{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T06:08:08Z","timestamp":1789625288857,"version":"build-2803163510"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T00:00:00Z","timestamp":1648598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007165","name":"University of Missouri","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007165","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Understanding the process of human placentation is important to the development of strategies for treatment of pregnancy complications. Several animal and <jats:italic>in vitro<\/jats:italic> human model systems for the general study human placentation have been used. The field has expanded rapidly over the past decades to include stem cell-derived approaches that mimic preclinical placental development, and these stem cell-based models have allowed us to better address the physiology and pathophysiology of normal and compromised trophoblast (TB) sublineage development. The application of transcriptomic approaches to these models has uncovered limitations that arise when studying the distinctive characteristics of the large and fragile multinucleated syncytiotrophoblast (STB), which plays a key role in fetal-maternal communication during pregnancy. The extension of these technologies to induced pluripotent stem cells (iPSCs) is just now being reported and will allow, for the first time, a reproducible and robust approach to the study of the developmental underpinnings of late-manifesting diseases such as preeclampsia (PE) and intrauterine growth retardation in a manner that is patient- and disease-specific. Here, we will first focus on the application of various RNA-seq technologies to TB, prior limitations in fully accessing the STB transcriptome, and recent leveraging of single nuclei RNA sequencing (snRNA-seq) technology to improve our understanding of the STB transcriptome. Next, we will discuss new stem-cell derived models that allow for disease- and patient-specific study of pregnancy disorders, with a focus on the study of STB developmental abnormalities in PE that combine snRNA-seq approaches and these new <jats:italic>in vitro<\/jats:italic> models.<\/jats:p>","DOI":"10.3389\/fgene.2022.872818","type":"journal-article","created":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T17:03:18Z","timestamp":1648659798000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Leveraging Optimized Transcriptomic and Personalized Stem Cell Technologies to Better Understand Syncytialization Defects in Preeclampsia"],"prefix":"10.3389","volume":"13","author":[{"given":"Sehee","family":"Choi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teka","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Michael","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny J.","family":"Schust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5350","DOI":"10.1073\/pnas.74.12.5350","article-title":"Method for Detection of Specific RNAs in Agarose Gels by Transfer to Diazobenzyloxymethyl-Paper and Hybridization with DNA Probes","volume":"74","author":"Alwine","year":"1977","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e01678","DOI":"10.1128\/mBio.01678-17","article-title":"Human Placental Syncytiotrophoblasts Restrict Toxoplasma Gondii Attachment and Replication and Respond to Infection by Producing Immunomodulatory Chemokines","volume":"9","author":"Ander","year":"2018","journal-title":"MBio"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2653","DOI":"10.1016\/j.celrep.2015.11.036","article-title":"Nuclear Retention of mRNA in Mammalian Tissues","volume":"13","author":"Bahar Halpern","year":"2015","journal-title":"Cell Rep"},{"key":"B4","doi-asserted-by":"publisher","first-page":"774","DOI":"10.2353\/ajpath.2006.060184","article-title":"Carbon Monoxide Inhibits Hypoxia\/reoxygenation-Induced Apoptosis and Secondary Necrosis in Syncytiotrophoblast","volume":"169","author":"Bainbridge","year":"2006","journal-title":"Am. J. Pathol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1002\/jmor.1051960203","article-title":"Trophoblast Concept as Applied to Therian Mammals","volume":"196","author":"Blackburn","year":"1988","journal-title":"J. Morphol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"108419","DOI":"10.1016\/j.celrep.2020.108419","article-title":"Induction of Human Trophoblast Stem Cells from Somatic Cells and Pluripotent Stem Cells","volume":"33","author":"Castel","year":"2020","journal-title":"Cel Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.siny.2004.03.006","article-title":"Developmental Biology of the Placenta and the Origins of Placental Insufficiency","volume":"9","author":"Chaddha","year":"2004","journal-title":"Semin. Fetal Neonatal Med."