Table_2_Transcriptomic Drivers of Differentiation, Maturation, and Polyploidy in Human Extravillous Trophoblast.DOCX

During pregnancy, conceptus-derived extravillous trophoblast (EVT) invades the endomyometrium, anchors the placenta to the maternal uterus, and remodels the spiral arteries in order to establish maternal blood supply to the fetoplacental unit. Recent reports have described early gestation EVT as polyploid and senescent. Here, we extend these reports by performing comprehensive profiling of both the genomic organization and transcriptome of first trimester and term EVT. We define pathways and gene regulatory networks involved in both initial differentiation and maturation of this important trophoblast lineage at the maternal–fetal interface. Our results suggest that like first trimester EVT, term EVT undergoes senescence and endoreduplication, is primarily tetraploid, and lacks high rates of copy number variations. Additionally, we have highlighted senescence and polyploidy-related genes, pathways, networks, and transcription factors that appeared to be important in normal EVT differentiation and maturation and validated a key role for the unfolded protein response in this context.

妊娠期间，胚源性绒毛外滋养层细胞（extravillous trophoblast, EVT）会侵入子宫内肌层，将胎盘锚定在母体子宫内，并对螺旋动脉进行重塑，以建立胎儿胎盘单位的母体血液供应。近期已有研究报道，早期妊娠状态下的EVT为多倍体且处于衰老状态。本研究通过对孕早期与足月EVT的基因组结构与转录组开展全面表征分析，拓展了上述研究结论。我们明确了母胎界面这一重要滋养层细胞谱系在初始分化与成熟过程中所涉及的通路与基因调控网络。研究结果显示，与孕早期EVT类似，足月EVT同样会发生衰老与核内复制，主要以四倍体形式存在，且拷贝数变异发生率较低。此外，我们还筛选出了与衰老及多倍体相关的基因、通路、调控网络及转录因子，这些分子在EVT的正常分化与成熟过程中发挥关键作用，并验证了未折叠蛋白反应在该过程中的核心调控功能。