Placental Fibroblasts Research Articles

Human placental cells are resistant to SARS-CoV-2 infection and replication.

Infection during pregnancy with SARS-CoV-2 can have a serious impact on both maternal and foetal health. Clinical studies have shown that SARS-CoV-2 transmission from the mother to the foetus typically does not occur. However, there is evidence that SARS-CoV-2 can infect the placenta in utero. Here we sought to quantify the permissiveness of placental cells to SARS-CoV-2 infection and to determine if they support viral release. By using publicly available single-cell RNA sequencing (scRNAseq) data sets and confocal microscopy we compared ACE2 transcript and protein expression across human first trimester and term placental cells. We also used in vitro infection assays to quantify the infection rates of a range of placenta-derived cells. Finally, we quantified the viral egress from these cells. ACE2 transcripts are found in a range of placental cell types across gestation, including trophoblast. However, ACE2 protein expression does not significantly change across placental cell types from first trimester to term. We find that 0.5±0.15 % of term trophoblast cells can be infected with SARS-CoV-2 while primary placental fibroblasts and macrophages, and JEG-3, JAR and HUVEC cell lines are resistant to infection. Furthermore, primary trophoblast cells poorly support viral release while JEG-3 cells allow relatively high levels of viral release. The low level of viral release by primary placental cells provides insight into how the virus is impaired from crossing the placenta to the foetus.

Optimizing lipid nanoparticles for fetal gene delivery in vitro, ex vivo, and aided with machine learning

There is a clinical need to develop lipid nanoparticles (LNPs) to deliver congenital therapies to the fetus during pregnancy. The aim of these therapies is to restore normal fetal development and prevent irreversible conditions after birth. As a first step, LNPs need to be optimized for transplacental transport, safety on the placental barrier and fetal organs and transfection efficiency. We developed and characterized a library of LNPs of varying compositions and used machine learning (ML) models to delineate the determinants of LNP size and zeta potential. Utilizing different in vitro placental models with the help of a Random Forest algorithm, we could identify the top features driving percentage LNP transport and kinetics at 24 h, out of a total of 18 input features represented by 41 LNP formulations and 48 different transport experiments. We further evaluated the LNPs for safety, placental cell uptake, transfection efficiency in placental trophoblasts and fetal lung fibroblasts. To ensure the integrity of the LNPs following transplacental transport, we screened LNPs for transport and transfection using a high-throughput integrated transport-transfection in vitro model. Finally, we assessed toxicity of the LNPs in a tracheal occlusion fetal lung explant model. LNPs showed little to no toxicity to fetal and placental cells. Immunoglobin G (IgG) orientation on the surface of LNPs, PEGylated lipids, and ionizable lipids had significant effects on placental transport. The Random Forest algorithm identified the top features driving LNPs placental transport percentage and kinetics. Zeta potential emerged in the top driving features. Building on the ML model results, we developed new LNP formulations to further optimize the transport leading to 622 % increase in transport at 24 h versus control LNP formulation. To induce preferential siRNA transfection of fetal lung, we further optimized cationic lipid percentage and the lipid-to-siRNA ratio. Studying LNPs in an integrated placental and fetal lung fibroblasts model showed a strong correlation between zeta potential and fetal lung transfection. Finally, we assessed the toxicity of LNPs in a tracheal occlusion lung explant model. The optimized formulations appeared to be safe on ex vivo fetal lungs as indicated by insignificant changes in apoptosis (Caspase-3) and proliferation (Ki67) markers. In conclusion, we have optimized an LNP formulation that is safe, with high transplacental transport and preferential transfection in fetal lung cells. Our research findings represent an important step toward establishing the safety and effectiveness of LNPs for gene delivery to the fetal organs.

Human placental villous stromal extracellular matrix regulates fetoplacental angiogenesis in severe fetal growth restriction.

