{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:57:41Z","timestamp":1792627061508,"version":"4.5.0"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T00:00:00Z","timestamp":1684713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality. Although increasing lines of evidence suggest that both the placenta and the decidua likely play roles in the pathogenesis of PE, the molecular mechanism of PE remains elusive partly because of the heterogeneity nature of the maternal-fetal interface. In this study, we perform single-cell RNA-seq on the placenta and the decidual from patients with late-onset PE (LOPE) and women in normal pregnancy. Analyses of single-cell transcriptomes reveal that in LOPE, there are likely a global development deficiency of trophoblasts with impaired invasion of extravillous trophoblasts (EVT) and increased maternal immune rejection and inflammation in the placenta, while there are likely insufficient decidualization of decidual stromal cells (DSC), increased inflammation, and suppressed regulatory functions of decidual immune cells. These findings improve our understanding of the molecular mechanisms of PE.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1142273","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T00:26:55Z","timestamp":1684715215000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Single-cell RNA-seq reveals developmental deficiencies in both the placentation and the decidualization in women with late-onset preeclampsia"],"prefix":"10.3389","volume":"14","author":[{"given":"Jing","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiming","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanqiang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zekun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiongjie","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)02800-2","article-title":"Pre-eclampsia","volume":"356","author":"Walker","year":"2000","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01864","article-title":"Mechanisms of key innate immune cells in early- and late-onset preeclampsia","volume":"11","author":"Aneman","year":"2020","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1055\/s-0035-1557924","article-title":"Diagnosis and treatment of hypertensive pregnancy disorders. guideline of DGGG (S1-level, AWMF registry no. 015\/018, December 2013)","volume":"75","author":"Stepan","year":"2015","journal-title":"Geburtsh Frauenheilk"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.8925","article-title":"Potential protein biomarkers for preeclampsia","volume":"12","author":"He","year":"2020","journal-title":"Cureus"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2020.08.045","article-title":"Prevention of preeclampsia with aspirin","volume":"226","author":"Rolnik","year":"2022","journal-title":"Am J Obstet Gynecol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/0143-4004(91)90339-H","article-title":"Current topic: pre-eclampsia and the placenta","volume":"12","author":"Redman","year":"1991","journal-title":"Placenta"},{"key":"B7","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s11892-015-0579-4","article-title":"Preeclampsia and diabetes","volume":"15","author":"Weissgerber","year":"2015","journal-title":"Curr Diabetes Rep"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jri.2019.07.004","article-title":"The two-stage placental model of preeclampsia: an update","volume":"134","author":"Staff","year":"2019","journal-title":"J Reprod Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1706546114","article-title":"Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology","volume":"114","author":"Garrido-Gomez","year":"2017","journal-title":"P Natl Acad Sci USA"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aau4788","article-title":"A single-cell survey of the human first-trimester placenta and decidua","volume":"4","author":"Suryawanshi","year":"2018","journal-title":"Sci Adv"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0698-6","article-title":"Single-cell reconstruction of the early maternal-fetal interface in humans","volume":"563","author":"Vento-Tormo","year":"2018","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/19336918.2016.1170258","article-title":"Epithelial-mesenchymal transition during extravillous trophoblast differentiation","volume":"10","author":"Davies","year":"2016","journal-title":"Cell Adh Migr"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21114092","article-title":"Endometrial decidualization: the primary driver of pregnancy health","volume":"21","author":"Ng","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B14","article-title":"Cell populations in human early pregnancy decidua: characterization and isolation of large granular lymphocytes by flow cytometry","volume":"65","author":"Starkey","year":"1988","journal-title":"Immunology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02317","article-title":"Dynamic function and composition changes of immune cells during normal and pathological pregnancy at the maternal-fetal interface","volume":"10","author":"Yang","year":"2019","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1016\/j.cell.2019.05.006","article-title":"Single-cell multi-omic integration compares and contrasts features of brain cell identity","volume":"177","author":"Welch","year":"2019","journal-title":"Cell"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2016.01.006","article-title":"What is trophoblast? a combination of criteria define human first-trimester trophoblast","volume":"6","author":"Lee","year":"2016","journal-title":"Stem Cell Rep"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1006\/cimm.1994.1125","article-title":"Resistance of hla-G and hla-A2 transfectants to lysis by decidual nk cells","volume":"155","author":"Chumbley","year":"1994","journal-title":"Cell Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dex058","article-title":"Extravillous trophoblast invasion of venous as well as lymphatic vessels is altered in idiopathic, recurrent, spontaneous abortions","volume":"32","author":"Windsperger","year":"2017","journal-title":"Hum Reprod"},{"key":"B21","first-page":"3","article-title":"The gene encoding the common alpha subunit of the four human glycoprotein