Proper placentation is fundamental to successful pregnancy. Placenta arises from differentiation of trophoblast stem (TS) cells during development. Despite being recognized as the counterpart of ES cells in placental development, the role of regulatory miRNAs in TS cell differentiation remains inadequately explored. Here, we have identified complete repertoire of microRNAs present in mouse trophoblast cells in proliferative and differentiated state. We demonstrated that two miRNA clusters, -290 and -322, displayed reciprocal expression during trophoblast differentiation. Loss of miR-290 cluster members or gain in miR-322 cluster members led to differentiation of TS cells. The trophoblast stemness factor, CDX2, transactivated the miR-290 cluster and Cyclin D1 MiR-290 cluster members repressed cell cycle repressors, P21, P27, WEE1, RBL2, and E2F7, in TS cells. MiR-322 cluster members repressed the cell cycle activators, CYCLIN D1, CYCLIN E1, CDC25B, and CDX2, to induce differentiation. Taken together, our findings highlight the importance of posttranscriptional regulation by conserved miRNA clusters that form a regulatory network with CDX2, cell cycle activators, and repressors in equipoising TS cell self-renewal and differentiation.

中文翻译：

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MicroRNA调节鼠滋养层干细胞的自我更新和分化。

正确的胎盘对于成功怀孕至关重要。胎盘源于发育过程中滋养层干（TS）细胞的分化。尽管被公认为是胎盘发育中ES细胞的对应物，但仍未充分研究调节性miRNA在TS细胞分化中的作用。在这里，我们已经确定了小鼠滋养层细胞中处于增殖和分化状态的microRNA的完整库。我们证明了两个miRNA簇，-290和-322，在滋养细胞分化过程中表现出相互表达。miR-290簇成员的丢失或miR-322簇成员的增加导致TS细胞分化。滋养细胞干因子CDX2激活了miR-290簇和Cyclin D1MiR-290集群成员在TS细胞中阻遏了细胞周期阻遏物P21，P27，WEE1，RBL2和E2F7。MiR-322簇成员抑制细胞周期激活因子CYCLIN D1，CYCLIN E1，CDC25B和CDX2，以诱导分化。综上所述，我们的发现强调了保守的miRNA簇进行转录后调控的重要性，这些簇与CDX2，细胞周期激活剂和阻遏物形成调控网络，从而平衡TS细胞的自我更新和分化。