Pregnancies complicated by severe, early-onset fetal growth restriction with abnormal Doppler velocimetry (FGRadv) have a sparse villous vascular tree secondary to impaired angiogenesis. As endothelial cell (EC) and stromal matrix interactions are key regulators of angiogenesis, we investigated the role of placental stromal villous matrix on fetoplacental EC angiogenesis. We have developed a novel model of generating placental fibroblast (FB) cell-derived matrices (CDMs), allowing us to interrogate placenta-specific human EC and stromal matrix interactions and their effects on fetoplacental angiogenesis. We found that as compared with control ECs plated on control matrix, FGRadv ECs plated on FGRadv matrix exhibited severe migrational defects, as measured by velocity, directionality, accumulated distance, and Euclidean distance in conjunction with less proliferation. However, control ECs, when interacting with FGRadv CDM, also demonstrated significant impairment in proliferation and migratory properties. Conversely several angiogenic attributes were rescued in FGRadv ECs subjected to control matrix, demonstrating the importance of placental villous stromal matrix and EC-stromal matrix interactions in regulation of fetoplacental angiogenesis.

Receptors in host pathogen interactions between human cytomegalovirus and the placenta during congenital infection.

Cellular receptors in human cytomegalovirus (HCMV) mother to child transmission play an important role in congenital infection. Placental trophoblast cells are a significant cell type in placental development, placental functional processes, and in HCMV transmission. Different cells within the placental floating and chorionic villi present alternate receptors for HCMV cell entry. Syncytiotrophoblasts present neonatal Fc receptors that bind and transport circulating maternal immunoglobulin G across the placental interface which can also be bound to HCMV virions, facilitating viral entry into the placenta and foetal circulation. Cytotrophoblast express HCMV receptors including integrin-α1β1, integrin-αVβ3, epidermal growth factor receptor and platelet-derived growth factor receptor alpha. The latter interacts with HCMV glycoprotein-H, glycoprotein-L and glycoprotein-O (gH/gL/gO) trimers (predominantly in placental fibroblasts) and the gH/gL/pUL128, UL130-UL131A pentameric complex in other placental cell types. The pentameric complex allows viral tropism of placental trophoblasts, endothelial cells, epithelial cells, leukocytes and monocytes. This review outlines HCMV ligands and target receptor proteins in congenital HCMV infection.

Inspired by the human placenta: a novel 3D bioprinted membrane system to create barrier models

Barrier organ models need a scaffold structure to create a two compartment culture. Technical filter membranes used most often as scaffolds may impact cell behaviour and present a barrier themselves, ultimately limiting transferability of test results. In this work we present an alternative for technical filter membrane systems: a 3D bioprinted biological membrane in 24 well format. The biological membrane, based on extracellular matrix (ECM), is highly permeable and presents a natural 3D environment for cell culture. Inspired by the human placenta we established a coculture of a trophoblast-derived cell line (BeWo b30), together with primary placental fibroblasts within the biological membrane (simulating villous stroma) and primary human placental endothelial cells—representing three cellular components of the human placental villus. All cell types maintained their cell type specific marker expression after two weeks of coculture on the biological membrane. In permeability assays the trophoblast layer developed a barrier on the biological membrane, which was even more pronounced when cocultured with fibroblasts. In this work we present a filter membrane free scaffold, we characterize its properties and assess its suitability for cell culture and barrier models. Further we show a novel placenta inspired model in a complex bioprinted coculture. In the absence of an artificial filter membrane, we demonstrate barrier architecture and functionality.

Respiratory syncytial virus exhibits differential tropism for distinct human placental cell types with Hofbauer cells acting as a permissive reservoir for infection.

