Chen Yihong, Gan Bei, Zheng Shan, Zhao Xiumei, Jin Leiyi, Wei Juanbing
Department of Obstetrics and Gynecology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, Fujian, 350005, P.R. China.
BMC Pregnancy Childbirth. 2024 Dec 20;24(1):840. doi: 10.1186/s12884-024-07054-1.
Recurrent spontaneous abortion (RSA), whose underlying cause has yet to be fully elucidated, is often classified as unexplained recurrent spontaneous abortion (URSA). Promoting the differentiation of CD4 T cells into Tregs may be the key to prevent URSA. The differentiation of CD4 T cells was controlled by mTOR, but the regulatory mechanism is still unclear. This study aims to explore the regulatory role of mTOR on CD4 T cells and evaluate the feasibility of metformin (Met) and 2-Deoxy-D-glucose (2-DG) treatment for URSA.
To elucidate the mechanism of mTOR regulating Th17/Treg, transcriptome sequencing was used to analyze gene differences in clinical decidua tissue, the AMPK, mTOR and glycolytic activity in URSA mice were evaluated by RT-qPCR and WB. In addition, FCM and ELISA were also used to measure the differentiation of CD4 T cells.
Compared to the Control group, significant differences in gene expressions of female pregnancy and Th17 cell differentiation were observed in URSA group. Activation of AMPK and inhibition of glycolysis reduced the abortion rate in URSA mice (p = 0.0013), and inhibited CD4 T cells differentiation to Th17 cells, which increased Treg/Th17 ratio (p < 0.001) and improved the pregnancy outcomes of URSA mice.
Our research had illustrated that AMPK-mTOR pathway regulated glycolysis reprogramming and improved the pregnancy outcomes of URSA. Furthormore, Met and 2-DG promoted the differentiation of CD4 T cells into Treg cells, providing theoretical basis for clinical prevention of URSA.
复发性自然流产（RSA）的潜在病因尚未完全阐明，常被归类为不明原因复发性自然流产（URSA）。促进CD4 T细胞分化为调节性T细胞（Tregs）可能是预防URSA的关键。CD4 T细胞的分化受哺乳动物雷帕霉素靶蛋白（mTOR）调控，但其调控机制仍不清楚。本研究旨在探讨mTOR对CD4 T细胞的调控作用，并评估二甲双胍（Met）和2-脱氧-D-葡萄糖（2-DG）治疗URSA的可行性。
为阐明mTOR调节Th17/Treg的机制，采用转录组测序分析临床蜕膜组织中的基因差异，通过逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹法（WB）评估URSA小鼠中的腺苷酸活化蛋白激酶（AMPK）、mTOR和糖酵解活性。此外，还采用流式细胞术（FCM）和酶联免疫吸附测定（ELISA）检测CD4 T细胞的分化情况。
与对照组相比，URSA组在女性妊娠和Th17细胞分化基因表达上存在显著差异。激活AMPK和抑制糖酵解降低了URSA小鼠的流产率（p = 0.0013），并抑制CD4 T细胞向Th17细胞分化，从而提高了调节性T细胞/辅助性T细胞17（Treg/Th17）比值（p < 0.001），改善了URSA小鼠的妊娠结局。
我们的研究表明，AMPK-mTOR信号通路调节糖酵解重编程并改善了URSA的妊娠结局。此外，Met和2-DG促进CD4 T细胞分化为Treg细胞，为临床预防URSA提供了理论依据。
