Derivation of intermediate pluripotent stem cells amenable to primordial germ cell specification

Dynamic pluripotent stem cell (PSC) states represent in vitro adaptations of the in vivo pluripotency continuum. Decades of studies have generated a number of PSCs with distinct molecular and phenotypic features. To date, however, no known PSCs have demonstrated direct primordial germ cell (PGC) specification responsiveness, a property unique to the embryonic day 5-6 (E5-6) epiblast in mice. Here, we developed a method that enabled the derivation of intermediate PSCs from mouse blastocysts, which not only shared transcriptional similarity with E5-6 epiblast but were also capable of efficient PGC specification in vitro and germline transmission in vivo. The same culture system supported the derivation of embryonic stem cells (ESCs) from horse blastocysts and transgene-free induced pluripotent stem cells (iPSCs) from horse and human fibroblasts, which could also be directly induced into PGC-like cells in vitro. PGC responsive PSCs are invaluable for studying mammalian pluripotency and early PGC development, and our method may be broadly applicable for the derivation of analogous stem cells from other mammalian species. Note: The supplementary data that support the findings of this study have been deposited into CNSA with accession number CNP0001190.

动态多能干细胞（pluripotent stem cell, PSC）状态是体内多能性连续谱系的体外适配体系。数十年来的相关研究已获得多种具备独特分子与表型特征的多能干细胞。然而截至目前，尚无已知的多能干细胞可展现出直接定向原始生殖细胞（primordial germ cell, PGC）特化的响应能力，而该特性是小鼠胚胎第5-6天（E5-6）上胚层所特有的。
本研究开发了一种可从小鼠囊胚中分离得到中间态多能干细胞的方法，该类细胞不仅在转录组层面与小鼠E5-6上胚层高度相似，还可在体外高效完成原始生殖细胞特化，并在体内实现种系传递。
该培养体系同样可支持从马囊胚中分离获得胚胎干细胞（embryonic stem cell, ESCs），以及从马和人成纤维细胞中分离获得无转基因诱导多能干细胞（induced pluripotent stem cell, iPSCs），这类细胞也可在体外直接诱导为类原始生殖细胞。
具备PGC响应能力的多能干细胞对于研究哺乳动物多能性及早期原始生殖细胞发育具有极高研究价值，本研究开发的方法或可广泛适用于从其他哺乳动物物种中分离获得同类干细胞。
注：支持本研究结果的补充数据已提交至中国国家核酸序列归档系统（China National Nucleic Acid Archive, CNSA），登录号为CNP0001190。