BackgroundRespiratory syncytial virus (RSV) is capable of transient viremia and extrapulmonary dissemination. Recently, this virus has been identified in fetal cord blood, suggesting the possibility of in utero acquisition in humans. Here, we assess permissivity and kinetics of RSV replication in primary human placental cells, examine their potential to transfer this infection to neighboring cells, and measure the inflammatory response evoked by the virus.Methods and findingsHuman placental villus tissue was collected immediately upon delivery and processed for isolation of placental cytotrophoblast, fibroblast, and macrophage (Hofbauer) cells. Isolated cells were infected with a recombinant RSV-A2 strain (rrRSV) expressing red fluorescent protein (RFP) and analyzed by fluorescence microscopy, Western blot, and quantitative PCR (qPCR). Based on RFP expression, rrRSV exhibited differential tropism for the three major placental cell types. Placental fibroblasts and Hofbauer cells were permissive and supported productive rrRSV replication. While infected cytotrophoblast cells expressed viral glycoprotein (G protein), only limited RSV replication was detected. Importantly, qPCR and fluorescence-focused unit assay revealed that the viral progeny remains trapped within infected Hofbauer cells for up to 30 days, with no release into surrounding media. Yet, Hofbauer cells passed the infection onto overlaid naïve 16HBE cells, suggesting contact-dependent trans-infection. Lastly, a significant increase in proinflammatory cytokines, particularly IL-6, TNF-alpha, and IFN-gamma was measured in the supernatant of infected Hofbauer cells by multiplex cytokine assay and conventional ELISA.ConclusionsThis study demonstrates that RSV can replicate in human placenta, exhibits differential tropism for distinct placental cell types, can be stored and transferred to neighboring cells by Hofbauer cells, and elicits an inflammatory response. It also supports the hypothesis that this respiratory virus can be vertically transferred to the fetus and potentially affect its development and the outcome of pregnancies.

RBMS1 Methylation and mRNA Expression Are Differentially Regulated in Placenta Tissue from Obese Women (P11-131-19)

ObjectivesThe maternal diet and obesity adversely affect placental structure/function, inflammation, and alters placental DNA methylation. RNA-binding motif single-stranded interacting protein 1 (RBMS1) regulates DNA replication and gene transcription and is expressed in the placenta. Although specific roles for RBMS1 in the context of obesity have not yet been fully explored, RBMS1 has been linked to type 2 diabetes mellitus risk. No data are available regarding the function of RBMS1 in placental tissue and whether placental expression of RBMS1 is regulated differentially in obesity. MethodsPlacental tissue from obese (BMI > 25, n = 15) and non-overweight (BMI < 25, n = 3) women was obtained from The Cooperative Human Tissue Network (CHTN) Western Division at Vanderbilt University Medical Center. Epigenetic changes in placental RBMS1 DNA methylation and histone acetylation were assessed by DNA methylation assays and chromatin immunoprecipitation, respectively. Placental RBMS1 gene expression was measured by RT-PCR and RBMS1 protein localization was assessed by immunohistochemistry. The anti-inflammatory effect of RBMS1 was measured in vitro using human placental fibroblast cells (HS 795.PI). Placental short-chain fatty acids (SCFAs) were measured by gas chromatography-mass spectrometry (GC-MS). ResultsRBMS1 mRNA (P = 0.0029) and DNA methylation (P < 0.05) were increased in placentae from obese mothers. RBMS1 protein expression was localized to placental resident macrophages and fibroblastic cells. In vitro, RBMS1 recombinant protein attenuated LPS-induced IL-6 mRNA expression in HS 795.PI cells (P < 0.001), suggesting a possible anti-inflammatory role for RBMS1 in the context of placental inflammation. SCFA analysis demonstrated an increase in placental butyrate (P = 0.0327), a known histone deacetylase (HDAC) inhibitor in placenta from obese women. ConclusionsThese data suggest a possible anti-inflammatory role for RBMS1 in the context of placental inflammation. Increased placental RBMS1 expression in obese women may serve as an adaptive response to reduce placental inflammation. Funding SourcesUSDA Agricultural Research Service Project #3062-51000-052-00D.

Noncanonical placental Fc receptors: What is their role in modulating transplacental transfer of maternal IgG?

