Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Zhengzhou, 450052, Henan Province, China.
Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Zhengzhou, 450052, Henan Province, China.
Stem Cell Res Ther. 2019 Nov 29;10(1):360. doi: 10.1186/s13287-019-1442-3.
BACKGROUND: This article aims to reveal the therapeutic effects and potential mechanisms of bone mesenchymal stem cell (BMSC)-derived exosomes on premature ovarian failure (POF). METHODS: Exosomes were collected from BMSCs and were used to treat cisplatin-induced POF mouse models. Pathological changes of ovarian tissue were detected by using HE staining and by Western blot that detected the expression of apoptosis-related proteins. In cisplatin-induced primary granulosa cell injury, exosomes were co-cultured with the granulosa cells. The apoptosis or viability of granulosa cells was analyzed by flow cytometry or MTT, respectively. In Target scan and microT-CDS databases, an intersection of miRNAs targeting to p53 was found. The expressions of miRNAs in BMSC-derived exosomes were detected by qRT-PCR. Besides, miR-664-5p targeted to p53 of cells was verified by dual-luciferase reporter assay. RESULTS: BMSC-derived exosomes improved the follicular morphology of POF mice and inhibited the expression of apoptosis-related protein. By co-culture of exosomes and primary granulosa cells, BMSC-derived exosomes repressed cisplatin-induced granulosa cells apoptosis and increased cells viability, while these effects were abrogated after the exosome-containing RNA was degraded by RNase. By Target scan, microT-CDS and qRT-PCR, miR-664-5p was regarded as the dominated RNA in BMSC-derived exosomes. By dual-luciferase reporter assay, miR-664-5p negatively regulated p53 luciferase activity. After shRNA interfering miR-664-5p of BMSC, BMSC-derived exosomes exerted no protective effect on cisplatin-induced granulosa cell apoptosis. CONCLUSION: Our results indicated that miR-644-5p carried by BMSC-derived exosomes inhibited the apoptosis of ovarian granulosa cell by targeting p53 of cells, suggesting that miR-644-5p had the potential to treat POF and restore ovarian function.
背景：本文旨在揭示骨髓间充质干细胞（BMSC）衍生的外泌体对早发性卵巢功能不全（POF）的治疗作用及潜在机制。
方法：从 BMSC 中收集外泌体，并将其用于治疗顺铂诱导的 POF 小鼠模型。通过 HE 染色和 Western blot 检测凋亡相关蛋白的表达来检测卵巢组织的病理变化。在顺铂诱导的原代颗粒细胞损伤中，将外泌体与颗粒细胞共培养。通过流式细胞术或 MTT 分别分析颗粒细胞的凋亡或活力。在 Targetscan 和 microT-CDS 数据库中，发现了一组靶向 p53 的 miRNA 的交集。通过 qRT-PCR 检测 BMSC 衍生的外泌体中的 miRNA 表达。此外，通过双荧光素酶报告基因实验验证细胞中靶向 p53 的 miR-664-5p。
结果：BMSC 衍生的外泌体改善了 POF 小鼠的卵泡形态，并抑制了凋亡相关蛋白的表达。通过外泌体与原代颗粒细胞共培养，BMSC 衍生的外泌体抑制了顺铂诱导的颗粒细胞凋亡并增加了细胞活力，而在用 RNase 降解外泌体含有的 RNA 后，这些作用被消除。通过 Targetscan、microT-CDS 和 qRT-PCR，miR-664-5p 被认为是 BMSC 衍生的外泌体中的主要 RNA。通过双荧光素酶报告基因实验，miR-664-5p 负调控 p53 荧光素酶活性。在用 shRNA 干扰 BMSC 中的 miR-664-5p 后，BMSC 衍生的外泌体对顺铂诱导的颗粒细胞凋亡没有保护作用。
结论：我们的结果表明，BMSC 衍生的外泌体携带的 miR-664-5p 通过靶向细胞中的 p53 抑制卵巢颗粒细胞的凋亡，提示 miR-664-5p 具有治疗 POF 和恢复卵巢功能的潜力。
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