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52504","article-title":"Derivation of Trophoblast Stem Cells from Na\u00efve Human Pluripotent Stem Cells","volume":"9","author":"Dong","year":"2020","journal-title":"Elife"},{"key":"B9","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1111\/j.1600-0854.2004.00221.x","article-title":"Endocytic and Transcytotic Processes in Villous Syncytiotrophoblast: Role in Nutrient Transport to the Human Fetus","volume":"5","author":"Fuchs","year":"2004","journal-title":"Traffic"},{"key":"B10","doi-asserted-by":"publisher","first-page":"12455","DOI":"10.1038\/s41598-017-12685-w","article-title":"Enhanced HIF2\u03b1 Expression during Human Trophoblast Differentiation into Syncytiotrophoblast Suppresses Transcription of Placental Growth Factor","volume":"7","author":"Fujii","year":"2017","journal-title":"Sci. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e33503","DOI":"10.1371\/journal.pone.0033503","article-title":"Increased Expression and Altered Methylation of HERVWE1 in the Human Placentas of Smaller Fetuses from Monozygotic, Dichorionic, Discordant Twins","volume":"7","author":"Gao","year":"2012","journal-title":"PLoS One"},{"key":"B12","unstructured":"Isolation of Nuclei for Single Cell RNA Sequencing, 2021\n            GenomicsX.\n          2021"},{"key":"B13","doi-asserted-by":"publisher","first-page":"S93","DOI":"10.1016\/j.placenta.2013.10.020","article-title":"Review: the Enigmatic Role of Endoglin in the Placenta","volume":"35","author":"Gregory","year":"2014","journal-title":"Placenta"},{"key":"B14","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.thromres.2004.06.038","article-title":"Growth and Function of the normal Human Placenta","volume":"114","author":"Gude","year":"2004","journal-title":"Thromb. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1016\/j.stem.2021.02.025","article-title":"Human Naive Epiblast Cells Possess Unrestricted Lineage Potential","volume":"28","author":"Guo","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.mce.2009.12.015","article-title":"New Insights into the Regulation of Human Cytotrophoblast Cell Differentiation","volume":"323","author":"Handwerger","year":"2010","journal-title":"Mol. Cell Endocrinol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"516","DOI":"10.3389\/fphys.2014.00516","article-title":"Oxidative Stress in Preeclampsia and the Role of Free Fetal Hemoglobin","volume":"5","author":"Hansson","year":"2014","journal-title":"Front. Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"5877","DOI":"10.1038\/s41598-021-85230-5","article-title":"Modeling Preeclampsia Using Human Induced Pluripotent Stem Cells","volume":"11","author":"Horii","year":"2021","journal-title":"Sci. Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"28","DOI":"10.3389\/fcell.2018.00028","article-title":"Single Cell Multi-Omics Technology: Methodology and Application","volume":"6","author":"Hu","year":"2018","journal-title":"Front. Cel Dev. Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms21010289","article-title":"Traditional and New Routes of Trophoblast Invasion and Their Implications for Pregnancy Diseases","volume":"21","author":"Huppertz","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1016\/j.stem.2021.03.013","article-title":"Capturing Human Trophoblast Development with Naive Pluripotent Stem Cells In Vitro","volume":"28","author":"Io","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.placenta.2020.10.029","article-title":"PlacentaCellEnrich: a Tool to Characterize Gene Sets Using Placenta Cell-specific Gene Enrichment Analysis","volume":"103","author":"Jain","year":"2021","journal-title":"Placenta"},{"key":"B23","doi-asserted-by":"publisher","first-page":"674162","DOI":"10.3389\/fcell.2021.674162","article-title":"Omics Approaches to Study Formation and Function of Human Placental Syncytiotrophoblast","volume":"9","author":"Jaremek","year":"2021","journal-title":"Front Cel Dev Biol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.3389\/fcell.2021.695248","article-title":"Single Nucleus RNA Sequence (snRNAseq) Analysis of the Spectrum of Trophoblast Lineages Generated from Human Pluripotent Stem Cells In Vitro","volume":"9","author":"Khan","year":"2021","journal-title":"Front. Cel Dev. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"679730","DOI":"10.1155\/2015\/679730","article-title":"First-trimester Uterine Artery Doppler Analysis in the Prediction of Later Pregnancy Complications","volume":"2015","author":"Khong","year":"2015","journal-title":"Dis. Markers"},{"key":"B26","doi-asserted-by":"publisher","first-page":"698","DOI":"10.5858\/arpa.2015-0225-cc","article-title":"Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement","volume":"140","author":"Khong","year":"2016","journal-title":"Arch. Pathol. Lab. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1038\/nbt.2052","article-title":"Donor Cell Type Can Influence the Epigenome and Differentiation Potential of Human Induced Pluripotent Stem Cells","volume":"29","author":"Kim","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1002\/mrd.20729","article-title":"Impaired Cytotrophoblast Cell-Cell Fusion Is Associated with Reduced Syncytin and Increased Apoptosis in Patients with Placental Dysfunction","volume":"75","author":"Langbein","year":"2008","journal-title":"Mol. Reprod. Dev."