Epigenetic regulation of the placental HSD11B2 barrier and its role as a critical regulator of fetal development

“Fetal programming” is a term used to describe how early-life experience influences fetal development and later disease risk. In humans, prenatal stress-induced fetal programming is associated with increased risk of preterm birth, and a heightened risk of metabolic and neurological diseases later in life. A critical determinant of this is the regulation of fetal exposure to glucocorticoids by the placenta. Glucocorticoids are the mediators through which maternal stress influences fetal development. Excessive fetal glucocorticoid exposure during pregnancy results in low birth weight and abnormalities in a number of tissues. The amount of fetal exposure to maternal glucocorticoids depends on the expression of HSD11B2, an enzyme predominantly produced by the syncytiotrophoblast in the placenta. This protects the fetus by converting active glucocorticoids into inactive forms. In this review we examine recent findings regarding placental HSD11B2 that suggest that its epigenetic regulation may mechanistically link maternal stress and long-term health consequences in affected offspring.     

Conservation of placentation during the tertiary radiation of mammals in South America

The eutherian placenta is considered to possess great plasticity, but it is not clear how this variation reflects adaptation to different ecological niches. Because South America was isolated for most of the Tertiary, it represents a natural laboratory to examine this question. We here describe placentation in three South American groups: Xenarthra have been part of the fauna from at least the mid‐Paleocene whereas caviomorph rodents and Neotropical primates are each derived from a single founder that reached South America in the Eocene and Oligocene, respectively. The common ancestor of Xenarthra had a villous, haemochorial placenta, from which the labyrinthine, endotheliochorial placenta of sloths later evolved. Placentation in Caviomorpha follows an extraordinary stable pattern, characterized by a haemomonochorial, labyrinthine and highly lobed structure with specialized growing areas. This pattern was present before arrival of these rodents in South America and enabled a successful radiation especially during the spread of grasslands. Neotropical primates have haemochorial, trabecular placentas with a specialized maternal blood supply; a pattern that contrasts with that of Old World monkeys and may have been present in the founder generation on arrival in South America. In conclusion, there is a dichotomy within Xenarthra but otherwise the ancient South American mammals do not show much variation in principal placental characters. Thus, the successful radiation of these three groups, and their adaptation to diverse ecological niches, did not require substantial alterations in placentation. J. Morphol., 2013. © 2013 Wiley Periodicals, Inc.     

Isolation of inhibin like peptides from human placenta

Two moieties of inhibin could be obtained by chromatography of partially purified preparations of inhibin from human placenta on Sephadex G-100, G-25 and ion exchange chromatography on diethylaminoethyl Sephadex A-50. The higher molecular weight moiety (14,000) designated as HPI-H appears to be similar to inhibin from human seminal plasma. While the lower molecular weight moiety (1500) designated as HPI-L appears to be similar to that of sheep testicular inhibin. The preparations from both human term placenta and human seminal plasma inhibited the binding of [¹²⁵I] human follicle stimulating hormone to rat testicular receptors. This effect of inhibins could be neutralized by antisera raised against corresponding polypeptide. Further these antibodies could neutralize endogenous inhibin resulting in 2 to 3 fold increase in serum follicle stimulating harmone levels, which could then be reversed by exogenous administration of the isolated inhibin preparations.     

Experimental models of maternal–fetal interface and their potential use for nanotechnology applications

During pregnancy, the placenta regulates the transfer of oxygen, nutrients, and residual products between the maternal and fetal bloodstreams and is a key determinant of fetal exposure to xenobiotics from the mother. To study the disposition of substances through the placenta, various experimental models are used, especially the perfused placenta, placental villi explants, and cell lineage models. In this context, nanotechnology, an area of study that is on the rise, enables the creation of particles on nanometric scales capable of releasing drugs aimed at specific tissues. An important reason for furthering the studies on transplacental transfer is to explore the potential of nanoparticles (NPs), in new delivery strategies for drugs that are specifically aimed at the mother, the placenta, or the fetus and that involve less toxicity. Due to the fact that the placental barrier is essential for the interaction between the maternal and fetal organisms as well as the possibility of NPs being used in the treatment of various pathologies, the aim of this review is to present the main experimental models used in studying the maternal–fetal interaction and the action of NPs in the placental environment.     

