类型：
--
作者：
Ishikura, Yukiko;Ohta, Hiroshi;Saitou, Mitinori
哺乳动物雄性生殖细胞的发育包括三个不同的阶段：原始生殖细胞（PGC）发育、雄性生殖细胞对精原细胞发育的规范以及随后的精子发生。在这里，我们展示了用多能干细胞（PSCs）体外重建整个男性生殖细胞发育。小鼠胚胎干细胞（mESCs）被诱导为pgc样细胞（mpgclc），其扩增用于表观遗传重编程。在优化条件下重建的睾丸中，mpgclc分化为具有适当发育转变、基因表达和细胞周期动力学的精原细胞样细胞，并作为具有适当雄激素表观基因组的种系干细胞样细胞（GSCLCs）强劲扩增。重要的是，gsscs不仅在体内移植到睾丸中，而且在睾丸移植的体外培养中也表现出旺盛的精子发生能力，所产生的精子有助于生育后代。通过对男性生殖细胞发育的三个阶段的忠实再现，我们的研究为psc在体外的男性配子发生创造了一个范例。
Mammalian male germ-cell development consists of three distinct phases: primordial germ cell (PGC) development, male germ-cell specification for spermatogonium development, and ensuing spermatogenesis. Here, we show an in vitro reconstitution of whole male germ-cell development by pluripotent stem cells (PSCs). Mouse embryonic stem cells (mESCs) are induced into PGC-like cells (mPGCLCs), which are expanded for epigenetic reprogramming. In reconstituted testes under an optimized condition, such mPGCLCs differentiate into spermatogonium-like cells with proper developmental transitions, gene expression, and cell-cycle dynamics and are expanded robustly as germline stem cell-like cells (GSCLCs) with an appropriate androgenetic epigenome. Importantly, GSCLCs show vigorous spermatogenesis, not only upon transplantation into testes in vivo but also under an in vitro culture of testis transplants, and the resultant spermatids contribute to fertile offspring. By uniting faithful recapitulations of the three phases of male germcell development, our study creates a paradigm for the in vitro male gametogenesis by PSCs.