},{"key":"B29","doi-asserted-by":"publisher","first-page":"257","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 Cel. Rep."},{"key":"B30","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1056\/nejmoa055352","article-title":"Soluble Endoglin and Other Circulating Antiangiogenic Factors in Preeclampsia","volume":"355","author":"Levine","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1056\/nejmoa031884","article-title":"Circulating Angiogenic Factors and the Risk of Preeclampsia","volume":"350","author":"Levine","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"R155","DOI":"10.1530\/rep-20-0231","article-title":"Single Cell Transcriptome Research in Human Placenta","volume":"160","author":"Li","year":"2020","journal-title":"Reproduction"},{"key":"B33","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1186\/s13287-019-1339-1","article-title":"Establishment of Human Trophoblast Stem Cells from Human Induced Pluripotent Stem Cell-Derived Cystic Cells under Micromesh Culture","volume":"10","author":"Li","year":"2019","journal-title":"Stem Cel Res Ther"},{"key":"B34","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41586-020-2734-6","article-title":"Reprogramming Roadmap Reveals Route to Human Induced Trophoblast Stem Cells","volume":"586","author":"Liu","year":"2020","journal-title":"Nature"},{"key":"B35","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1038\/s41422-018-0066-y","article-title":"Single-cell RNA-Seq Reveals the Diversity of Trophoblast Subtypes and Patterns of Differentiation in the Human Placenta","volume":"28","author":"Liu","year":"2018","journal-title":"Cell Res"},{"key":"B36","doi-asserted-by":"publisher","first-page":"305","DOI":"10.2350\/09-08-0692-oa.1","article-title":"Syncytial Knots as a Reflection of Placental Maturity: Reference Values for 20 to 40 Weeks' Gestational Age","volume":"13","author":"Loukeris","year":"2010","journal-title":"Pediatr. Dev. Pathol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1073\/pnas.1121003109","article-title":"Direct Conversion of Mouse Fibroblasts to Self-Renewing, Tripotent Neural Precursor Cells","volume":"109","author":"Lujan","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3202","DOI":"10.4049\/jimmunol.0902118","article-title":"Chemokine Scavenger D6 Is Expressed by Trophoblasts and Aids the Survival of Mouse Embryos Transferred into Allogeneic Recipients","volume":"184","author":"Madigan","year":"2010","journal-title":"J.I."},{"key":"B39","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/nature25501","article-title":"TGF\u03b2 Attenuates Tumour Response to PD-L1 Blockade by Contributing to Exclusion of T Cells","volume":"554","author":"Mariathasan","year":"2018","journal-title":"Nature"},{"key":"B40","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.steroids.2015.09.006","article-title":"Multiple Functions of Syncytiotrophoblast Mitochondria","volume":"103","author":"Martinez","year":"2015","journal-title":"Steroids"},{"key":"B41","doi-asserted-by":"publisher","first-page":"100386","DOI":"10.1016\/j.jbc.2021.100386","article-title":"Two Distinct Trophectoderm Lineage Stem Cells from Human Pluripotent Stem Cells","volume":"296","author":"Mischler","year":"2021","journal-title":"J. Biol. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/s0140-6736(15)00070-7","article-title":"Pre-eclampsia","volume":"387","author":"Mol","year":"2016","journal-title":"The Lancet"},{"key":"B43","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1146\/annurev-genom-082908-145957","article-title":"Applications of New Sequencing Technologies for Transcriptome Analysis","volume":"10","author":"Morozova","year":"2009","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"B44","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/s00418-016-1509-5","article-title":"Extravillous Trophoblasts Invade More Than Uterine Arteries: Evidence for the Invasion of Uterine Veins","volume":"147","author":"Moser","year":"2017","journal-title":"Histochem. Cel Biol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.copbio.2012.09.004","article-title":"Transcriptome Analysis Using Next-Generation Sequencing","volume":"24","author":"Mutz","year":"2013","journal-title":"Curr. Opin. Biotechnol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"Unit 4.11. 13","DOI":"10.1002\/0471142727.mb0411s89","article-title":"RNA-seq: a Method for Comprehensive Transcriptome Analysis","author":"Nagalakshmi","year":"2010","journal-title":"Curr. Protoc. Mol. Biol."