Porcine placental immunoexpression of vascular endothelial growth factor,placenta growth factor,Flt-1 and Flk-1

Porcine embryo mortalities cause economic losses. Development of the placental vascular bed is required for successful gestation and postnatal survival. We studied the temporal and spatial distributions of vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and their receptors, Flt-1 and Flk-1. We used crossbred swine placental tissues from 30, 60, 80, 90 and 114 (term) days of gestation. Both VEGF and PlGF were present during gestation. At early pregnancy and at term, VEGF probably acts through Flt-1; during intermediate periods, its function is mediated by Flk-1. By day 90, factors other than members of VEGF family appear to be involved.     

Assessment of the total effective xenoestrogen burden in extracts of human placentas

We have standardized a method to assess the total effective xenoestrogen burden (TEXB) in human placentas by the extraction and separation by high-performance liquid chromatography of two fractions containing lipophilic xenoestrogens (alpha) and endogenous hormones (beta), followed by assessing their estrogenicity in MCF-7 breast cancer cell-based E-Screen and Yeast Estrogen Screen (YES) bioassays. The means of TEXB alpha concentrations (in estradiol equivalent (Eeq) units) were 1.32 and 0.77 Eeq pM g^?1 placenta in the E-Screen and YES, respectively; TEXB beta concentrations were 6.97 and 11.56 Eeq pM g^?1 placenta, respectively. The interclass correlation coefficient was low and a fair level of agreement was observed after kappa test correction. According to the E-Screen and YES, TEXB alpha was ≥LOD in 70.0 and 55.0% of the placentas and 92.5 and 82.5% in beta, respectively. Although both bioassays can be recommended for assessing TEXB, there is greater experience with the use of the E-Screen for estrogenic assessment after extensive extraction of complex human matrices.     

Fetal mesenchymal stromal cells from cryopreserved human chorionic villi: cytogenetic and molecular analysis of genome stability in long-term cultures

Background aimsFirst-trimester chorionic villi (CV) are an attractive source of human mesenchymal stromal cells (hMSC) for possible applications in cellular therapy and regenerative medicine. Human MSC from CV were monitored for genetic stability in long-term cultures.MethodsWe set up a good manufacturing practice cryopreservation procedure for small amounts of native CV samples. After isolation, hMSC were in vitro cultured and analyzed for biological end points. Genome stability at different passages of expansion was explored by karyotype, genome-wide array-comparative genomic hybridization and microsatellite genotyping.ResultsGrowth curve analysis revealed a high proliferative potential of CV-derived cells. Immunophenotyping showed expression of typical MSC markers and absence of hematopoietic markers. Analysis of multilineage potential demonstrated efficient differentiation into adipocytes, osteocytes, chondrocytes and induction of neuro-glial commitment. In angiogenic experiments, differentiation in endothelial cells was detected by in vitro Matrigel assay after vascular endothelial growth factor stimulation. Data obtained from karyotyping, array-comparative genomic hybridization and microsatellite genotyping comparing early with late DNA passages did not show any genomic variation at least up to passage 10. Aneuploid clones appeared in four of 14 cases at latest passages, immediately before culture growth arrest.ConclusionsOur findings indicate that hCV-MSC are genetically stable in long-term cultures at least up to passage 10 and that it is possible to achieve clinically relevant amounts of hCV-MSC even after few stages of expansion. Genome abnormalities at higher passages can occasionally occur and are always associated with spontaneous growth arrest. Under these circumstances, hCV-MSC could be suitable for therapeutic purposes.     

The prion protein family

Although the pivotal implication of the host-encoded Prion protein, PrP, in the neuropathology of transmissible spongiform encephalopathy is known for decades, its biological role remains mostly elusive. Genetic inactivation is one way to assess such issue but, so far, PrP-knockout mice did not help much. However, recent reports involving (1) further studies of these mice during embryogenesis, (2) knockdown experiments in Zebrafish and (3) knockdown of Shadoo, a protein with PrP-like functional domains, in PrP-knockout mice, all suggested a role of the Prion protein family in early embryogenesis. This view is challenged by the recent report that PrP/Shadoo knockout mice are healthy and fertile. Although puzzling, these apparently contradictory data may on the contrary help at deciphering the Prion protein family role through focusing scientific attention outside the central nervous system and by helping the identification of other loci involved in the genetic robustness associated with PrP.