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首页> 外文期刊>Cellular Physiology and Biochemistry >The Hippo Signaling Pathway Regulates Ovarian Function via the Proliferation of Ovarian Germline Stem Cells
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The Hippo Signaling Pathway Regulates Ovarian Function via the Proliferation of Ovarian Germline Stem Cells

机译：河马信号通路通过卵巢生殖干细胞的增殖来调节卵巢功能。

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>Objective: To improve the separation, identification and cultivation of ovarian germline stem cells (OGSCs), to clarify the relationship between the Hippo signaling pathway effector YAP1 and the proliferation and differentiation of OGSCs in vitro and to identify the major contribution of Hippo signaling to ovarian function. Methods: Two-step enzymatic separation processes and magnetic separation were used to isolate and identify OGSCs by determining the expression of Mvh, Oct4, Nanog, Fragilis and Stella markers. Then, YAP1, as the main effector molecule in the Hippo signaling pathway, was chosen as the target gene of the study. Lentivirus containing overexpressed YAP1 or a YAP1-targeted shRNA was transduced into OGSCs. The effects of modulating the Hippo signaling pathway on the proliferation, differentiation, reproduction and endocrine function of ovaries were observed by microinjecting the lentiviral vectors with overexpressed YAP1 or YAP1 shRNA into infertile mouse models or natural mice of reproductive age. Results: (1) The specific expression of Mvh, Oct4, Nanog, Fragilis and Stella markers was observed in isolated stem cells. Thus, the isolated cells were preliminarily identified as OGSCs. (2) The co-expression of LATS2, MST1, YAP1 and MVH was observed in isolated OGSCs. Mvh and Oct4 expression levels were significantly increased in OGSCs overexpressing YAP1 compared to GFP controls. Consistently, Mvh and Oct4 levels were significantly decreased in cells expressing YAP1-targeted shRNA. (3) After 14-75 days of YAP1 overexpression in infertile mouse models, we detected follicle regeneration in ovaries, the activation of primordial follicles and increased birth rate, accompanied by increasing levels of E2 and FSH. (4) However, we detected decreasing follicles in ovaries, lower birth rate, and decreasing E2 and FSH in serum from healthy mice of reproductive age following YAP1 shRNA expression. Conclusion: Methods for the isolation, identification and culture of OGSCs were successfully established. Further results indicate that isolated OGSCs can specifically recognize Hippo signaling molecules and that manipulation of YAP1 expression can be used to regulate the proliferation and differentiation of OGSCs, as well as ovarian function in mice. This study suggests that the Hippo signaling pathway may represent a new molecular target for the regulation of mouse ovarian functional remodeling.
机译：> 目的： 改善卵巢种系干细胞（OGSCs）的分离，鉴定和培养，阐明Hippo信号通路效应子YAP1与增殖之间的关系。和OGSCs的体外分化，并确定河马信号对卵巢功能的主要贡献。 方法： 通过确定 Mvh，Oct4，Nanog，Fragillis 的表达，采用两步酶法分离和磁分离来分离和鉴定OGSC。 >和 Stella 标记。然后，选择YAP1作为Hippo信号通路中的主要效应分子，作为研究的目标基因。将含有过量表达的YAP1或YAP1靶向的shRNA的慢病毒转导至OGSC。通过将过表达的YAP1或YAP1 shRNA慢病毒载体微注射入不育小鼠模型或生殖年龄自然小鼠中，观察到调节Hippo信号通路对卵巢增殖，分化，繁殖和内分泌功能的影响。 结果： （1）观察到 Mvh，Oct4，Nanog，Fragillis 和 Stella 标记的特异性表达分离的干细胞。因此，将分离出的细胞初步鉴定为OGSC。 （2）在分离的OGSC中观察到LATS2，MST1，YAP1和MVH的共表达。与GFP对照相比，过表达YAP1的OGSC中 Mvh 和 Oct4 表达水平显着增加。一致地，在表达YAP1靶向shRNA的细胞中， Mvh 和 Oct4 水平显着降低。 （3）在不育小鼠模型中YAP1过表达14-75天后，我们检测到卵巢中的卵泡再生，原始卵泡的激活和出生率的增加，同时伴随着E2和FSH水平的升高。 （4）然而，我们检测到YAP1 shRNA表达后，来自生殖年龄健康小鼠的卵巢中的卵泡减少，出生率降低，血清E2和FSH降低。 结论： 成功建立了OGSC的分离，鉴定和培养方法。进一步的结果表明，分离的OGSC可以特异性识别Hippo信号分子，并且可以使用YAP1表达的调控来调节OGSC的增殖和分化以及小鼠的卵巢功能。这项研究表明，河马信号通路可能代表了小鼠卵巢功能重塑调控的新分子靶标。

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