The transplacental transfer of maternal Immunoglobulin G (IgG) to the fetus is critical for protection against infectious diseases in the first year of life [1]. Maternal protective IgG is transferred from the maternal to the fetal circulatory system via the placenta, and this process begins in the first trimester of pregnancy [2]. By 37–40 weeks of gestation, maternal passively acquired IgG concentrations in newborns can exceed maternal IgG serum levels in normal pregnancies [3–7]. Yet, the molecular mechanisms of transplacental transfer of maternal IgG remain poorly understood. In order to reach the fetal circulatory system, maternal IgG must traverse three distinct placental anatomical barriers: (1) the syncytiotrophoblast cell barrier, (2) the villous stroma containing placental fibroblasts and Hofbauer cells, and (3) fetal endothelial cells. It is well established that IgG crosses the syncytiotrophoblast by binding to the canonical IgG shuttle receptor: Fragment crystallizable (Fc) receptor neonatal (FcRn) [2, 8]. However, how maternal IgG traverses the subsequent placental barriers is not completely understood, as they do not express FcRn, yet recent RNAseq analyses have shown that Fcγ receptors, including FcγRIIIa, FcγRIIa, FcγRIIb, and FcγRI, are expressed in term placentas [9]. However, it should be cautioned that it is not yet known if these noncanonical placental FcRs play a role, if at all, in the transplacental transfer of maternal IgG. A deeper understanding of the molecular mechanism(s) of IgG binding to placentally expressed Fc receptors could be important (1) for the design of novel maternal IgG-based therapeutics and vaccines with optimal transplacental transfer efficiency, with the ultimate goal of increasing infant protection against congenital and neonatal infectious diseases, and (2) to optimize the Fc region of immunomodulatory IgG monoclonal antibody therapeutics for blunted transplacental transfer to potentially reduce the transplacental transport of maternal self-reactive IgG in women with autoimmune disorders.

Fibrosis in Preeclamptic Placentas Is Associated with Stromal Fibroblasts Activated by the Transforming Growth Factor-β1 Signaling Pathway

Although fibrosis is one of the most prominent pathologic features of preeclamptic (PE) placentas, its mechanism remains largely unknown. Consistent with previous reports, we observed overexpression of collagen; actin, α2, smooth muscle, aorta; connective tissue growth factor; and fibronectin in PE placentas compared with control ones. To investigate the mechanism of fibrosis in PE placentas, placental fibroblasts were isolated from PE placentas or normal pregnancies at delivery. The expression of fibrosis-related factors in fibroblasts was evaluated by real-time RT-PCR, Western blotting, enzyme-linked immunosorbent assay, and gene microarrays. An invitro collagen gel contraction assay was also performed. Fibroblasts isolated from PE placentas showed higher expression levels of fibrosis-related factors compared with those from control ones. Global gene expression profiling of PE fibroblasts was contrasted with that of control ones and indicated an intimate association with transforming growth factor-β1 (TGFB1) signaling. Furthermore, the PE fibroblasts expressed abundant phosphorylated SMAD family member 2 and showed higher expression levels of target genes of TGFB1 signaling compared with the control ones. The PE fibroblasts also had a greater ability to contract compared with the control ones. Contractility also depended on TGFB1 signaling. Our results suggest that TGFB1 signaling is activated in the fibroblasts in PE placentas and that these active fibroblasts contribute to fibrosis.

Placental pericytes and cytomegalovirus infectivity: Implications for HCMV placental pathology and congenital disease

Placental pericytes are essential for placental microvascular function, stability, and integrity. Mechanisms of human cytomegalovirus (HCMV) pathogenesis incorporating placental pericytes are unknown. HCMV-infected placental tissue was stained by dual-labeled immunohistochemistry. Primary placental pericytes, cytotrophoblasts, and villous fibroblasts were exposed to HCMV; and infectivity was analyzed by microscopy and immunofluorescence. Cytokine expression was examined by Luminex assay. A HCMV-GFP recombinant virus was used to examine replication kinetics. Immunohistochemistry showed HCMV in trophoblast and the villous core with T-cell and macrophage infiltration. Primary HCMV isolate from a patient (SBCMV)- infected pericytes showed dysregulation of proinflammatory and angiogenic cytokines when compared to control cells. A tri-cell model of the villous floor showed a unique expression profile. Finally, we show pericytes infected in vivo with HCMV in placental tissue from a congenitally infected child. Placental pericytes support HCMV replication, inducing proinflammatory and angiogenic cytokines that likely contribute to viral dissemination, placenta inflammation, and dysregulation of placental angiogenesis.

