Department of Gynecology and Obstetrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Medicine, Shandong University, Jinan, China.
Cancer Med. 2022 Jun;11(12):2414-2426. doi: 10.1002/cam4.4615. Epub 2022 Mar 1.
This study is to explore the therapeutic effect and potential mechanisms of exosomal microRNAs (miRNAs) derived from the ovaries with primary ovarian insufficiency (POI). The POI mouse model was established by intraperitoneal injection of cyclophosphamide (CTX) and busulfan. The apoptosis of granulosa cells (GCs) incubated with exosomes extracted from ovarian tissues of control and POI groups was analyzed by flow cytometry. Then, high-throughput sequencing was performed to detect the difference of miRNAs profile in ovarian tissue-derived exosomes between the control and POI mice. The effect of differential miRNA on the apoptosis of CTX-induced ovarian GCs was analyzed by flow cytometry. The results showed that POI mouse model was successfully established. Exosomes extracted from ovarian of normal and POI group have different effects on apoptosis of GCs induced by CTX. miRNA-seq found that exosomal miR-122-5p in POI group increased significantly. miR-122-5p as the dominant miRNA targeting BCL9 was significantly upregulated in ovarian tissues of chemotherapy-induced POI group. Exosomes derived from the ovaries in the control group and miR-122-5p inhibitor group attenuated the apoptosis of primary cultured ovarian GCs. In conclusion, exosomal miR-122-5p promoted the apoptosis of ovarian GCs by targeting BCL9, suggested that miR-122-5p may function as a potential target to restore ovarian function.
本研究旨在探讨来源于原发性卵巢功能不全（POI）卵巢的外泌体 microRNAs（miRNAs）的治疗效果及潜在机制。通过腹腔注射环磷酰胺（CTX）和白消安建立 POI 小鼠模型。通过流式细胞术分析与来自对照组和 POI 组卵巢组织的外泌体孵育的颗粒细胞（GCs）的凋亡情况。然后，通过高通量测序检测对照组和 POI 小鼠卵巢组织来源的外泌体中 miRNAs 谱的差异。通过流式细胞术分析差异 miRNA 对 CTX 诱导的卵巢 GCs 凋亡的影响。结果表明，成功建立了 POI 小鼠模型。来自正常和 POI 组卵巢的外泌体对 CTX 诱导的 GCs 凋亡有不同的影响。miRNA-seq 发现 POI 组外泌体 miR-122-5p 显著增加。化疗诱导的 POI 组卵巢组织中 miR-122-5p 作为靶向 BCL9 的优势 miRNA 明显上调。对照组和 miR-122-5p 抑制剂组来源的外泌体可减轻原代培养的卵巢 GCs 的凋亡。综上所述，外泌体 miR-122-5p 通过靶向 BCL9 促进卵巢 GCs 的凋亡，提示 miR-122-5p 可能作为恢复卵巢功能的潜在靶点。
