Zhou Hong, Zhou Jiaxin, Liu ShanShan, Niu Jing, Pan Jinghua, Li Ruiman
Reproductive Medical Center, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, China.
Reproductive Medical Center, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, China; International School, Jinan University, Guangzhou, Guangdong, 510632, China.
Redox Biol. 2025 Mar;80:103508. doi: 10.1016/j.redox.2025.103508. Epub 2025 Feb 1.
Human decidual mesenchymal stem cells (hDMSCs) play crucial roles in pregnancy. The decreased resistance of hDMSCs to oxidative stress is a key factor contributing to recurrent spontaneous abortion (RSA). miRNAs have essential functions in the proliferation and apoptosis of decidual tissues. However, the miRNAs involved in regulating oxidative stress in hDMSCs remain unclear.
Decidual tissues and hDMSCs were collected from patients with RSA and early pregnancy miscarriages. We assessed the antioxidant capacity of hDMSCs in both groups by detecting relevant indicators. Furthermore, differentially expressed miRNAs in hDMSCs were analyzed through miRNA sequencing. We evaluated the interaction between hsa-miR-532-3p and KEAP1 using a luciferase reporter assay. A mouse model of RSA was constructed for confirmation. Finally, we analyzed the correlations between serum hsa-miR-532-3p levels and the clinical features of pregnant women with RSA.
miRNA sequencing revealed 44 miRNAs whose expression was downregulated and 9 miRNAs whose expression was upregulated in hDMSCs from the RSA group compared with those from the control group. The overexpression of hsa-miR-532-3p led to a significantly increased antioxidant capacity in hDMSCs. The knockdown or overexpression of hsa-miR-532-3p led to the upregulation or downregulation of KEAP1 expression, respectively. In a mouse model, the overexpression of hsa-miR-532-3p reduced embryo absorption rates in RSA mice, decreased KEAP1 expression levels in decidual tissues, and concurrently enhanced the resistance to oxidative stress. Furthermore, in patients diagnosed with RSA, serum hsa-miR-532-3p levels were significantly and negatively correlated with the gestational age.
Our study revealed a lower expression level of hsa-miR-532-3p in the hDMSCs of patients with RSA. Moreover, hsa-miR-532-3p protects hDMSCs from oxidative stress by targeting the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (KEAP1/NRF2) pathway. Hsa-miR-532-3p is closely related to gestational age and has good predictive value for identifying RSA.
人蜕膜间充质干细胞（hDMSCs）在妊娠过程中发挥着关键作用。hDMSCs对氧化应激的抵抗力下降是导致复发性自然流产（RSA）的关键因素。微小RNA（miRNAs）在蜕膜组织的增殖和凋亡中具有重要作用。然而，参与调节hDMSCs氧化应激的miRNAs仍不清楚。
从RSA患者和早孕流产患者中收集蜕膜组织和hDMSCs。我们通过检测相关指标评估两组中hDMSCs的抗氧化能力。此外，通过miRNA测序分析hDMSCs中差异表达的miRNAs。我们使用荧光素酶报告基因检测评估hsa-miR-532-3p与KEAP1之间的相互作用。构建RSA小鼠模型进行验证。最后，我们分析了血清hsa-miR-532-3p水平与RSA孕妇临床特征之间的相关性。
miRNA测序显示，与对照组相比，RSA组hDMSCs中有44种miRNAs表达下调，9种miRNAs表达上调。hsa-miR-532-3p的过表达导致hDMSCs的抗氧化能力显著增强。hsa-miR-532-3p的敲低或过表达分别导致KEAP1表达的上调或下调。在小鼠模型中，hsa-miR-532-3p的过表达降低了RSA小鼠的胚胎吸收率，降低了蜕膜组织中KEAP1的表达水平，同时增强了对氧化应激的抵抗力。此外，在被诊断为RSA的患者中，血清hsa-miR-532-3p水平与孕周显著负相关。
我们的研究揭示了RSA患者hDMSCs中hsa-miR-532-3p的表达水平较低。此外，hsa-miR-532-3p通过靶向 Kelch样ECH相关蛋白1/核因子红细胞2相关因子2（KEAP1/NRF2）途径保护hDMSCs免受氧化应激。Hsa-miR-532-3p与孕周密切相关，对识别RSA具有良好的预测价值。
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