State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Stem Cell Res Ther. 2020 Nov 4;11(1):466. doi: 10.1186/s13287-020-01972-5.
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.
卵巢早衰（POI）是一种严重影响女性生理健康和生殖功能的卵巢功能障碍。间充质干细胞（MSC）移植为治疗啮齿动物 POI 模型中的卵巢恢复提供了一种有前途的治疗选择。然而，其疗效和机制仍不清楚。
通过环磷酰胺和白消安生成 POI 小鼠模型，随后通过尾静脉注射人脐带间充质干细胞（hUCMSCs）进行治疗。检测母鼠的生理变化和后代的行为。为了揭示 POI 的发病机制和治疗机制，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。在干细胞治疗后，我们从对照组、POI 组和 hUCMSC 治疗的 POI 组收集卵巢进行脂质代谢组学和伪靶向代谢组学分析。
我们的结果显示，POI 生成后卵巢组织中多种代谢物，特别是脂质，发生了显著变化。在移植临床级 hUCMSCs 后，POI 小鼠的体重、性激素水平、发情周期和生殖能力均有显著改善。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 组的代谢物水平（主要是脂质、甘油磷脂、类固醇和氨基酸）发生了显著变化，在接受 hUCMSC 治疗后大部分恢复到接近健康水平。同时，我们还观察到 POI 小鼠卵巢中单糖水平升高，干细胞治疗后降低。
hUCMSCs 通过激活 PI3K 通路，促进游离氨基酸水平，从而改善脂质代谢，降低单糖浓度，恢复卵巢功能。这些发现为 POI 的临床诊断和治疗提供了潜在的靶点。
