Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 39 Huaxiang Road, Tiexi District, Shenyang, 110022, China.
Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, No. 39 Huaxiang Road, Tiexi District, Shenyang, 110022, China.
J Nanobiotechnology. 2023 Aug 29;21(1):305. doi: 10.1186/s12951-023-02070-3.
Intrauterine adhesion (IUA) is a recurrent and refractory reproductive dysfunction disorder for which menstrual blood-derived stromal cells (MenSCs) might be a promising intervention. We reported that administration of MenSCs-derived exosomes (MenSCs-EXO) could achieve similar therapeutic effects to MenSCs transplantation, including alleviating endometrial fibrosis and improving fertility in IUA rats. The mass spectrometry sequencing result suggested that UBR4, a member of the proteasome family, was abundantly enriched in MenSCs-EXO. This study aimed to investigate the key role of UBR4 in MenSCs-EXO for the treatment of IUA and the specific molecular mechanism.
UBR4 was lowly expressed in the endometrial stromal cells (EndoSCs) of IUA patients. MenSCs-EXO treatment could restore the morphology of IUA endometrium, reduce the extent of fibrosis, and promote endometrial and vascular proliferation. Knockdown of UBR4 in MenSCs did not affect the characteristics of exosomes but attenuated the therapeutic effect of exosomes. UBR4 in MenSCs-EXO could alleviate endometrial fibrosis by boosting YAP ubiquitination degradation and promoting YAP nuclear-cytoplasmic translocation. Moreover, P65 could bind to the UBR4 promoter region to transcriptionally promote the expression level of UBR4 in MenSCs.
Our study clarified that MenSCs-EXO ameliorated endometrial fibrosis in IUA primarily by affecting YAP activity mediated through UBR4, while inflammatory signaling P65 may affect UBR4 expression in MenSCs to enhance MenSCs-EXO therapeutic effects. This revealed a novel mechanism for the treatment of IUA with MenSCs-EXO, proposing a potential option for the clinical treatment of endometrial injury.
宫腔粘连（IUA）是一种反复发作且难治的生殖功能障碍疾病，间充质干细胞来源的外泌体（MenSCs-EXO）可能是一种有前途的干预手段。我们曾报道过，MenSCs-EXO 的给药可以达到与 MenSCs 移植相似的治疗效果，包括缓解子宫内膜纤维化和改善 IUA 大鼠的生育能力。质谱测序结果表明，多聚体蛋白降解酶家族的成员 UBR4 在 MenSCs-EXO 中大量富集。本研究旨在探讨 UBR4 在 MenSCs-EXO 治疗 IUA 中的关键作用及其具体的分子机制。
IUA 患者的子宫内膜基质细胞（EndoSCs）中 UBR4 表达水平较低。MenSCs-EXO 治疗可恢复 IUA 子宫内膜的形态，减少纤维化程度，并促进子宫内膜和血管增殖。在 MenSCs 中敲低 UBR4 并不影响外泌体的特征，但会减弱外泌体的治疗效果。MenSCs-EXO 中的 UBR4 通过促进 YAP 泛素化降解和促进 YAP 核质转位来缓解子宫内膜纤维化。此外，P65 可以结合 UBR4 启动子区域，从而转录促进 MenSCs 中 UBR4 的表达水平。
本研究阐明了 MenSCs-EXO 主要通过影响 UBR4 介导的 YAP 活性来改善 IUA 中的子宫内膜纤维化，而炎症信号 P65 可能通过影响 MenSCs 中 UBR4 的表达来增强 MenSCs-EXO 的治疗效果。这揭示了 MenSCs-EXO 治疗 IUA 的一种新机制，为子宫内膜损伤的临床治疗提供了一种潜在选择。
