m6A甲基转移酶METTL3调控胎盘滋养层细胞干性维持和分化的分子机制研究

滋养层细胞的干性维持和分化是胎盘发育过程中的关键事件，对妊娠维持尤为重要。有研究发现m6A修饰会影响滋养层细胞的浸润能力。我们的预实验发现，METTL3的缺失导致小鼠滋养层细胞的干性下降和分化异常，人复发流产胎盘绒毛中METTL3的表达下降。因此，我们推测METTL3及其介导的m6A修饰在胎盘滋养层细胞的发育过程中起重要作用，并提出关键科学问题“METTL3及其介导的m6A修饰如何调控胎盘滋养层细胞的干性维持和分化从而形成具有正常功能的胎盘？” 本项目中，我们拟利用人胎盘绒毛样本、多种小鼠模型和体外滋养层干细胞系等，系统研究：（1）METTL3及其介导的m6A修饰调控胎盘滋养层细胞干性维持和分化的分子机制；（2）METTL3及其介导的m6A修饰异常导致复发流产的分子机理。通过本项目，我们将进一步探究胎盘滋养层细胞干性维持和分化的分子机制，为妊娠相关疾病的防治提供新的思路和理论基础。

The stemness maintenance and differentiation of trophoblast cells is the key events during the development of the placenta and is essential for the maintenance of pregnancy. Previous studies have found that m6A modification affected the invasion of trophoblast cells. Our preliminary experiments indicated that METTL3 deletion resulted in decreased stemness and abnormal differentiation of trophoblast cells, and led to reduced METTL3 expression in the placental villi of women with recurrent spontaneous abortion (RSA). Therefore, we speculate that METTL3 and m6A modification play an important role during the development of placental trophoblast cells, and raise the key scientific question "How does METTL3 and m6A modification regulate the stemness maintenance and differentiation of placental trophoblast cells to form functional placenta?" In this project, employing human placental villi, multiple mouse models, as well as cultured trophoblast stem cell lines, we will systematically study: (1) The molecular mechanism of METTL3 and m6A modification regulating the stemness maintenance and differentiation of placental trophoblast cells; (2) The mechanism of RSA caused by abnormal METTL3 and m6A. Through this project, we will further explore the molecular mechanism of stemness maintenance and differentiation of placental trophoblast cells, and provide new theoretical foundations for the prevention and treatment of pregnancy-related diseases.