Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
J Mol Med (Berl). 2024 Nov;102(11):1327-1342. doi: 10.1007/s00109-024-02483-z. Epub 2024 Sep 4.
Endometriosis is a multifactorial gynecological disease, with angiogenesis as a key hallmark. The role of exosomal microRNAs (miRNAs) in endometriosis is not well understood. This study investigates differentially expressed exosomal miRNAs linked to angiogenesis in endometriosis, clarifies their molecular mechanisms, and identifies potential targets. Primary endometrial stromal cells (ESCs) were cultured, and exosomes were extracted. In a co-culture system, ESC-derived exosomes were taken up by human umbilical vein endothelial cells (HUVECs). Endometriosis implant-ESC-derived exosomes (EI-EXOs) significantly promoted HUVEC proliferation, migration and tube formation compared to normal endometrium-exosomes (NE-EXOs), a finding consistent in vivo in mice. MiRNA sequencing and bioinformatics identified differentially expressed miR-21-5p from EI-EXOs, confirmed by RT-qPCR. The miR-21-5p inhibitor or GW4869 attenuated EI-EXO-induced HUVEC proliferation, migration, and tube formation. TIMP3 overexpression diminished the pro-angiogenic effect of EI-EXOs, which was reversed by adding EI-EXOs or upregulating miR-21-5p. These findings validate the crosstalk between ESCs and HUVECs mediated by exosomal miR-21-5p, and confirm the miR-21-5p-TIMP3 axis in promoting angiogenesis in endometriosis. KEY MESSAGES: ESC-derived exosomes were found to be taken up by recipient cells, i.e. HUVECs. Functionally, endometriosis implant-ESC-derived exosomes (EI-EXOs) could significantly promote the proliferation, migration and tube formation of HUVECs compared to normal endometrium-exosomes (NE-EXOs). Through miRNA sequencing and bioinformatics analysis, differentially expressed miR-21-5p released by EI-EXOs was chosen, as confirmed by qRT-PCR. miR-21-5p inhibitor or GW4869 was found to attenuate the proliferation, migration, and tube formation of HUVECs induced by EI-EXOs. In turn, TIMP3 overexpression diminished the pro-angiogenic effect of EI-EXOs, and this angiogenic phenotype was reversed once EI-EXOs were added or miR-21-5p was upregulated.
子宫内膜异位症是一种多因素的妇科疾病，其关键标志之一是血管生成。外泌体 microRNAs（miRNAs）在子宫内膜异位症中的作用尚不清楚。本研究旨在探讨与子宫内膜异位症血管生成相关的差异表达的外泌体 miRNAs，阐明其分子机制，并确定潜在的靶点。培养原代子宫内膜基质细胞（ESCs）并提取外泌体。在共培养系统中，ESC 来源的外泌体被人脐静脉内皮细胞（HUVECs）摄取。与正常子宫内膜来源的外泌体（NE-EXOs）相比，子宫内膜异位症病灶来源的 ESC 衍生外泌体（EI-EXOs）显著促进了 HUVEC 的增殖、迁移和管形成，这一发现也在小鼠体内得到了验证。miRNA 测序和生物信息学分析从 EI-EXOs 中鉴定出差异表达的 miR-21-5p，并通过 RT-qPCR 进行了验证。miR-21-5p 抑制剂或 GW4869 可减弱 EI-EXO 诱导的 HUVEC 增殖、迁移和管形成。TIMP3 过表达可减弱 EI-EXO 的促血管生成作用，而添加 EI-EXO 或上调 miR-21-5p 则可逆转这一作用。这些发现证实了 ESC 和 HUVEC 之间通过外泌体 miR-21-5p 进行的串扰，并证实了 miR-21-5p-TIMP3 轴在子宫内膜异位症中促进血管生成的作用。关键信息：已发现 ESC 衍生的外泌体被受体细胞（即 HUVECs）摄取。功能上，与正常子宫内膜来源的外泌体（NE-EXOs）相比，子宫内膜异位症病灶来源的 ESC 衍生外泌体（EI-EXOs）可显著促进 HUVEC 的增殖、迁移和管形成。通过 miRNA 测序和生物信息学分析，选择了 EI-EXOs 释放的差异表达 miR-21-5p，并通过 qRT-PCR 进行了验证。miR-21-5p 抑制剂或 GW4869 可减弱 EI-EXO 诱导的 HUVEC 增殖、迁移和管形成。相反，TIMP3 过表达可减弱 EI-EXO 的促血管生成作用，而添加 EI-EXO 或上调 miR-21-5p 则可逆转这一作用。
