Jones Helen N, Davenport Baylea N, Wilson Rebecca L
bioRxiv. 2024 Jun 8:2024.06.05.597595. doi: 10.1101/2024.06.05.597595.
The etiology of fetal growth restriction (FGR) is multifactorial, although many cases often involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion resulting in high resistance to blood flow, decreased availability of nutrients, and increased hypoxia. We have developed a non-viral, polymer-based nanoparticle that facilitates delivery and transient gene expression of ( ) in placental trophoblast for the treatment of placenta insufficiency and FGR. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, the aim of the study was to identify novel pathways in the sub-placenta/decidua that provide insight into the underlying mechanism driving placental insufficiency, and may be corrected with nanoparticle treatment. Pregnant guinea pigs underwent ultrasound-guided sham or nanoparticle treatment at mid-pregnancy, and sub-placenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. The MNR sub-placenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion and downregulation of genelists involved in the regulation of cell migration. nanoparticle treatment resulted in marked changes to transporter activity in the MNR + sub-placenta/decidua when compared to sham MNR. Under normal growth conditions however, nanoparticle treatment decreased genelists enriched for kinase signaling pathways and increased genelists enriched for proteolysis indicative of homeostasis. Overall, this study identified changes to the sub-placenta/decidua transcriptome that likely result in inadequate trophoblast invasion and increases our understanding of pathways that nanoparticle treatment acts on in order to restore or maintain appropriate placenta function.
胎儿生长受限（FGR）的病因是多因素的，尽管许多病例常涉及胎盘功能不全。胎盘功能不全与滋养层细胞浸润不足有关，导致血流阻力增加、营养物质供应减少和缺氧增加。我们开发了一种基于聚合物的非病毒纳米颗粒，可促进（此处原文括号内容缺失，无法准确翻译）在胎盘滋养层中的递送和瞬时基因表达，以治疗胎盘功能不全和FGR。利用已建立的胎盘功能不全和FGR的豚鼠母体营养限制（MNR）模型，本研究的目的是确定胎盘下/蜕膜中的新途径，以深入了解驱动胎盘功能不全的潜在机制，并可能通过纳米颗粒治疗得到纠正。怀孕的豚鼠在妊娠中期接受超声引导下的假手术或纳米颗粒治疗，5天后收集胎盘下/蜕膜组织。使用Illumina平台上的RNA测序进行转录组分析。MNR胎盘下/蜕膜显示由滋养层排列的母体螺旋动脉较少，滋养层浸润较浅，以及参与细胞迁移调节的基因列表下调。与假手术MNR相比，纳米颗粒治疗导致MNR +（此处原文括号内容缺失，无法准确翻译）胎盘下/蜕膜中的转运蛋白活性发生显著变化。然而，在正常生长条件下，纳米颗粒治疗减少了富含激酶信号通路的基因列表，并增加了富含蛋白水解的基因列表，这表明处于稳态。总体而言，本研究确定了胎盘下/蜕膜转录组的变化，这些变化可能导致滋养层浸润不足，并增加了我们对纳米颗粒治疗作用的途径的理解，以便恢复或维持适当的胎盘功能。
