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Abstract
A contributing factor to poor placental perfusion, leading to intrauterine growth restriction and preeclampsia, is the failure of invading extravillous trophoblast (EVT) cells to remodel the maternal uterine arteries during the first and second trimesters of pregnancy. Noninvasive assessment of EVT cells in ongoing pregnancies is possible beginning three weeks after conception, using trophoblast retrieval and isolation from the cervix (TRIC). Seven proteins were semi-quantified by immunofluorescence microscopy in EVT cells obtained between gestational weeks 6 and 20 from pregnancies with normal outcomes (N = 29) and those with intrauterine growth restriction or preeclampsia (N = 12). Significant differences were measured in expression of PAPPA, FLT1, ENG, AFP, PGF, and LGALS14, but not LGALS13 or the lineage marker KRT7. These findings provide for the first time direct evidence of pathology-associated protein dysregulation in EVT cells during early placentation. The TRIC platform provides a novel approach to acquire molecular signatures of EVT cells that can be correlated with pregnancy outcome.
Highlights
Histological examination of placentas delivered by women with severe PE and IUGR suggests a prior disruption of extravillous trophoblast (EVT) function in the first trimester that predisposes to uteroplacental insufficiency, characterized by reduced EVT invasion, inadequate remodeling of the spiral arteries, deferred elimination of endovascular trophoblastic plugs, and elevated EVT cell death[4,5,6,7,8,9]
Molecular characterization showed that the isolated cells have an EVT phenotype, based on expression of three trophoblast-specific proteins, β-subunit of human chorionic gonadotropin, placental lactogen (CSH1), and cytokeratin 7 (KRT7); as well as five EVT-specific proteins, human leukocyte antigen G (HLA-G), VE-cadherin (CDH5), platelet endothelial cell adhesion molecule 1 (PECAM1), integrin-α1 (ITGA1) and matrix metalloproteinase 9 (MMP9); and the absence of three proteins exclusive to villous trophoblast, pregnancy specific beta-1-glycoprotein 1 (PSG1), integrin-α6 (ITGA6) and cadherin 1 (CDH1)[24]
When protein expression patterns were compared in EVT cells obtained by TRIC from pregnancies that ended in a miscarriage with gestational age-matched control pregnancies, significant differences were found[25], suggesting that EVT cells in the cervix reflect the physiological status of the pregnancy
Summary
Histological examination of placentas delivered by women with severe PE and IUGR suggests a prior disruption of EVT function in the first trimester that predisposes to uteroplacental insufficiency, characterized by reduced EVT invasion, inadequate remodeling of the spiral arteries, deferred elimination of endovascular trophoblastic plugs, and elevated EVT cell death[4,5,6,7,8,9]. Following this landmark finding, multiple investigators have isolated trophoblast cells from the cervix of pregnant patients with varying degrees of success, ranging between 23–97%, depending on collections method, status of pregnancy, and gestational age[13]. Successful methods to obtain trophoblast cells during ongoing pregnancies include the antenatal cell extractor, cervical aspiration, endocervical canal lavage, intrauterine lavage, and transcervical smears with a cytobrush[13]. Diseases linked to uteroplacental insufficiency share a similar trophoblast pathophysiology that generates abnormal placentation[9] Expression of these seven proteins was evaluated in EVT cells obtained by TRIC prior to 20 weeks of gestational age to determine whether their levels are altered in women who later develop IUGR or PE
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