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19040930","article-title":"Induced Tissue-specific Stem Cells and Epigenetic Memory in Induced Pluripotent Stem Cells","volume":"19","author":"Noguchi","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/s0076-6879(06)19015-1","article-title":"Trophoblast Stem Cells","volume":"419","author":"Oda","year":"2006","journal-title":"Methods Enzymol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1515\/jpm.2011.098","article-title":"Placental Lesions Associated with Maternal Underperfusion Are More Frequent in Early-Onset Than in Late-Onset Preeclampsia","volume":"39","author":"Ogge","year":"2011","journal-title":"J. Perinat Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.stem.2017.11.004","article-title":"Derivation of Human Trophoblast Stem Cells","volume":"22","author":"Okae","year":"2018","journal-title":"Cell Stem Cell"},{"key":"B51","doi-asserted-by":"publisher","first-page":"440","DOI":"10.3389\/fgene.2018.00440","article-title":"Sequence Determinants for Nuclear Retention and Cytoplasmic Export of mRNAs and lncRNAs","volume":"9","author":"Palazzo","year":"2018","journal-title":"Front. Genet."},{"key":"B52","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1101\/gr.207597.116","article-title":"Single-cell Transcriptomics of the Human Placenta: Inferring the Cell Communication Network of the Maternal-Fetal Interface","volume":"27","author":"Pavli\u010dev","year":"2017","journal-title":"Genome Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1242\/dmm.008516","article-title":"Preeclampsia: Multiple Approaches for a Multifactorial Disease","volume":"5","author":"Pennington","year":"2012","journal-title":"Dis. Model. Mech."},{"key":"B54","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1038\/s41581-019-0156-1","article-title":"Author Correction: Pre-eclampsia: Pathogenesis, Novel Diagnostics and Therapies","volume":"15","author":"Phipps","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.preghy.2010.10.010","article-title":"Endovascular Trophoblast and Preeclampsia: A Reassessment","volume":"1","author":"Pijnenborg","year":"2011","journal-title":"Pregnancy Hypertens. Int. J. Women's Cardiovasc. Health"},{"key":"B56","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":"B57","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1093\/molehr\/gau102","article-title":"Trophoblast Syncytialisation Necessitates Mitochondrial Function through Estrogen-Related Receptor- Activation","volume":"21","author":"Poidatz","year":"2015","journal-title":"Mol. Hum. Reprod."},{"key":"B58","doi-asserted-by":"publisher","first-page":"2597","DOI":"10.3389\/fimmu.2018.02597","article-title":"Regulation of Placental Extravillous Trophoblasts by the Maternal Uterine Environment","volume":"9","author":"Pollheimer","year":"2018","journal-title":"Front. Immunol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"S1019","DOI":"10.1016\/j.ajog.2020.10.022","article-title":"Imbalances in Circulating Angiogenic Factors in the Pathophysiology of Preeclampsia and Related Disorders","volume":"226","author":"Rana","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1210\/edrv-11-1-105","article-title":"In VitroSystems for the Study of Human Placental Endocrine Function*","volume":"11","author":"Ringler","year":"1990","journal-title":"Endocr. Rev."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1161\/01.hyp.0000188408.49896.c5","article-title":"Preeclampsia","volume":"46","author":"Roberts","year":"2005","journal-title":"Hypertension"},{"key":"B62","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.placenta.2017.07.012","article-title":"Global Pregnancy Collaboration Symposium: Prepregnancy and Very Early Pregnancy Antecedents of Adverse Pregnancy Outcomes: Overview and Recommendations","volume":"60","author":"Roberts","year":"2017","journal-title":"Placenta"},{"key":"B63","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1093\/biolre\/ioy070","article-title":"Specification of Trophoblast from Embryonic Stem Cells Exposed to BMP4\u2020","volume":"99","author":"Roberts","year":"2018","journal-title":"Biol. Reprod."},{"key":"B64","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1095\/biolreprod.110.088724","article-title":"Trophoblast Stem Cells1","volume":"84","author":"Roberts","year":"2011","journal-title":"Biol. Reprod."},{"key":"B65","doi-asserted-by":"publisher","first-page":"2775","DOI":"10.1172\/jci70431","article-title":"Preeclampsia: a Link between Trophoblast Dysregulation and an Antiangiogenic State","volume":"123","author":"Romero","year":"2013","journal-title":"J. Clin. Invest."},{"key":"B66","doi-asserted-by":"publisher","first-page":"e56145","DOI":"10.1371\/journal.pone.0056145","article-title":"Reduced Syncytin-1 Expression Levels in Placental Syndromes Correlates with Epigenetic Hypermethylation of the ERVW-1 Promoter Region","volume":"8","author":"Ruebner","year":"2013","journal-title":"PLoS One"},{"key":"B67","doi-asserted-by":"publisher","first-page":"108255","DOI":"10.1016\/j.abb.2020.108255","article-title":"Oxidative Stress in Pregnancy Complicated by Preeclampsia","volume":"681","author":"San Juan-Reyes","year":"2020","journal-title":"Arch. Biochem. Biophys."