来源于月经血基质细胞的外泌体通过递送血栓素-1，调控 SMAD3/AKT/MDM2/P53 通路，改善了卵巢早衰和颗粒细胞凋亡。

Exosomes derived from menstrual blood stromal cells ameliorated premature ovarian insufficiency and granulosa cell apoptosis by regulating SMAD3/AKT/MDM2/P53 pathway via delivery of thrombospondin-1.

机构信息

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; Key Laboratory of Reproductive and Genetic Medicine (China Medical University), National Health Commission, Shenyang 110004, China.

出版信息

Biomed Pharmacother. 2023 Oct;166:115319. doi: 10.1016/j.biopha.2023.115319. Epub 2023 Aug 11.

DOI:10.1016/j.biopha.2023.115319

PMID:37573658

Abstract

Premature ovarian insufficiency (POI) is clinically irreversible and seriously damages female fertility. We previously demonstrated that menstrual blood stromal cells (MenSCs)-derived exosomes (EXOs) effectively improved ovarian functions in the POI rat model. In this study, we investigated whether TSP1 is the key component in EXOs to ameliorate ovarian functions and further explored the molecular mechanism of EXOs in improving granulosa cell (GCs) activities. Our results demonstrated that knockdown TSP1 significantly debilitated the therapeutic effect of EXOs on estrous cyclicity, ovarian morphology, follicle numbers and pregnancy outcomes in 4-vinylcyclohexene diepoxide (VCD) induced POI rat model. In addition, EXOs treatment significantly promoted the activities and inhibited the apoptosis of VCD induced granulosa cells in vitro. Moreover, EXOs stimulation markedly activated the phosphorylation of SMAD3(Ser425) and AKT(Ser473), up-regulated the expressions of BCL2 and MDM2 as well as down-regulated the expressions of CASPASE3, CASPASE8, P53 and BAX. All these effects were supressed by SIS3, a inhibitor of TGF1/SMAD3. Our study revealed the key role of TSP1 in EXOs in improving POI pathology, restoring ovarian functions and GCs activities, andprovided a promising basis for EXOs in the treatment of ovarian dysfunction.

摘要

卵巢早衰（POI）是一种临床不可逆的疾病，严重损害女性生育能力。我们之前的研究表明，经血基质细胞（MenSCs）衍生的外泌体（EXOs）可有效改善 POI 大鼠模型的卵巢功能。在本研究中，我们研究了 TSP1 是否是 EXOs 中改善卵巢功能的关键成分，并进一步探讨了 EXOs 改善颗粒细胞（GCs）活性的分子机制。结果表明，敲低 TSP1 显著削弱了 EXOs 对 4-乙烯环己烯二氧化物（VCD）诱导的 POI 大鼠模型动情周期、卵巢形态、卵泡数量和妊娠结局的治疗作用。此外，EXOs 处理显著促进了 VCD 诱导的颗粒细胞的体外活性并抑制了其凋亡。此外，EXOs 刺激显著激活了 SMAD3（Ser425）和 AKT（Ser473）的磷酸化，上调了 BCL2 和 MDM2 的表达，下调了 CASPASE3、CASPASE8、P53 和 BAX 的表达。这些作用均被 TGF1/SMAD3 的抑制剂 SIS3 所抑制。本研究揭示了 TSP1 在 EXOs 改善 POI 病理、恢复卵巢功能和 GCs 活性中的关键作用，为 EXOs 在卵巢功能障碍治疗中的应用提供了有前景的依据。