Similar articles

Abstract: The mechanisms underlying pregnancy complications caused by advanced maternal age (AMA) remain unclear. We analyzed the cellular signature and transcriptomes of human placentas in AMA women to elucidate these mechanisms. placental tissues from two AMA women and two controls were used for single-cell RNA-sequencing (scRNA-seq). Controls consisted of AMA women who did not experience any pregnancy complications and pregnant women below the age of 35 years without pregnancy complications. trophoblast cells were obtained from the placentas of another six pregnant women (three AMA women and three controls), and in-vitro transwell assays were conducted to observe the cell invasion ability. Thirty additional samples (from 15 AMA women and 15 controls) were analyzed to verify the specific expression of serine protease inhibitor clade E member 1 (SERPINE1). Preliminary study of the role of SERPINE1 in cell invasion was carried out with HTR8-S/Vneo cells. High-quality transcriptomes of 27‍607 cells were detected. Three types of trophoblast cells were detected, which were further classified into eight subtypes according to differences in gene expression and Gene Ontology (GO) function. We identified 110 differentially expressed genes (DEGs) in trophoblast cells between the AMA and control groups, and the DEGs were enriched in multiple pathways related to cell invasion. In-vitro transwell assays suggested that the invading trophoblast cells in AMA women were reduced. SERPINE1 was specifically expressed in the trophoblast, and its expression was higher in AMA women (P<0.05). Transfection of human SERPINE1 (hSERPINE1) into HTR8-S/Vneo trophoblast cells showed fewer invading cells in the hSERPINE1 group. Impaired cell invasion may underlie the increased risk of adverse pregnancy outcomes in AMA women. Abnormal expression of SERPINE1 in extravillous trophoblast (EVT) cells appears to play an important role.

从单细胞水平揭示细胞侵袭减少可能是高龄孕妇胎盘缺陷特征

[1]AizaraniN, SavianoA, Sagar, et al., 2019. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature, 572(7768):199-204.

[2]BauerS, PollheimerJ, HartmannJ, et al., 2004. Tumor necrosis factor-α inhibits trophoblast migration through elevation of plasminogen activator inhibitor-1 in first-trimester villous explant cultures. J Clin Endocrinol Metab, 89(2):812-822.

[3]BurlRB, RamseyerVD, RondiniEA, et al., 2018. Deconstructing adipogenesis induced by β3-adrenergic receptor activation with single-cell expression profiling. Cell Metab, 28(2):300-309.e4.

[4]BurtonGJ, JauniauxE, 2017. The cytotrophoblastic shell and complications of pregnancy. Placenta, 60:134-139.

[5]ButlerA, HoffmanP, SmibertP, et al., 2018. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol, 36(5):411-420.

[6]FisherSJ, 2015. Why is placentation abnormal in preeclampsia? Am J Obstet Gynecol, 213(4 Suppl):S115-S122.

[7]HanXP, ZhouZM, FeiLJ, et al., 2020. Construction of a human cell landscape at single-cell level. Nature, 581(7808):303-309.

[8]HeffnerLJ, 2004. Advanced maternal age—how old is too old? N Engl J Med, 351(19):1927-1929.

[9]HuberAV, SalehL, BauerS, et al., 2006. TNFα-mediated induction of PAI-1 restricts invasion of HTR-8/SVneo trophoblast cells. Placenta, 27(2-3):127-136.

[10]HuppertzB, KadyrovM, KingdomJCP, 2006. Apoptosis and its role in the trophoblast. Am J Obstet Gynecol, 195(1):29-39.

[11]IoS, KondohE, ChigusaY, et al., 2020. New era of trophoblast research: integrating morphological and molecular approaches. Hum Reprod Update, 26(5):611-633.

[12]KhanWN, TeglundS, BremerK, et al., 1992. The pregnancy-specific glycoprotein family of the immunoglobulin superfamily: identification of new members and estimation of family size. Genomics, 12(4):780-787.

[13]KortleverRM, HigginsPJ, BernardsR, 2006. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol, 8(8):877-884.

[14]la MannoG, SoldatovR, ZeiselA, et al., 2018. RNA velocity of single cells. Nature, 560(7719):494-498.

[15]LambrechtsD, WautersE, BoeckxB, et al., 2018. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med, 24(8):1277-1289.

[16]LaopaiboonM, LumbiganonP, IntarutN, et al., 2014. Advanced maternal age and pregnancy outcomes: a multicountry assessment. BJOG, 121(Suppl 1):49-56.

[17]LiuYW, FanXY, WangR, et al., 2018. Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta. Cell Res, 28(8):819-832.

[18]LvB, AnQ, ZengQ, et al., 2019. Single-cell RNA sequencing reveals regulatory mechanism for trophoblast cell-fate divergence in human peri-implantation conceptuses. PLoS Biol, 17(10):e3000187.

[19]MaY, RyuJS, DulayA, et al., 2002. Regulation of plasminogen activator inhibitor (PAI)-1 expression in a human trophoblast cell line by glucocorticoid (GC) and transforming growth factor (TGF)-β. Placenta, 23(10):727-734.