},{"key":"B68","doi-asserted-by":"publisher","first-page":"e323","DOI":"10.1016\/s2214-109x(14)70227-x","article-title":"Global Causes of Maternal Death: a WHO Systematic Analysis","volume":"2","author":"Say","year":"2014","journal-title":"Lancet Glob. Health"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1242\/dev.199840","article-title":"Cell Trajectory Modeling Identifies a Primitive Trophoblast State Defined by BCAM Enrichment","volume":"149","author":"Shannon","year":"2022","journal-title":"Development"},{"key":"B70","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1038\/mt.2012.207","article-title":"Induced Pluripotent Mesenchymal Stromal Cell Clones Retain Donor-Derived Differences in DNA Methylation Profiles","volume":"21","author":"Shao","year":"2013","journal-title":"Mol. Ther."},{"key":"B71","doi-asserted-by":"publisher","first-page":"4336","DOI":"10.1073\/pnas.1816150116","article-title":"Early Onset Preeclampsia in a Model for Human Placental Trophoblast","volume":"116","author":"Sheridan","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B72","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1242\/dev.199749","article-title":"Characterization of Primary Models of Human Trophoblast","volume":"148","author":"Sheridan","year":"2021","journal-title":"Development"},{"key":"B73","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/s0140-6736(10)60279-6","article-title":"Pre-eclampsia","volume":"376","author":"Steegers","year":"2010","journal-title":"The Lancet"},{"key":"B74","doi-asserted-by":"publisher","first-page":"1888","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":"B75","doi-asserted-by":"publisher","first-page":"eaau4788","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":"B76","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"B77","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1016\/s0002-9378(40)90458-6","article-title":"The Placenta in Toxemia of Pregnancy","volume":"39","author":"Tenney","year":"1940","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"E7786","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":"Proc. Natl. Acad. Sci. U S A."},{"key":"B79","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1161\/hypertensionaha.108.117358","article-title":"Early and Late Preeclampsia","volume":"52","author":"Valensise","year":"2008","journal-title":"Hypertension"},{"key":"B80","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1177\/1933719111404608","article-title":"Reduced Expression of Both Syncytin 1 and Syncytin 2 Correlates with Severity of Preeclampsia","volume":"18","author":"Vargas","year":"2011","journal-title":"Reprod. Sci."},{"key":"B81","doi-asserted-by":"publisher","first-page":"347","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":"B82","doi-asserted-by":"publisher","first-page":"2298","DOI":"10.3892\/etm.2019.7178","article-title":"Crosstalk Analysis of Dysregulated Pathways in Preeclampsia","volume":"17","author":"Wang","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"B83","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nrg2484","article-title":"RNA-seq: a Revolutionary Tool for Transcriptomics","volume":"10","author":"Wang","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"B84","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciadv.abf4416","article-title":"Efficient Derivation of Human Trophoblast Stem Cells from Primed Pluripotent Stem Cells","volume":"7","author":"Wei","year":"2021","journal-title":"Sci. Adv."},{"key":"B85","doi-asserted-by":"publisher","first-page":"1208","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":"B86","doi-asserted-by":"publisher","first-page":"E2598","DOI":"10.1073\/pnas.1601630113","article-title":"Comparison of Syncytiotrophoblast Generated from Human Embryonic Stem Cells and from Term Placentas","volume":"113","author":"Yabe","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B87","doi-asserted-by":"publisher","first-page":"e103110","DOI":"10.1371\/journal.pone.0103110","article-title":"Abnormal Oxidative Stress Responses in Fibroblasts from Preeclampsia Infants","volume":"9","author":"Yang","year":"2014","journal-title":"PLoS One"},{"key":"B88","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1093\/humupd\/dmaa028","article-title":"Current Approaches and Developments in Transcript Profiling of the Human Placenta","volume":"26","author":"Yong","year":"2020","journal-title":"Hum. Reprod. Update"},{"key":"B89","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1093\/biolre\/ioab080","article-title":"Modeling Human Peri-Implantation Placental Development and Function","volume":"105","author":"Zhou","year":"2021","journal-title":"Biol. Reprod."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.2174\/13816128113199990541","article-title":"Decreased Expression and Altered Methylation of Syncytin-1 Gene in Human Placentas Associated with Preeclampsia","volume":"20","author":"Zhuang","year":"2014","journal-title":"Cpd"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.872818\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T17:03:23Z","timestamp":1648659803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.872818\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,30]]},"references-count":90,"alternative-id":["10.3389\/fgene.2022.872818"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.872818","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,30]]},"article-number":"872818"}}