Abstract 618: Hypoxia Inducible Factor 1a Stabilization in Autosomal Dominant Hyper IgE Syndrome Fibroblasts Rescues Impaired Ability to Support Angiogenesis

Background: Autosomal dominant Hyper-IgE syndrome (AD-HIES) is a rare primary immunodeficiency caused by dominant negative mutations in signal transducer and activator of transcription 3 (STAT3 ) , a mediator of widespread physiological processes. It is characterized by dermatitis, recurrent infections, elevated IgE, poor post-surgical healing, and connective tissue abnormalities. How STAT3 deficiency leads to this phenotype, however, is not known. Current treatment options are limited to antimicrobials for infection control. The aim of this study was to investigate which of STAT3’s many functions are dis-regulated in AD-HIES, and where potential targets for therapy may lie. Methods: We used skin fibroblasts (SF) from 3 AD-HIES patients and 3 normal volunteers. To evaluate potentially affected pathways, we utilized RNA- Seq and subsequent Gene Set Enrichment (GSEA) and pathway analysis (Pathway Studio, GeneGo Metacore). Endothelial cell tube formation assay was used to assess ability of AD-HIES SFs to support angiogenesis. Results: GSEA and pathway analysis showed deficiencies in signaling pathways linked to wound healing, extracellular matrix remodeling and angiogenesis including targets of Hypoxia Inducible Factor 1a (HIF1a) (P values for enrichments &lt; 0.001) . Therefore, we hypothesized that AD-HIES SFs have impaired ability to support angiogenesis due to deficient Hif1a-dependent secretion of matrix proteases and growth factors. Indeed, AD-HIES SF secreted up to 5 times less matrix metalloprotease 1, 3, and 9, placental growth factor and fibroblast growth factors 1 and 2 (Luminex Multiplex, n=3-9, P&lt;0.05). Culture medium from AD-HIES SFs failed to fully support tube formation by endothelial cells resulting in lower number of junctions, meshes, and total tubule length (n=6, P&lt;0.005). Stabilization of Hif1a in AD-HIES SFs by prolyl hydroxylase inhibitor dimethyl fumarate restored its transcriptional activity leading to increased number of junctions, meshes, and tubule length (n=12, P&lt;0.05) Conclusion: AD-HIES SFs have deficiencies in pro-angiogenic signaling pathways that lead to decreased growth factor secretion and angiogenesis. Stabilization of HIF1a corrects this deficiency and is an enticing target for future therapy.

Increased dietary protein in the second trimester of gestation increases live weight gain and carcass composition in weaner calves to 6 months of age

Genetically similar nulliparous Polled Hereford heifers from a closed pedigree herd were used to evaluate the effects of dietary protein during the first and second trimester of gestation upon foetal, placental and postnatal growth. Heifers were randomly allocated into two groups at 35 days after artificial insemination (35 days post conception (dpc)) to a single bull and fed high (15.7% CP) or low (5.9% CP) protein in the first trimester (T1). At 90 dpc, half of each nutritional treatment group changed to a high- or low-protein diet for the second trimester until 180 dpc (T2). High protein intake in the second trimester increased birth weight in females (P=0.05), but there was no effect of treatment upon birth weight when taken over both sexes. Biparietal diameter was significantly increased by high protein in the second trimester with the effect being greater in the female (P=0.02), but also significant overall (P=0.05). Placental weight was positively correlated with birth weight, fibroblast volume and relative blood vessel volume (P<0.05). Placental fibroblast density was increased and trophoblast volume decreased in the high-protein first trimester treatment group (P<0.05). There was a trend for placental weight to be increased by high protein in the second trimester (P=0.06). Calves from heifers fed the high-protein treatment in the second trimester weighed significantly more on all occasions preweaning (at 1 month (P=0.0004), 2 months (P=0.006), 3 months (P=0.002), 4 months (P=0.01), 5 months (P=0.03), 6 months (P=0.001)), and grew at a faster rate over the 6-month period. By 6 months of age, the calves from heifers fed high nutrition in the second trimester weighed 33 kg heavier than those fed the low diet in the second trimester. These results suggest that dietary protein in early pregnancy alters the development of the bovine placenta and calf growth to weaning.

