{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:37:59Z","timestamp":1790242679068,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,31]],"date-time":"2019-12-31T00:00:00Z","timestamp":1577750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Historically, invasion of placental trophoblasts was thought to be extremely specific, only invading into the connective tissues of the maternal uterus and finally reaching and transforming the uterine spiral arteries. Only recently, identification of new routes of trophoblast invasion into different structures of the maternal uterus has been achieved. Thorough morphological analysis has resulted in the identification of trophoblasts invading into glands, veins, and lymph vessels of the uterine wall. These new routes pave the way for a re-evaluation of trophoblast invasion during normal placental development. Of course, such new routes of trophoblast invasion may well be altered, especially in pregnancy pathologies such as intra-uterine growth restriction, preeclampsia, early and recurrent pregnancy loss, stillbirth, and spontaneous abortion. Maybe one or more of these pregnancy pathologies show alterations in different pathways of trophoblast invasion, and, thus, etiologies may need to be redefined, and new therapies may be developed.<\/jats:p>","DOI":"10.3390\/ijms21010289","type":"journal-article","created":{"date-parts":[[2020,1,3]],"date-time":"2020-01-03T04:43:03Z","timestamp":1578026583000},"page":"289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":128,"title":["Traditional and New Routes of Trophoblast Invasion and Their Implications for Pregnancy Diseases"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4814-2158","authenticated-orcid":false,"given":"Berthold","family":"Huppertz","sequence":"first","affiliation":[{"name":"Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Benirschke, K., Burton, G.J., and Baergen, R.N. (2012). Nonvillous Parts and Trophoblast Invasion. Pathology of the Human Placenta, Springer. [6th ed.].","DOI":"10.1007\/978-3-642-23941-0"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1053\/plac.2002.0946","article-title":"Pre-eclampsia and maternal anaemia display reduced apoptosis and opposite invasive phenotypes of extravillous trophoblast","volume":"24","author":"Kadyrov","year":"2003","journal-title":"Placenta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1034\/j.1399-0039.2003.00085.x","article-title":"Evidence of a limited contribution of feto-maternal interactions to trophoblast differentiation along the invasive pathway","volume":"62","author":"Goffin","year":"2003","journal-title":"Tissue Antigens"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.placenta.2010.04.003","article-title":"Matrix metalloproteinase 1 in pre-eclampsia and fetal growth restriction: Reduced gene expression in decidual tissue and protein expression in extravillous trophoblasts","volume":"31","author":"Lian","year":"2010","journal-title":"Placenta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1093\/humrep\/deq035","article-title":"Endoglandular trophoblast, an alternative route of trophoblast invasion? Analysis with novel confrontation co-culture models","volume":"25","author":"Moser","year":"2010","journal-title":"Hum. Reprod."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.placenta.2010.11.008","article-title":"The art of identification of extravillous trophoblast","volume":"32","author":"Moser","year":"2011","journal-title":"Placenta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.it.2008.02.012","article-title":"A critical look at HLA-G","volume":"29","author":"Apps","year":"2008","journal-title":"Trends Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3771","DOI":"10.4049\/jimmunol.154.8.3771","article-title":"Human placental HLA-G expression is restricted to differentiated cytotrophoblasts","volume":"154","author":"McMaster","year":"1995","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1089\/thy.1999.9.643","article-title":"The immunology of pregnancy","volume":"9","author":"Weetman","year":"1999","journal-title":"Thyroid"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.placenta.2007.12.004","article-title":"A caution on the use of HLA-G isoforms as markers of extravillous trophoblasts","volume":"29","author":"James","year":"2008","journal-title":"Placenta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"771","DOI":"10.2174\/1389201019666180427110547","article-title":"The critical role of abnormal trophoblast development in the etiology of preeclampsia","volume":"19","author":"Huppertz","year":"2018","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1161\/HYPERTENSIONAHA.107.107607","article-title":"Placental origins of preeclampsia: Challenging the current hypothesis","volume":"51","author":"Huppertz","year":"2008","journal-title":"Hypertension"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1080\/14737159.2018.1546579","article-title":"An updated view on the origin and use of angiogenic biomarkers for preeclampsia","volume":"18","author":"Huppertz","year":"2018","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_14","unstructured":"Hunter, W. (1774). Anatomia uteri humani gravidi tabulis illustrata [The Anatomy of the Human Gravid Uterus Exhibited in Figures], John Baskerville."},{"key":"ref_15","unstructured":"Grosser, O. (1927). Fr\u00fchentwicklung, Eihautbildung und Placentation des Menschen und der S\u00e4ugetiere, J.F. Bergmann."},{"key":"ref_16","first-page":"59e70","article-title":"Comparison of uteroplacental vasculature and circulation in the rhesus monkey and man","volume":"38","author":"Ramsey","year":"1966","journal-title":"Contrib. Embryol. Carnegie Inst. Wash."},{"key":"ref_17","first-page":"43e58","article-title":"The morphology of human uteroplacental vasculature","volume":"38","author":"Harris","year":"1966","journal-title":"Contrib. Embryol. Carnegie Inst. Wash."},{"key":"ref_18","first-page":"595","article-title":"Cells in the spiral arteries of the pregnant uterus","volume":"90","author":"Boyd","year":"1956","journal-title":"J. Anat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1038\/212906a0","article-title":"Trophoblast in human utero-placental arteries","volume":"212","author":"Hamilton","year":"1966","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/path.1700930219","article-title":"The pathological response of the vessels of the placental bed to hypertensive pregnancy","volume":"93","author":"Robertson","year":"1967","journal-title":"J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.placenta.2017.02.007","article-title":"Implantation and extravillous trophoblast invasion: From rare archival specimens to modern biobanking","volume":"56","author":"Moser","year":"2017","journal-title":"Placenta"},{"key":"ref_22","unstructured":"Enders, A. (2019, October 25). Available online: https:\/\/www.trophoblast.cam.ac.uk\/Resources\/enders."