hormones","volume":"1","author":"Fiddes","year":"1981","journal-title":"J Mol Appl Genet"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/exd.12601","article-title":"Periostin induces fibroblast proliferation and myofibroblast persistence in hypertrophic scarring","volume":"24","author":"Crawford","year":"2015","journal-title":"Exp Dermatol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3016","DOI":"10.1038\/s41467-018-05274-6","article-title":"A positive feedback loop bi-stably activates fibroblasts","volume":"9","author":"Yeo","year":"2018","journal-title":"Nat Commun"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007826","article-title":"Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition","volume":"14","author":"Nagai","year":"2018","journal-title":"PloS Genet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3953","DOI":"10.1038\/s41467-020-17740-1","article-title":"Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination","volume":"11","author":"Muhl","year":"2020","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/4.5.472","article-title":"Marker genes of decidualization: activation of the decidual prolactin gene","volume":"4","author":"Telgmann","year":"1998","journal-title":"Hum Reprod Update"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1387\/ijdb.072393hl","article-title":"Coexpression of Notch3 and Rgs5 in the pericyte-vascular smooth muscle cell axis in response to pulp injury","volume":"51","author":"Lovschall","year":"2007","journal-title":"Int J Dev Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.133103","article-title":"Discovery of specialized NK cell populations infiltrating human melanoma metastases","author":"de Andrade","year":"2019","journal-title":"JCI Insight"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52004","article-title":"Single cell transcriptional signatures of the human placenta in term and preterm parturition","volume":"8","author":"Pique-Regi","year":"2019","journal-title":"Elife"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.089326","article-title":"ERK1\/2 and p38 regulate trophoblasts differentiation in human term placenta","volume":"566","author":"Daoud","year":"2005","journal-title":"J Physiol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1385\/ENDO:19:1:3","article-title":"Hormones and human trophoblast differentiation: a review","volume":"19","author":"Malassine","year":"2002","journal-title":"Endocrine"},{"key":"B32","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.placenta.2011.06.025","article-title":"Role of nitric oxide in placental vascular development and function","volume":"32","author":"Krause","year":"2011","journal-title":"Placenta"},{"key":"B33","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s13578-019-0284-0","article-title":"MFAP5 promotes basal-like breast cancer progression by activating the EMT program","volume":"9","author":"Wu","year":"2019","journal-title":"Cell Biosci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1023\/A:1025348417078","article-title":"Functions of lumican and fibromodulin: lessons from knockout mice","volume":"19","author":"Chakravarti","year":"2002","journal-title":"Glycoconj J"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-012-2418-z","article-title":"Expression of mesenchymal markers vimentin and fibronectin: the clinical significance in esophageal squamous cell carcinoma","volume":"20","author":"Sudo","year":"2013","journal-title":"Ann Surg Oncol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1080\/10641950701825937","article-title":"Placental growth factor (PlGF) is a surrogate marker in preeclamptic hypertension","volume":"27","author":"Teixeira","year":"2008","journal-title":"Hypertens Pregnancy"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041214","article-title":"Combinations of maternal KIR and fetal HLA-c genes influence the risk of preeclampsia and reproductive success","volume":"200","author":"Hiby","year":"2004","journal-title":"J Exp Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(94)70134-2","article-title":"Expression of the nonclassic histocompatibility antigen HLA-G by preeclamptic placenta","volume":"170","author":"Colbern","year":"1994","journal-title":"Am J Obstet Gynecol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301885","article-title":"Exosomes secreted by human placenta carry functional fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus","volume":"191","author":"Stenqvist","year":"2013","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2003.10.019","article-title":"Macrophage inflammatory protein-1","volume":"36","author":"Maurer","year":"2004","journal-title":"Int J Biochem Cell Biol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btl056","article-title":"maSigPro: a method to identify significantly differential expression profiles in time-course microarray experiments","volume":"22","author":"Conesa","year":"2006","journal-title":"Bioinformatics"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0040378","article-title":"The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion","volume":"7","author":"Fenouille","year":"2012","journal-title":"PloS One"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27344","article-title":"Pre-eclampsia onset and SPARC: a possible involvement in placenta development","volume":"234","author":"Tossetta","year":"2019","journal-title":"J Cell Physiol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-016-0337-1","article-title":"Decidual natural killer cells and the immune microenvironment at the maternal-fetal interface","volume":"59","author":"Fu","year":"2016","journal-title":"Sci China Life Sci"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2020.07.011","article-title":"Tryptophan and kynurenine stimulate human decidualization via activating aryl hydrocarbon receptor: short title: kynurenine action on human decidualization","volume":"96","author":"Wang","year":"2020","journal-title":"Reprod Toxicol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.656629","article-title":"Warburg-like glycolysis and lactate shuttle in mouse decidua during early pregnancy","volume":"290","author":"Zuo","year":"2015","journal-title":"J Biol Chem"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1177\/1933719112472738","article-title":"The