Zika virus productively infects primary human placenta-specific macrophages.

The strong association of Zika virus infection with congenital defects has led to questions of how a flavivirus is capable of crossing the placental barrier to reach the fetal brain. Here, we demonstrate permissive Zika virus infection of primary human placental macrophages, commonly referred to as Hofbauer cells, and placental villous fibroblasts. We also demonstrate Zika virus infection of Hofbauer cells within the context of the tissue ex vivo using term placental villous explants. In addition to amplifying infectious virus within a usually inaccessible area, the putative migratory activities of Hofbauer cells may aid in dissemination of Zika virus to the fetal brain. Understanding the susceptibility of placenta-specific cell types will aid future work around and understanding of Zika virus-associated pregnancy complications.

Abstract 52: Isolation, Characterization and Partial Direct Differentiation of Patient Derived Human Primary Cardiac and Placental Fibroblasts From Surgical Discard Tissue into Induced Mesoderm Progenitor Cell

Background: Human primary cells more closely mimic the physiological state of cells in vivo and generate more relevant data representing living systems. Access to the surgical discard tissue enables the possibility of patient derived, disease specific, cellular bio-bank. In achieving this goal, target cellular lines must be isolated, characterized and fully expanded under specific Standard Operating Procedures(SOP). In this project, we aim in achieving and implementing such goal for Fibroblasts derived from two distinct patient tissues. In parallel, in light of cardiac regenerative therapy, with reference to the published work on Cardiomyocyte Direct Differentiation on mouse fibroblasts into induced cardiomyocyte-like cells (iCMs) by transduction with MicroRNAs (1,133a, 208a and 499) we sought to determine whether primary human cardiac and placental fibroblasts could have the potential in direct differentiation to induced cardiomyocyte-like cells (iCM) through sequential administration of small molecule (ITD-1) in combination with MicroRNAs. Methods and Results: Primary right atrial appendage cardiac and smooth chorion laeve placental fibroblast isolates were generated from surgical discard patient derived tissues subjected for identification of the most efficient isolation method through available enzymatic and mechanical techniques. We have shown through FACS analysis that both groups extracellular marker expression can be limited to CD90+CD31-CD44+FBSP+ which constitutes the majority of cultured primary fibroblasts. Respectively, intercellular expression of DDR2+ VIM+ COL1+CD90+ markers was validated through immunofluorescence microscopy. Transcriptional profiling of Noted lines showed expression of Fibroblast specific genes at higher rate.Furthermore, sorted placental fibroblast isolates were subjected to (ITD-1)treatment and mature MicroRNA mimic cocktail. Transcriptional profiling analysis through RT-PCR concluded down regulation of most distinct fibroblast markers and partial expression of MESP1.

A 3D co-culture microtissue model of the human placenta for nanotoxicity assessment.

There is increasing evidence that certain nanoparticles (NPs) can overcome the placental barrier, raising concerns on potential adverse effects on the growing fetus. But even in the absence of placental transfer, NPs may pose a risk to proper fetal development if they interfere with the viability and functionality of the placental tissue. The effects of NPs on the human placenta are not well studied or understood, and predictive in vitro placenta models to achieve mechanistic insights on NP-placenta interactions are essentially lacking. Using the scaffold-free hanging drop technology, we developed a well-organized and highly reproducible 3D co-culture microtissue (MT) model consisting of a core of placental fibroblasts surrounded by a trophoblast cell layer, which resembles the structure of the in vivo placental tissue. We could show that secretion levels of human chorionic gonadotropin (hCG) were significantly higher in 3D than in 2D cell cultures, which indicates an enhanced differentiation of trophoblasts grown on 3D MTs. NP toxicity assessment revealed that cadmium telluride (CdTe) and copper oxide (CuO) NPs but not titanium dioxide (TiO2) NPs decreased MT viability and reduced the release of hCG. NP acute toxicity was significantly reduced in 3D co-culture MTs compared to 2D monocultures. Taken together, 3D placental MTs provide a new and promising model for the fast generation of tissue-relevant acute NP toxicity data, which are indispensable for the safe development of NPs for industrial, commercial and medical applications.