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.1210\/jcem.87.6.8563","article-title":"Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy","volume":"87","author":"Burton","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"He, N., van Iperen, L., de Jong, D., Szuhai, K., Helmerhorst, F.M., van der Westerlaken, L.A.J., and Chuva de Sousa Lopes, S.M. (2017). Human extravillous trophoblasts penetrate decidual veins and lymphatics before remodeling spiral arteries during early pregnancy. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169849"},{"key":"ref_25","doi-asserted-by":"crossref","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. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","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":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod.102.014977","article-title":"Endovascular trophoblast invasion: Implications for the pathogenesis of intrauterine growth retardation and preeclampsia","volume":"69","author":"Kaufmann","year":"2003","journal-title":"Biol. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s00418-016-1474-z","article-title":"The trophoblast plug during early pregnancy: A deeper insight","volume":"146","author":"Weiss","year":"2016","journal-title":"Histochem. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1016\/S0002-9440(10)64849-3","article-title":"Onset of maternal arterial blood flow and placental oxidative stress","volume":"157","author":"Jauniaux","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s00418-018-1699-0","article-title":"Human trophoblast invasion: New and unexpected routes and functions","volume":"150","author":"Moser","year":"2018","journal-title":"Histochem. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.placenta.2004.11.005","article-title":"The current molecular phylogeny of Eutherian mammals challenges previous interpretations of placental evolution","volume":"26","author":"Vogel","year":"2005","journal-title":"Placenta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1093\/humrep\/dev266","article-title":"Evidence from the very beginning: Endoglandular trophoblasts penetrate and replace uterine glands in situ and in vitro","volume":"30","author":"Moser","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1093\/humupd\/dmy008","article-title":"Trophoblast retrieval and isolation from the cervix: Origins of cervical trophoblasts and their potential value for risk assessment of ongoing pregnancies","volume":"24","author":"Moser","year":"2018","journal-title":"Hum. Reprod. Update"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.placenta.2009.02.009","article-title":"Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy","volume":"30","author":"Burton","year":"2009","journal-title":"Placenta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1002\/path.1926","article-title":"Early embryonic demise: No evidence of abnormal spiral artery transformation or trophoblast invasion","volume":"208","author":"Ball","year":"2006","journal-title":"J. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1111\/j.1471-0528.1990.tb02468.x","article-title":"A morphological and immunological study of human placental bed biopsies in miscarriage","volume":"97","author":"Michel","year":"1990","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1093\/humrep\/17.4.1067","article-title":"Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure","volume":"17","author":"Sebire","year":"2002","journal-title":"Hum. Reprod."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1093\/humrep\/den348","article-title":"Uterine natural killer cells and angiogenesis in recurrent reproductive failure","volume":"24","author":"Quenby","year":"2009","journal-title":"Hum. Reprod."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/nmeth.4407","article-title":"Massively parallel single-nucleus RNA-seq with DroNc-seq","volume":"14","author":"Habib","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1126\/science.aam8940","article-title":"Comprehensive single-cell transcriptional profiling of a multicellular organism","volume":"357","author":"Cao","year":"2017","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","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":"ref_42","doi-asserted-by":"crossref","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":"ref_43","doi-asserted-by":"crossref","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":"Efremova","year":"2018","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Mezger, A., \u00d6hrmalm, C., Herthnek, D., Blomberg, J., and Nilsson, M. (2014). Detection of rotavirus using padlock probes and rolling circle amplification. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111874"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s00418-017-1557-5","article-title":"Visualization of tumor heterogeneity by in situ padlock probe technology in colorectal cancer","volume":"148","author":"Kashofer","year":"2017","journal-title":"Histochem. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/labinvest.2015.159","article-title":"TNF-\u03b1 alters the inflammatory secretion profile of human first trimester placenta","volume":"96","author":"Siwetz","year":"2016","journal-title":"Lab. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.placenta.2017.10.003","article-title":"Modelling the effect of intervillous flow on solute transfer based on 3D imaging of the human placental microstructure","volume":"60","author":"Perazzolo","year":"2017","journal-title":"Placenta"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/1\/289\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:47:20Z","timestamp":1760190440000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/1\/289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,31]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["ijms21010289"],"URL":"https:\/\/doi.org\/10.3390\/ijms21010289","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,31]]}}}