Barak Oren, Bauer Alexander D, Parks W Tony, Lovelace Tyler C, Benos Panayiotis V, Chu Tianjiao, Sadovsky Yoel
Magee-Women's Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Placenta. 2025 Mar 6;161:31-38. doi: 10.1016/j.placenta.2025.01.009. Epub 2025 Jan 20.
Fusion of mononucleated cytotrophoblasts into syncytium leads to trophoblast senescence. Yet, premature senescence is associated with preeclampsia, fetal growth restriction (FGR), and related obstetrical syndromes. A set of 28 transcripts that comprise senescence-associated secretory phenotype (SASP) was recently described in placentas from women with preeclampsia. We posited that this transcript set is uniquely regulated in late-term placentas or in placentas derived from participants with major obstetrical syndromes.
Using our large placental RNAseq bank, we analyzed data from healthy participants (n = 33) with histologically normal placentas, representing delivery at 37-41 weeks. To represent diseases, we included RNAseq data from participants (n = 220) with severe preeclampsia, FGR, FGR with a hypertensive disorder (FGR + HDP), or spontaneous preterm delivery, and healthy controls (n = 129). We also assessed the expression of several SASPs in primary human trophoblasts that were exposed in vitro to hypoxia, reduced differentiation, or ferroptotic or apoptotic signals.
Among the 28 SASP transcripts analyzed, eight had a significant change between deliveries at <37 weeks vs ≥ 41 weeks, including upregulation of FSTL3, IL1RL1, INHBA, and VEGFA and downregulation of STC1, RARRES2, MRC2, and SELP. The expression of SASP mRNAs was enriched in the placentas from the assessed syndromes, with most expression changes in placentas from FGR/HDP. Our in vitro analysis associated hypoxia or apoptosis with altered expression of FSTL3, VEGFA, and DKK1.
A set of placental SASPs defines late-term placentas, placental dysfunction-related clinical syndromes, and in vitro-defined trophoblast injury. Trophoblastic SASP signatures may assist in characterizing placental senescence in health and disease.
单核细胞滋养层细胞融合形成合体滋养层会导致滋养层细胞衰老。然而，过早衰老与子痫前期、胎儿生长受限（FGR）及相关产科综合征有关。最近在子痫前期女性的胎盘中发现了一组由衰老相关分泌表型（SASP）组成的28种转录本。我们推测，这组转录本在足月胎盘或患有主要产科综合征的参与者的胎盘中受到独特调控。
利用我们庞大的胎盘RNA测序文库，我们分析了来自健康参与者（n = 33）的数据，这些参与者的胎盘组织学正常，代表37 - 41周分娩。为了代表疾病情况，我们纳入了来自患有严重子痫前期、FGR、伴有高血压疾病的FGR（FGR + HDP）或自发性早产的参与者（n = 220）以及健康对照者（n = 129）的RNA测序数据。我们还评估了原代人滋养层细胞在体外暴露于缺氧、分化降低、铁死亡或凋亡信号时几种SASP的表达情况。
在分析的28种SASP转录本中，8种在<37周与≥41周分娩之间有显著变化，包括FSTL3、IL1RL1、INHBA和VEGFA上调，以及STC1、RARRES2、MRC2和SELP下调。SASP mRNA的表达在评估的综合征胎盘中富集，其中FGR/HDP胎盘的表达变化最为明显。我们的体外分析表明，缺氧或凋亡与FSTL3、VEGFA和DKK1表达改变有关。
一组胎盘SASP定义了足月胎盘、与胎盘功能障碍相关的临床综合征以及体外定义的滋养层细胞损伤。滋养层细胞SASP特征可能有助于在健康和疾病状态下表征胎盘衰老。
