Brodowski Lars, Zindler Tristan, von Hardenberg Sandra, Schröder-Heurich Bianca, von Kaisenberg Constantin S, Frieling Helge, Hubel Carl A, Dörk Thilo, von Versen-Höynck Frauke
Department of Obstetrics and Gynecology, Hannover Medical School, Hanover, Germany.
Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hanover, Germany.
Front Cell Dev Biol. 2019 Mar 19;7:32. doi: 10.3389/fcell.2019.00032. eCollection 2019.
The pregnancy complication preeclampsia represents an independent risk factor for cardiovascular disease. Our previous research shows a diminished function of fetal endothelial colony-forming cells (ECFC), a proliferative subgroup of endothelial progenitor cells (EPC) in preeclampsia. The aim of this study was to further investigate whether DNA methylation of fetal EPC is affected in preeclampsia.
The genomic methylation pattern of fetal ECFC from uncomplicated and preeclamptic pregnancies was compared for 865918 CpG sites, and genes were classified into gene networks. Low and advanced cell culture passages were compared to explore whether expansion of fetal ECFC in cell culture leads to changes in global methylation status and if methylation characteristics in preeclampsia are maintained with increasing passage.
A differential methylation pattern of fetal ECFC from preeclampsia compared to uncomplicated pregnancy was detected for a total of 1266 CpG sites in passage 3, and for 2362 sites in passage 5. Key features of primary networks implicated by methylation differences included cell metabolism, cell cycle and transcription and, more specifically, genes involved in cell-cell interaction and Wnt signaling. We identified an overlap between differentially regulated pathways in preeclampsia and cardiovascular system development and function. Cell culture passages 3 and 5 showed similar gene network profiles, and 1260 out of 1266 preeclampsia-associated methylation changes detected in passage 3 were confirmed in passage 5.
Methylation modification caused by preeclampsia is stable and detectable even in higher cell culture passages. An epigenetically modified endothelial precursor may influence both normal morphogenesis and postnatal vascular repair capacity. Further studies on epigenetic modifications in complicated pregnancies are needed to facilitate development of EPC based therapies for cardiovascular alterations.
妊娠并发症子痫前期是心血管疾病的独立危险因素。我们之前的研究表明，子痫前期胎儿内皮集落形成细胞（ECFC）功能受损，ECFC是内皮祖细胞（EPC）的一个增殖亚群。本研究的目的是进一步调查子痫前期胎儿EPC的DNA甲基化是否受到影响。
比较了正常妊娠和子痫前期妊娠胎儿ECFC的865918个CpG位点的基因组甲基化模式，并将基因分类到基因网络中。比较了低代和高代细胞培养传代情况，以探讨胎儿ECFC在细胞培养中的扩增是否会导致整体甲基化状态的变化，以及子痫前期的甲基化特征是否会随着传代增加而保持。
在第3代中，共检测到1266个CpG位点的子痫前期胎儿ECFC与正常妊娠相比存在差异甲基化模式，在第5代中为2362个位点。甲基化差异涉及的主要网络的关键特征包括细胞代谢、细胞周期和转录，更具体地说，涉及细胞间相互作用和Wnt信号传导的基因。我们确定了子痫前期差异调节途径与心血管系统发育和功能之间的重叠。第3代和第5代细胞培养显示出相似的基因网络图谱，第3代中检测到的1266个与子痫前期相关的甲基化变化中有1260个在第5代中得到证实。
子痫前期引起的甲基化修饰是稳定的，即使在较高代细胞培养中也可检测到。表观遗传修饰的内皮前体细胞可能影响正常形态发生和出生后血管修复能力。需要进一步研究复杂妊娠中的表观遗传修饰，以促进基于EPC的心血管改变治疗方法的开发。
