Reconstituting a human ovary Human pluripotent stem cells (hPSCs) have been induced into human primordial germ cell–like cells (hPGCLCs) in vitro, the first step toward human in vitro gametogenesis. Yamashiro et al. went a step closer to generating mature gametes by culturing hPSCs with mouse embryonic ovarian somatic cells in xenogeneic reconstituted ovaries (see the Perspective by Gill and Peters). Over a period of 4 months, hPGCLCs underwent hallmark epigenetic reprogramming and differentiated progressively into cells closely resembling human oogonia, an immediate embryonic precursor for human oocytes. This study creates opportunities for human germ cell research and provides a foundation for human in vitro gametogenesis. Science, this issue p. 356; see also p. 291 Human primordial germ cell–like cells differentiate into oogonia in xenogeneic reconstituted ovaries in vitro. Human in vitro gametogenesis may transform reproductive medicine. Human pluripotent stem cells (hPSCs) have been induced into primordial germ cell–like cells (hPGCLCs); however, further differentiation to a mature germ cell has not been achieved. Here, we show that hPGCLCs differentiate progressively into oogonia-like cells during a long-term in vitro culture (approximately 4 months) in xenogeneic reconstituted ovaries with mouse embryonic ovarian somatic cells. The hPGCLC-derived oogonia display hallmarks of epigenetic reprogramming—genome-wide DNA demethylation, imprint erasure, and extinguishment of aberrant DNA methylation in hPSCs—and acquire an immediate precursory state for meiotic recombination. Furthermore, the inactive X chromosome shows a progressive demethylation and reactivation, albeit partially. These findings establish the germline competence of hPSCs and provide a critical step toward human in vitro gametogenesis.

中文翻译：

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从体外诱导多能干细胞产生人卵原细胞

重建人类卵巢 人类多能干细胞 (hPSC) 已在体外被诱导为人类原始生殖细胞样细胞 (hPGCLC)，这是人类体外配子发生的第一步。山城等人。通过在异种重建卵巢中培养 hPSC 和小鼠胚胎卵巢体细胞，更接近于产生成熟配子（参见 Gill 和 Peters 的观​​点）。在 4 个月的时间里，hPGCLCs 经历了标志性的表观遗传重编程，并逐渐分化为与人类卵原细胞非常相似的细胞，人类卵母细胞的直接胚胎前体。这项研究为人类生殖细胞研究创造了机会，并为人类体外配子发生奠定了基础。科学，这个问题 p。356; 另见第。291 人类原始生殖细胞样细胞在体外异种重建卵巢中分化为卵原细胞。人类体外配子发生可能会改变生殖医学。人类多能干细胞 (hPSCs) 已被诱导为原始生殖细胞样细胞 (hPGCLCs)；然而，尚未实现向成熟生殖细胞的进一步分化。在这里，我们展示了 hPGCLC 在长期体外培养（大约 4 个月）期间，在具有小鼠胚胎卵巢体细胞的异种重建卵巢中逐渐分化为卵原细胞样细胞。hPGCLC 衍生的卵原细胞显示出表观遗传重编程的标志——全基因组 DNA 去甲基化、印记擦除和 hPSC 中异常 DNA 甲基化的消失——并获得减数分裂重组的直接前兆状态。此外，失活的 X 染色体显示出渐进的去甲基化和重新激活，尽管是部分的。这些发现确立了 hPSC 的生殖能力，并为人类体外配子发生提供了关键的一步。