Endoglandular Trophoblast Research Articles

Evidence from the very beginning: endoglandular trophoblasts penetrate and replace uterine glands in situ and in vitro.

How is histiotrophic nutrition of the embryo secured during the first trimester of pregnancy? Rather than specifically focusing on invasion into spiral arteries, extravillous trophoblasts also invade into uterine glands (endoglandular trophoblast) from the very beginning and open them toward the intervillous space. Extravillous trophoblasts can be found in close contact and within the lumen of uterine glands, sometimes replacing glandular epithelial cells. As well as extensive screening of specimens from first trimester placentation sites in situ we used a previously established three-dimensional co-culture in vitro model system of first trimester villous explants with non-invaded decidua parietalis. First trimester placentas were obtained from elective terminations of pregnancies (n = 48) at 5-11 weeks of gestational age. A subset was processed for confrontation co-culture (n = 31). Invaded decidua basalis was obtained from 20 placentas. All tissues were sectioned, subsequently immunostained and immunodoublestained with antibodies against keratin 7 (KRT7), major histocompatibility complex, class I, G (HLA-G), matrix metallopeptidase 9 (MMP9), von Willebrand factor (VWF) and the appropriate Immunoglobulin G (IgG) negative controls. Replacement of endothelial/epithelial cells by extravillous trophoblasts was quantified semi-quantitatively. Additionally, hematoxylin and eosin-stained archival specimens from early implantation sites were assessed. The earliest available specimen was from around Day 10 after conception; already at this stage trophoblasts had penetrated into uterine glands and had started to replace the epithelium of the glands. Endoglandular trophoblasts replaced uterine glands in vitro and in situ and could be found in the lumen of invaded glands. Quantitative analysis revealed significantly more replacement of epithelial cells in glands (63.8 ± 22.1%) compared with endothelial cells in vessels (26.4 ± 8.8%). Accumulated detached glandular epithelial cells could be repeatedly observed in the lumen of invaded glands. Additionally, in areas of trophoblast invasion the glandular epithelium seemed to be completely disintegrated compared with glandular epithelium in the non-invaded parts of the decidua. Whole tissue specimens were used in vitro and in situ instead of cell lines; these systems mostly maintain the context of the in vivo situation. This is a descriptive study supported by in vitro experiments. However, a histological section will always only be a snapshot and quantification from histological sections has its limitations. This study further strengthens the hypothesis of histiotrophic nutrition of the embryo prior to the establishment of the maternal blood flow toward the placenta. Invasion of uterine glands by endoglandular trophoblasts may have more impact on the outcome of early pregnancy than assumed up to now.

Endoglandular trophoblasts disintegrate and replace uterine glandular epithelium in vitro and in situ

Endoglandular trophoblasts disintegrate and replace uterine glandular epithelium in vitro and in situ

Trophoblast invasion and oxygenation of the placenta: measurements versus presumptions

Invasion of extravillous trophoblast into maternal tissues has a profound effect on the oxygenation of the placenta and hence the fetus. The main route of trophoblast invasion is interstitial invasion into the tissues of the decidua and myometrium. From this main route side branches reach the spiral arteries (endovascular trophoblast) as well as the uterine glands (endoglandular trophoblast) to open both structures toward the intervillous space. This enables histiotrophic nutrition in the first trimester and hemotrophic nutrition in the second and third trimesters of pregnancy. Failure of endovascular trophoblast invasion has profound effects on the oxygenation of the placenta. Interestingly, this does not lead to hypoxia as has long been presumed. Rather, all measurements available today point to increased oxygen levels within the placenta in patients with a failure of spiral artery transformation. This should lead to a rethink regarding pathological conditions such as intrauterine growth restriction and preeclampsia.

T9.5 Placental homeobox gene TGIF, a potential regulator of trophoblast function, shows increased expression in pre-eclampsia and fetal growth restriction

Extravillous trophoblasts (EVTs) invade the decidual stroma (interstitial trophoblast) and thereby attach the placenta to the uterus. They also invade toward spiral arteries (endovascular trophoblast) for the establishment of the uteroplacental blood flow. The latter does not start before the end of the first trimester of pregnancy. A new type of extravillous trophoblast invading into uterine glands (endoglandular trophoblast) has been described recently opening uterine glands toward the intervillous space of the placenta to enable histiotrophic nutrition. This review gives an overview about the different subtypes of EVTs and presents novel peculiarities in the field of EVT invasion. EVTs invade more structures in the maternal decidua than previously assumed. Especially a proper invasion of uterine glands by endoglandular trophoblasts may have more impact on the outcome of pregnancy than assumed so far.

REVIEW ARTICLE: Governing the Invasive Trophoblast: Current Aspects on Intra‐ and Extracellular Regulation

This review summarizes several aspects especially of regulating factors governing trophoblast invasion. Those include the composition of the extracellular matrix containing a variety of matrix metalloproeinases and their inhibitors, but also intracellular signals. Furthermore, a newly described trophoblast subtype, the endoglandular trophoblast, is presented. Its presence may provide a possible mechanism for opening and connecting uterine glands into the intervillous space. Amongst others, two intracellular signalling pathways are crucial for regulation of trophoblast functions and development: Wnt- and signal transducer and activator of transcription (STAT)3 signalling. Wnt signalling promotes implantation, placentation and trophoblast differentiation. Several Wnt-dependent cascades and regulatory mechanisms display different functions in trophoblast cells. The STAT3 signalling system is fundamental for induction and regulation of invasiveness in physiological trophoblastic cells, but also in tumours. The role of galectins (Gal) in trophoblast regulation and placenta development comes increasingly into focus. The Gal- 1-4, 7-10 and 12-14 have been detected in humans. Detailed information is only available for Gal-1, -2, -3, -4, -9 and -12 in endometrium and decidua. Gal-1, -3 and -13 (-14) have been detected and studied in trophoblast cells.

Endoglandular trophoblast, an alternative route of trophoblast invasion? Analysis with novel confrontation co-culture models

Routes of trophoblast invasion seem to be clear, whereas specific invasive pathways need further elucidation. Extravillous trophoblasts (EVTs) transform spiral arteries to guarantee appropriate blood flow to the placenta in the second trimester. Embryo nutrition during the first trimester is thought to be histiotrophic, whereas proof that EVTs also invade uterine glands is lacking. We developed novel three-dimensional confrontation co-culture models to elucidate invasion of EVTs into uterine glands. First trimester decidua parietalis and placental villous explants were directly confronted and co-cultured for 72 h, or confronted indirectly after 72 h pre-culture for re-epithelialization of decidua pieces. Cryosections were stained by immunohistochemistry or immunofluorescent/immunohistochemical double labelling and compared with first trimester placentation sites in situ. EVTs deeply invaded decidual tissues in direct confrontation assays and were found between the decidual epithelial cells and epithelial basement membrane. EVTs were also detected in the decidual stroma in direct proximity to glands, sometimes even replacing glandular epithelial cells. Similar observations were made in sections from the first trimester decidua/placental bed. In the invaded parts of sections of decidua basalis, 55% +/- 7% (mean +/- SEM; n = 10, range 6-11 weeks) of glandular cross sections were associated with or infiltrated by EVTs. Using novel confrontation co-culture assays, a potential new route of EVT invasion was detected. EVTs appear to break through the basement membrane of uterine glands to open their lumen towards the intervillous space. These data support the hypothesis of histiotrophic nutrition of the embryo prior to onset of maternal blood flow within the placenta.