Human Amniotic Epithelial Cell-Derived Exosomes Restore Ovarian Function by Transferring MicroRNAs against Apoptosis
Human Amniotic Epithelial Cell-Derived Exosomes Restore Ovarian Function by Transferring MicroRNAs against Apoptosis
复制标题
人羊膜上皮细胞衍生的外泌体通过转移 MicroRNA 抗凋亡来恢复卵巢功能
DOI：
10.1016/j.omtn.2019.03.008
复制
发表时间：
2019-06-07
影响因子：
8.8
通讯作者：
Lai, Dongmei
中科院分区：
文献类型：
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作者：
Zhang, Qiuwan;Sun, Junyan;Lai, Dongmei
卵巢早衰(POF)是接受化疗的女性肿瘤患者最常见的并发症之一，需要先进的治疗策略。以人羊膜上皮细胞(HAEC)为基础的治疗在多种疾病中介导组织再生，越来越多的证据表明hAEC的治疗效果主要依赖于旁分泌作用。本研究旨在鉴定hAECs来源的外切体，并探讨其对化疗所致卵巢损伤的治疗潜力及其分子机制。HAEC来源的外切体呈杯状或球状，平均直径100 nm，Alix、CD63和CD9阳性。HAEC外切体能增加卵巢早衰小鼠的卵泡数，改善卵巢功能。在移植早期，hAEC外切体显著抑制颗粒细胞的凋亡，保护卵巢血管免受损伤，并参与维持受损卵巢中原始卵泡的数量。HAEC外切体中存在富集型microRNAs(MiRNAs)，靶基因富含磷脂酰肌醇信号转导通路和细胞凋亡通路。体外研究表明，hAEC外切体通过转移功能性miRNAs，如miR-1246，抑制化疗诱导的颗粒细胞凋亡。我们的发现表明，hAEC衍生的外切体有可能通过转移miRNAs来恢复化疗诱导的POF小鼠的卵巢功能。
Premature ovarian failure (POF) is one of the most common complications among female patients with tumors treated with chemotherapy and requires advanced treatment strategies. Human amniotic epithelial cell (hAEC)-based therapy mediates tissue regeneration in a variety of diseases, and increasing evidence suggests that the therapeutic efficacy of hAECs mainly depends on paracrine action. This study aimed to identify exosomes derived from hAECs and explored the therapeutic potential in ovaries damaged by chemotherapy and the underlying molecular mechanism. hAEC-derived exosomes exhibited a cup- or sphere-shaped morphology with a mean diameter of 100 nm and were positive for Alix, CD63, and CD9. hAEC exosomes increased the number of follicles and improved ovarian function in POF mice. During the early stage of transplantation, hAEC exosomes significantly inhibited granulosa cell apoptosis, protected the ovarian vasculature from damage, and were involved in maintaining the number of primordial follicles in the injured ovaries. Enriched microRNAs (miRNAs) existed in hAEC exosomes, and target genes were enriched in phosphatidylinositol signaling and apoptosis pathways. Studies in vitro demonstrated that hAEC exosomes inhibited chemotherapy-induced granulosa cell apoptosis via transferring functional miRNAs, such as miR-1246. Our findings demonstrate that hAEC-derived exosomes have the potential to restore ovarian function in chemotherapy-induced POF mice by transferring miRNAs.