Wu Zhi-Hong, Yi Cen, Chen En-Xiang, Xu Jia-Qi, Li Cong, Yao Lu, Li Fang-Fang, Fu Li-Juan, Ge Lu-Xing, Wang Ying-Xiong, Xie You-Long, Ding Yu-Bin, Tang Jing
Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China.
Joint International Research Laboratory of Reproduction and Development of the Ministry of Education of China, School of Public Health, Chongqing Medical University, Chongqing 400016, China.
Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2421653122. doi: 10.1073/pnas.2421653122. Epub 2025 Apr 28.
Recurrent spontaneous abortion (RSA) is a pregnancy-related condition characterized by a complex etiology. While placental trophoblast dysfunction is strongly associated with the development and progression of RSA, the underlying molecular mechanisms remain poorly understood. In this study, we observed a significant decrease in the expression of MYB Proto-Oncogene Like 2 (MYBL2) in the villous tissue of patients with RSA and the placentas of abortion-prone (AP) mice. Utilizing human trophoblast stem cells (hTSCs), we identified MYBL2 as a critical regulator of hTSCs stemness maintenance, promoting the expression of the stemness-associated genes Tumor protein p63 (TP63) and TEA Domain Transcription Factor 4 (TEAD4). Furthermore, MYBL2 facilitates the differentiation of hTSCs into extravillous trophoblast (EVT) by positively regulating Ajuba LIM Protein (AJUBA) expression. Using HTR-8/SVneo cell line, an immortalized EVT-like model, we found that MYBL2 positively regulates AJUBA expression by binding to the distal region of the AJUBA promoter. Additionally, the MYBL2-AJUBA axis enhances the migration and invasion of HTR-8/SVneo cells by suppressing the Hippo signaling pathway. Our study indicates that the dysregulation of MYBL2 expression in placental trophoblasts is associated with the pathogenesis of RSA, highlighting its potential as a therapeutic target for this condition.
复发性自然流产（RSA）是一种与妊娠相关的疾病，其病因复杂。虽然胎盘滋养层细胞功能障碍与RSA的发生和发展密切相关，但其潜在的分子机制仍知之甚少。在本研究中，我们观察到RSA患者绒毛组织和易流产（AP）小鼠胎盘中MYB原癌基因样2（MYBL2）的表达显著降低。利用人滋养层干细胞（hTSCs），我们确定MYBL2是hTSCs干性维持的关键调节因子，可促进干性相关基因肿瘤蛋白p63（TP63）和TEA结构域转录因子4（TEAD4）的表达。此外，MYBL2通过正向调节Ajuba LIM蛋白（AJUBA）的表达促进hTSCs向绒毛外滋养层细胞（EVT）分化。使用永生化的EVT样模型HTR-8/SVneo细胞系，我们发现MYBL2通过与AJUBA启动子的远端区域结合来正向调节AJUBA的表达。此外，MYBL2-AJUBA轴通过抑制Hippo信号通路增强HTR-8/SVneo细胞的迁移和侵袭。我们的研究表明，胎盘滋养层细胞中MYBL2表达失调与RSA的发病机制有关，突出了其作为该疾病治疗靶点的潜力。