mesenchymal-epithelial transition during in vitro decidualization","volume":"20","author":"Zhang","year":"2013","journal-title":"Reprod Sci"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.23799","article-title":"Transcriptional profiling identifies an interferon-associated host immune response in invasive squamous cell carcinoma of the skin","volume":"123","author":"Wenzel","year":"2008","journal-title":"Int J Cancer"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.682461","article-title":"PGK1 is a key target for anti-glycolytic therapy of ovarian cancer: based on the comprehensive analysis of glycolysis-related genes","volume":"11","author":"Gou","year":"2021","journal-title":"Front Oncol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1093\/biolre\/ioz102","article-title":"Glycogen in the uterus and fallopian tubes is an important source of glucose during early pregnancy","volume":"101","author":"Dean","year":"2019","journal-title":"Biol Reprod"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12970","article-title":"Abnormal lymphatic vessel development is associated with decreased decidual regulatory T cells in severe preeclampsia","volume":"80","author":"Jung","year":"2018","journal-title":"Am J Reprod Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.5653\/cerm.2011.38.3.119","article-title":"Role of endometrial immune cells in implantation","volume":"38","author":"Lee","year":"2011","journal-title":"Clin Exp Reprod Med"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0292-x","article-title":"CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes","volume":"15","author":"Efremova","year":"2020","journal-title":"Nat Protoc"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14276","article-title":"CD155 contributes to the mesenchymal phenotype of triple-negative breast cancer","volume":"111","author":"Zheng","year":"2020","journal-title":"Cancer Sci"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049766","article-title":"Hypoxia activated EGFR signaling induces epithelial to mesenchymal transition (EMT)","volume":"7","author":"Misra","year":"2012","journal-title":"PloS One"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2008.08.021","article-title":"Dynamic regulation of alpha-dystroglycan in mouse placenta","volume":"29","author":"Santhanakrishnan","year":"2008","journal-title":"Placenta"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900562","article-title":"Structural and functional basis for LILRB immune checkpoint receptor recognition of HLA-G isoforms","volume":"203","author":"Kuroki","year":"2019","journal-title":"J Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1080","article-title":"ANTXR1, a stem cell-enriched functional biomarker, connects collagen signaling to cancer stem-like cells and metastasis in breast cancer","volume":"73","author":"Chen","year":"2013","journal-title":"Cancer Res"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0072321","article-title":"CCL18 exhibits a regulatory role through inhibition of receptor and glycosaminoglycan binding","volume":"8","author":"Krohn","year":"2013","journal-title":"PloS One"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.726513","article-title":"Preeclampsia: from cellular wellness to inappropriate cell death, and the roles of nutrition","volume":"9","author":"Lokeswara","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2018.04.012","article-title":"Innate immune cells in the placental bed in healthy pregnancy and preeclampsia","volume":"69","author":"Faas","year":"2018","journal-title":"Placenta"},{"key":"B62","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1093\/eurheartj\/ehi015","article-title":"Regional differences in the prevalence of pre-eclampsia in relation to the risk factors for coronary artery disease in women in Finland","volume":"26","author":"Kaaja","year":"2005","journal-title":"Eur Heart J"},{"key":"B63","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s12884-021-03602-1","article-title":"A population-based study of preeclampsia and eclampsia in Ecuador: ethnic, geographical and altitudes differences","volume":"21","author":"Tejera","year":"2021","journal-title":"BMC Pregnancy Childbirth"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1710470114","article-title":"Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics","volume":"114","author":"Tsang","year":"2017","journal-title":"P Natl Acad Sci USA"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1080\/10641955.2020.1754852","article-title":"Decreased placental IL9 and IL9R in preeclampsia impair trophoblast cell proliferation, invasion, and angiogenesis","volume":"39","author":"Sun","year":"2020","journal-title":"Hypertens Pregnancy"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2004.07.003","article-title":"The correlation between sampling site and gene expression in the term human placenta","volume":"26","author":"Wyatt","year":"2005","journal-title":"Placenta"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(99)70259-0","article-title":"Increased contents of phospholipids, cholesterol, and lipid peroxides in decidua basalis in women with preeclampsia","volume":"180","author":"Staff","year":"1999","journal-title":"Am J Obstet Gynecol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096","article-title":"Integrating single-cell transcriptomic data across different conditions, technologies, and species","volume":"36","author":"Butler","year":"2018","journal-title":"Nat Biotechnol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4314","article-title":"Dimensionality reduction for visualizing single-cell data using UMAP","author":"Becht","year":"2018","journal-title":"Nat Biotechnol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an r package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1142273\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T00:27:00Z","timestamp":1684715220000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1142273\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,22]]},"references-count":70,"alternative-id":["10.3389\/fimmu.2023.1142273"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1142273","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,22]]},"article-number":"1142273"}}