Premature ovarian insufficiency (POI) is an ovarian dysfunction that seriously affects a woman’s physiological health and reproduction. Mesenchymal stem cell (MSC) transplantation offers a promising treatment option for ovarian restoration in rodent POI models. However, the efficacy and mechanism of it remain unclear. POI mice model was generated by cyclophosphamide and busulfan, followed with the treatment of tail-vein injection of the human umbilical cord mesenchymal stem cells (hUCMSCs). Maternal physiological changes and offspring behavior were detected. To reveal the pathogenesis and therapeutic mechanisms of POI, we first compared the metabolite profiles of healthy and POI ovarian tissues using untargeted metabolomics analyses. After stem cell therapy, we then collected the ovaries from control, POI, and hUCMSC-treated POI groups for lipid metabolomics and pseudotargeted metabolomics analysis. Our results revealed remarkable changes of multiple metabolites, especially lipids, in ovarian tissues after POI generation. Following the transplantation of clinical-grade hUCMSCs, POI mice exhibited significant improvements in body weight, sex hormone levels, estrous cycles, and reproductive capacity. Lipid metabolomics and pseudotargeted metabolomics analyses for the ovaries showed that the metabolite levels in the POI group, mainly lipids, glycerophospholipids, steroids, and amino acids changed significantly compared with the controls’, and most of them returned to near-healthy levels after receiving hUCMSC treatment. Meanwhile, we also observed an increase of monosaccharide levels in the ovaries from POI mice and a decrease after stem cell treatment. hUCMSCs restore ovarian function through activating the PI3K pathway by promoting the level of free amino acids, consequently improving lipid metabolism and reducing the concentration of monosaccharides. These findings provide potential targets for the clinical diagnosis and treatment of POI.

中文翻译：

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人脐带间充质干细胞恢复小鼠卵巢代谢组并挽救卵巢早衰

卵巢功能不全（POI）是严重影响女性生理健康和生殖能力的卵巢功能障碍。间充质干细胞（MSC）移植为啮齿动物POI模型中的卵巢修复提供了有希望的治疗选择。但是，其功效和机理尚不清楚。POI小鼠模型是通过环磷酰胺和白消安制备的，然后经尾静脉注射人脐带间充质干细胞（hUCMSCs）。检测母体生理变化和后代行为。为了揭示POI的发病机理和治疗机制，我们首先使用非靶向代谢组学分析比较了健康和POI卵巢组织的代谢物谱。干细胞治疗后，我们从对照，POI，和hUCMSC处理的POI组进行脂质代谢组学和伪靶向代谢组学分析。我们的研究结果显示，POI生成后，卵巢组织中多种代谢物（尤其是脂质）发生了显着变化。在临床级hUCMSC移植后，POI小鼠的体重，性激素水平，发情周期和生殖能力均表现出显着改善。卵巢的脂质代谢组学和伪靶向代谢组学分析表明，与对照组相比，POI组的代谢产物水平（主要是脂质，甘油磷脂，类固醇和氨基酸）发生了显着变化，并且大多数接受hUCMSC后恢复了接近健康的水平。治疗。与此同时，我们还观察到POI小鼠卵巢中的单糖水平升高，而干细胞治疗后降低。hUCMSC通过促进游离氨基酸水平激活PI3K途径来恢复卵巢功能，从而改善脂质代谢并降低单糖浓度。这些发现为POI的临床诊断和治疗提供了潜在的目标。