True Heather E, Doratt Brianna M, Wagner Sheridan, Malherbe Delphine C, Shelman Nathan R, Boroujeni Mahdi Eskandarian, Cockerham Cynthia, O'Brien John, Messaoudi Ilhem
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky; Lexington, KY 40536, USA.
Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky; Lexington, KY 40536, USA.
bioRxiv. 2025 Jul 31:2025.07.30.667651. doi: 10.1101/2025.07.30.667651.
Maternal opioid use disorder (OUD) poses significant risks to maternal and fetal health. Adverse outcomes associated with maternal OUD are believed to be mediated, in part, by changes in placenta structure and function; however, few studies have addressed this question. Here, we utilized a combination of flow cytometry, histology, spatial and single-cell transcriptomics to uncover the impact of OUD on placental tissues. Given that nearly half of subjects with chronic OUD contract hepatitis C (HCV), we further stratified our findings by maternal HCV status. Our results indicate that maternal OUD leads to a higher incidence of vascular malperfusion accompanied by increased levels of inflammatory markers and dysregulated secretion of placental development factors. Furthermore, spatial transcriptomics revealed that maternal OUD disrupts the communication between trophoblasts and immune cells important for placental vascular development. Additionally, CellChat analysis revealed aberrant VEGF and FN1 signaling across trophoblast, endothelial, and myeloid cells. Processes associated with tissue homeostasis and repair were also downregulated across trophoblast and leukocytes. Frequencies and responses to ex-vivo stimulation of decidual macrophages and cytolytic NK cells, critical for tissue remodeling and fetal tolerance, were decreased. Finally, transcriptional analyses of placental leukocytes also indicate shifts towards more regulatory/tissue surveillant phenotypes. Altogether, these results highlight the significant disruptions to placental health by maternal OUD.
孕妇阿片类物质使用障碍（OUD）对孕产妇和胎儿健康构成重大风险。与孕妇OUD相关的不良后果被认为部分是由胎盘结构和功能的变化介导的；然而，很少有研究探讨这个问题。在这里，我们结合流式细胞术、组织学、空间和单细胞转录组学来揭示OUD对胎盘组织的影响。鉴于近一半的慢性OUD患者感染丙型肝炎病毒（HCV），我们进一步根据孕妇的HCV状态对研究结果进行分层。我们的结果表明，孕妇OUD会导致血管灌注不良的发生率更高，同时炎症标志物水平升高，胎盘发育因子的分泌失调。此外，空间转录组学显示，孕妇OUD会破坏对胎盘血管发育至关重要的滋养层细胞和免疫细胞之间的通讯。此外，CellChat分析揭示了滋养层细胞、内皮细胞和髓样细胞之间异常的VEGF和FN1信号传导。与组织稳态和修复相关的过程在滋养层细胞和白细胞中也下调。对蜕膜巨噬细胞和细胞溶解性NK细胞进行体外刺激的频率和反应（对组织重塑和胎儿耐受性至关重要）降低。最后，胎盘白细胞的转录分析也表明向更多调节性/组织监视性表型转变。总之，这些结果突出了孕妇OUD对胎盘健康的重大破坏。
