Dynamic shift in trophoblast nucleos(t)ide metabolism, transport, and adenosine signaling during gestion and preterm birth

To understand the role of nucleos(t)ide metabolism (de novo synthesis and salvage patways), transport, and adenosine signaling in placental development and the adaptive response during spontaneous preterm birth (PTB), we analyzed gene expression in first-trimester and term human placentas, PTB placentas, primary human trophoblasts, and BeWo cells. Additionally, we examined rat placentas at different gestation days (GD12, GD15, and GD20) to provide developmental context and validate findings from human samples. Our results highlight the upregulation of nucleos(t)ide metabolism and adenosine signaling during placental growth and trophoblast differentiation (cytotrophoblast to syncytiotrophoblast), with further metabolic shifts in PTB placentas, particularly in pyrimidine de novo synthesis, purine salvage, and adenosine metabolism, suggesting an adaptive stress response. Additionally enhanced and also adenosine signaling and nucleoside transport was observed. This integrated approach provides novel insights into the metabolic regulation of placental function under both normal and pathological conditions为明确核苷（酸）代谢（nucleos(t)ide metabolism，含从头合成与补救途径）、核苷（酸）转运及腺苷信号通路在胎盘发育及自发性早产（spontaneous preterm birth, PTB）过程中的适应性应答中的作用，我们对妊娠早期人胎盘、足月人胎盘、自发性早产胎盘、原代人滋养层细胞及BeWo细胞开展了基因表达分析。此外，我们检测了不同妊娠天数（GD12、GD15、GD20）的大鼠胎盘，以构建发育背景并验证人类样本的研究结果。本研究结果显示，在胎盘生长及滋养层细胞分化（细胞滋养层向合体滋养层转化）过程中，核苷（酸）代谢与腺苷信号通路显著上调；自发性早产胎盘存在进一步的代谢重编程，尤其在嘧啶从头合成、嘌呤补救途径及腺苷代谢层面，提示机体存在适应性应激反应。此外，腺苷信号通路与核苷转运过程亦被增强。本整合性研究为正常与病理状态下胎盘功能的代谢调控机制提供了全新的研究视角。