Placental fibroblast growth factor 21 is not altered in late-onset preeclampsia.

BackgroundPreeclampsia (PE) is associated with alterations of placental function. The incidence of PE is higher in insulin resistant states. Women with PE have high circulating levels of the metabolic regulator fibroblast growth factor 21 (FGF21). FGF21 is synthesized in the placenta. The aim of this study was to compare the expression of FGF21, its receptors, downstream targets and transcriptional regulators in placental tissue from pregnancies with and without late-onset PE. Circulating FGF21 in maternal and cord blood was also studied.MethodsmRNA expression was determined by semi-quantitative real-time PCR and normalized for cellular composition in 17 women with and 20 without PE. Protein expression was quantified by Western Blot. FGF21 levels were measured by ELISA in maternal and cord serum of ten mother-baby dyads per condition.ResultsPlacental FGF21 mRNA and protein expression were similar in PE compared with control. Placental mRNA expression of the FGF receptors (1–4) and the co-receptor beta-Klotho was not different between the groups. There was no difference in the expression of the glucose transporters GLUT1, 3 or 4. PPAR-alpha but not PPAR-gamma expression was decreased in PE. Maternal FGF21 serum levels were not significantly different in PE. FGF21 was detected in cord blood of 6 infants (4 PE, 2 controls) but was undetectable in 14 infants.ConclusionsLate-onset PE is not associated with major changes to the expression of FGF21, its receptors or metabolic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-015-0006-3) contains supplementary material, which is available to authorized users.

A high-affinity native human antibody neutralizes human cytomegalovirus infection of diverse cell types.

Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission are major causes of permanent birth defects. Although no active vaccines to prevent HCMV infection have been approved, passive immunization with HCMV-specific immunoglobulin has shown promise in the treatment of both transplant and congenital indications. Antibodies targeting the viral glycoprotein B (gB) surface protein are known to neutralize HCMV infectivity, with high-affinity binding being a desirable trait, both to compete with low-affinity antibodies that promote the transmission of virus across the placenta and to displace nonneutralizing antibodies binding nearby epitopes. Using a miniaturized screening technology to characterize secreted IgG from single human B lymphocytes, 30 antibodies directed against gB were previously cloned. The most potent clone, TRL345, is described here. Its measured affinity was 1 pM for the highly conserved site I of the AD-2 epitope of gB. Strain-independent neutralization was confirmed for 15 primary HCMV clinical isolates. TRL345 prevented HCMV infection of placental fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, and it inhibited postinfection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by the blockage of HCMV infection of placental cell types central to virus transmission to the fetus, including differentiating cytotrophoblasts, trophoblast progenitor cells, and placental fibroblasts. Further, TRL345 was effective at controlling an ex vivo infection of human placental anchoring villi. TRL345 has been utilized on a commercial scale and is a candidate for clinical evaluation.

Expression of placental fibroblast growth factor 21 (FGF21) is increased in placental tissue from pregnancies with preeclampsia

Expression of placental fibroblast growth factor 21 (FGF21) is increased in placental tissue from pregnancies with preeclampsia

Placental cellular products affect the expression of extracellular matrix (ECM) components and corresponding matrix metalloproteinases (MMP) in bovine placental fibroblasts and trophoblasts in vitro

Placental cellular products affect the expression of extracellular matrix (ECM) components and corresponding matrix metalloproteinases (MMP) in bovine placental fibroblasts and trophoblasts in vitro

CTLA-4 gene polymorphisms and risk of idiopathic recurrent pregnancy loss in a Tunisian population

Background An aberrant regulation of immunological, metabolic, vascular and endocrine processes leads to obstetric complications, including recurrent pregnancy loss (RPL) [1]. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a negative regulator of T cell activation [2] expressed in placental fibroblasts and may modulate peripheral selftolerance of the allogenic fetus [3,4]. It is a stimulatory molecule involved in T-cell activation at the maternal– fetal interface in women with unexplained pregnancy loss [5,6]. In this study, we investigate the possible associations of Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms with idiopathic recurrent pregnancy loss (RPL).