Premature ovarian insufficiency (POI) is clinically irreversible in women aged over 40 years. Although numerous studies have demonstrated satisfactory outcomes of mesenchymal stem cell therapy, the underlying therapeutic mechanism remains unclear. Exosomes were collected from the culture medium of human umbilical cord mesenchymal stem cells (hUMSCs) and assessed by electron microscopy and Western blot (WB) analysis. Then, exosomes were added to the culture medium of cyclophosphamide (CTX)‐damaged human granulosa cells (hGCs), and the mixture was injected into the ovaries of CTX‐induced POI model mice before detection of antiapoptotic and apoptotic gene expression. Next, the microRNA expression profiles of hUMSC‐derived exosomes (hUMSC‐Exos) were detected by small RNA sequencing. The ameliorative effect of exosomal microRNA‐17‐5P (miR‐17‐5P) was demonstrated by miR‐17‐5P knockdown before assessment of ovarian phenotype and function, reactive oxygen species (ROS) levels and SIRT7 expression. Finally, SIRT7 was inhibited or overexpressed by RNA interference or retrovirus transduction, and the protein expression of PARP1, γH2AX, and XRCC6 was analyzed. The ameliorative effect of hUMSC‐Exos on POI was validated. Our results illustrated that hUMSC‐Exos restored ovarian phenotype and function in a POI mouse model, promoted proliferation of CTX‐damaged hGCs and ovarian cells, and alleviated ROS accumulation by delivering exosomal miR‐17‐5P and inhibiting SIRT7 expression. Moreover, our findings elucidated that miR‐17‐5P repressed PARP1, γH2AX, and XRCC6 by inhibiting SIRT7. Our findings suggest a critical role for exosomal miR‐17‐5P and its downstream target mRNA SIRT7 in hUMSC transplantation therapy. This study indicates the promise of exosome‐based therapy for POI treatment.

中文翻译：

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源自人脐带间充质干细胞的外泌体miRNA-17-5p通过调节SIRT7改善卵巢早衰患者的卵巢功能

卵巢早衰 (POI) 在 40 岁以上的女性中临床上是不可逆转的。尽管许多研究已经证明了间充质干细胞治疗的令人满意的结果，但潜在的治疗机制仍不清楚。从人脐带间充质干细胞 (hUMCs) 的培养基中收集外泌体，并通过电子显微镜和蛋白质印迹 (WB) 分析进行评估。然后，将外泌体添加到环磷酰胺（CTX）损伤的人颗粒细胞（hGCs）的培养基中，并将混合物注射到 CTX 诱导的 POI 模型小鼠的卵巢中，然后检测抗凋亡和凋亡基因的表达。接下来，通过小 RNA 测序检测 hUMMSC 衍生的外泌体（hUMC-Exos）的 microRNA 表达谱。在评估卵巢表型和功能、活性氧 (ROS) 水平和 SIRT7 表达之前，通过敲除 miR-17-5P 证明了外泌体 microRNA-17-5P (miR-17-5P) 的改善作用。最后，通过RNA干扰或逆转录病毒转导抑制或过表达SIRT7，分析PARP1、γH2AX和XRCC6的蛋白表达。验证了 hUMSC-Exos 对 POI 的改善作用。我们的结果表明，hUMMSC-Exos 恢复了 POI 小鼠模型中的卵巢表型和功能，促进了 CTX 损伤的 hGC 和卵巢细胞的增殖，并通过传递外泌体 miR-17-5P 和抑制 SIRT7 表达来减轻 ROS 积累。此外，我们的研究结果阐明了 miR-17-5P 通过抑制 SIRT7 来抑制 PARP1、γH2AX 和 XRCC6。我们的研究结果表明外泌体 miR-17-5P 及其下游靶标 mRNA SIRT7 在 hUMMSC 移植治疗中的关键作用。该研究表明基于外泌体的疗法有望用于 POI 治疗。