[20]MacoskoEZ, BasuA, SatijaR, et al., 2015. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell, 161(5):1202-1214.

[21]MarkovichD, RegeerRR, KunzelmannK, et al., 2005. Functional characterization and genomic organization of the human Na⁺-sulfate cotransporter hNaS2 gene (SLC13A4). Biochem Biophys Res Commun, 326(4):729-734.

[22]NapsoT, HungYP, DavidgeST, et al., 2019. Advanced maternal age compromises fetal growth and induces sex-specific changes in placental phenotype in rats. Sci Rep, 9:16916.

[23]NelsonAC, MouldAW, BikoffEK, et al., 2016. Single-cell RNA-seq reveals cell type-specific transcriptional signatures at the maternal-foetal interface during pregnancy. Nat Commun, 7:11414.

[24]NelsonSM, TelferEE, AndersonRA, 2013. The ageing ovary and uterus: new biological insights. Hum Reprod Update, 19(1):67-83.

[25]NorwitzER, 2006. Defective implantation and placentation: laying the blueprint for pregnancy complications. Reprod BioMed Online, 13(4):591-599.

[26]ParkJ, ShresthaR, QiuCX, et al., 2018. Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science, 360(6390):758-763.

[27]ParkJE, BottingRA, Domínguez CondeC, et al., 2020. A cell atlas of human thymic development defines T cell repertoire formation. Science, 367(6480):eaay3224.

[28]PavličevM, WagnerGP, ChavanAR, et al., 2017. Single-cell transcriptomics of the human placenta: inferring the cell communication network of the maternal-fetal interface. Genome Res, 27(3):349-361.

[29]Pique-RegiR, RomeroR, TarcaAL, et al., 2019. Single cell transcriptional signatures of the human placenta in term and preterm parturition. Elife, 8:e52004.

[30]ReyesM, FilbinMR, BhattacharyyaRP, et al., 2020. An immune-cell signature of bacterial sepsis. Nat Med, 26(3):333-340.

[31]SoodR, ZehnderJL, DruzinML, et al., 2006. Gene expression patterns in human placenta. Proc Natl Acad Sci USA, 103(14):5478-5483.

[32]SunD, ZhuH, AiL, et al., 2021. Mitochondrial fusion protein 2 regulates endoplasmic reticulum stress in preeclampsia. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(2):165-170.

[33]SuryawanshiH, MorozovP, StrausA, et al., 2018. A single-cell survey of the human first-trimester placenta and decidua. Sci Adv, 4(10):eaau4788.

[34]SweeneyEM, DockeryP, CrankshawDJ, et al., 2014. Human uterine lower segment myometrial cell and nuclear volume at term: influence of maternal age. J Anat, 225(6):625-633.

[35]TeglundS, ZhouGQ, HammarströmS, 1995. Characterization of cDNA encoding novel pregnancy-specific glycoprotein variants. Biochem Biophys Res Commun, 211(2):656-664.

[36]TrapnellC, CacchiarelliD, GrimsbyJ, et al., 2014. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol, 32(4):381-386.

[37]TsangJCH, VongJSL, JiL, et al., 2017. Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics. Proc Natl Acad Sci USA, 114(37):E7786-E7795.

[38]Vento-TormoR, EfremovaM, BottingRA, et al., 2018. Single-cell reconstruction of the early maternal-fetal interface in humans. Nature, 563(7731):347-353.

[39]WaldenströmU, CnattingiusS, VixnerL, et al., 2017. Advanced maternal age increases the risk of very preterm birth, irrespective of parity: a population-based register study. BJOG, 124(8):1235-1244.

[40]WalshSTR, KossiakoffAA, 2006. Crystal structure and site 1 binding energetics of human placental lactogen. J Mol Biol, 358(3):773-784.

[41]WangS, ZhengYX, LiJY, et al., 2020. Single-cell transcriptomic atlas of primate ovarian aging. Cell, 180(3):‍‍585-600.e19.

[42]WoodsL, Perez-GarciaV, KieckbuschJ, et al., 2017. Decidualisation and placentation defects are a major cause of age-related reproductive decline. Nat Commun, 8:352.

[43]YangYQ, GuoF, PengY, et al., 2021. Transcriptomic profiling of human placenta in gestational diabetes mellitus at the single-cell level. Front Endocrinol, 12:679582.

[44]YaoYL, XuXH, JinLP, 2019. Macrophage polarization in physiological and pathological pregnancy. Front Immunol, 10:792.

[45]ZhangXQ, GreenKE, YallampalliC, et al., 2005. Adrenomedullin enhances invasion by trophoblast cell lines. Biol Reprod, 73(4):619-626.

[46]ZhouWB, WangHY, YangJJ, et al., 2019. Down-regulated circPAPPA suppresses the proliferation and invasion of trophoblast cells via the miR-384/STAT3 pathway. Biosci Rep, 39(9):BSR20191965.