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Driven by a lack of appropriate human placenta models, recent years have seen the introduction of bioengineered in vitro models to better understand placental health and disease. Thus far, the focus has been on the maternal–foetal barrier. However, there are many other physiologically and pathologically significant aspects of the placenta that would benefit from state-of-the-art bioengineered models, in particular, integrating advanced culture systems with contemporary biological concepts such as organoids. This critical review defines and discusses the key parameters required for the development of physiologically relevant in vitro models of the placenta. Specifically, it highlights the importance of cell type, mechanical forces, and culture microenvironment towards the use of physiologically relevant models to improve the understanding of human placental function and dysfunction. Refereed/Peer-reviewed

BackgroundMicroRNAs (miRNAs) are increasingly seen as important regulators of placental development and opportunistic biomarker targets. Given the difficulty in obtaining samples from early gestation and subsequent paucity of the same, investigation of the role of miRNAs in early gestation human placenta has been limited. To address this, we generated miRNA profiles using 96 placentas from presumed normal pregnancies, across early gestation, in combination with matched profiles from maternal plasma. Placenta samples range from 6–23 weeks’ gestation, a time period that includes placenta from the early, relatively low but physiological (6–10 weeks’ gestation) oxygen environment, and later, physiologically normal oxygen environment (11–23 weeks’ gestation).ResultsWe identified 637 miRNAs with expression in 86 samples (after removing poor quality samples), showing a clear gestational age gradient from 6–23 weeks’ gestation. We identified 374 differentially expressed (DE) miRNAs between placentas from 6–10 weeks’ versus 11–23 weeks’ gestation. We see a clear gestational age group bias in miRNA clusters C19MC, C14MC, miR-17∼92 and paralogs, regions that also include many DE miRNAs. Proportional change in expression of placenta-specific miRNA clusters was reflected in maternal plasma.ConclusionThe presumed introduction of oxygenated maternal blood into the placenta (between ∼10–12 weeks’ gestation) changes the miRNA profile of the chorionic villus, particularly in placenta-specific miRNA clusters. Data presented here comprise a clinically important reference set for studying early placenta development and may underpin the generation of minimally invasive methods for monitoring placental health.

Refereed/Peer-reviewed The search for novel microRNA (miRNA) biomarkers in plasma is hampered by haemolysis, the lysis and subsequent release of red blood cell contents, including miRNAs, into surrounding fluid. The biomarker potential of miRNAs comes in part from their multicompartment origin and the long-lived nature of miRNA transcripts in plasma, giving researchers a functional window for tissues that are otherwise difficult or disadvantageous to sample. The inclusion of red-blood-cell-derived miRNA transcripts in downstream analysis introduces a source of error that is difficult to identify posthoc and may lead to spurious results. Where access to a physical specimen is not possible, our tool will provide an in silico approach to haemolysis prediction. We present DraculR, an interactive Shiny/R application that enables a user to upload miRNA expression data from a short-read sequencing of human plasma as a raw read counts table and interactively calculate a metric that indicates the degree of haemolysis contamination. The code, DraculR web tool and its tutorial are freely available as detailed herein.

The abundance of cell-free microRNA (miRNA) has been measured in many body fluids, including blood plasma, which has been proposed as a source with novel, minimally invasive biomarker potential for several diseases. Despite improvements in quantification methods for plasma miRNAs, there is no consensus on optimal reference miRNAs or to what extent haemolysis may affect plasma miRNA content. Here we propose a new method for the detection of haemolysis in miRNA high-throughput sequencing (HTS) data from libraries prepared using human plasma. To establish a miRNA haemolysis signature in plasma we first identified differentially expressed miRNAs between samples with known haemolysis status and selected miRNA with statistically significant higher abundance in our haemolysed group. Given there may be both technical and biological reasons for differential abundance of signature miRNA, and to ensure the method developed here was relevant outside of our specific context, that is women of reproductive age, we tested for significant differences between pregnant and non-pregnant groups. Here we report a novel 20 miRNA signature (miR-106b-3p, miR-140-3p, miR-142-5p, miR-532-5p, miR-17-5p, miR-19b-3p, miR-30c-5p, miR-324-5p, miR-192-5p, miR-660-5p, miR-186-5p, miR-425-5p, miR-25-3p, miR-363-3p, miR-183-5p, miR-451a, miR-182-5p, miR-191-5p, miR-194-5p, miR-20b-5p) that can be used to identify the presence of haemolysis, in silico, in high throughput miRNA sequencing data. Given the potential for haemolysis contamination, we recommend that assay for haemolysis detection become standard pre-analytical practice and provide here a simple method for haemolysis detection.

ContextMany studies assert a negative influence of inappropriate maternal diet and nutritional status during pregnancy on offspring, not only in utero but throughout life, because of the role in the programing of noncommunicable diseases. Telomere length is a biomarker of aging, and shorter telomeres are associated with chronic disease later in life. Maternal nutrition and nutritional status may be an important determinant of offspring telomere length.ObjectiveA systematic review was conducted to determine the effect of maternal nutrition and nutritional status in pregnancy on offspring telomere length.Data SourcesThis systematic review was conducted according to PRISMA guidelines. Database searches of PubMed, CINAHL, Scopus, Medline, and Web of Science were performed.Study SelectionIncluded studies assessed the association between maternal nutrition (dietary intake and nutritional status) during pregnancy and offspring telomere length measured in cord blood, serum, plasma, and peripheral blood mononuclear cells.Data ExtractionThree authors screened and determined the quality of the articles; disagreements were resolved by a fourth author. All authors compared the compiled data.ResultsSeven studies were extracted and evaluated. Studies comprised a double-blind placebo-controlled trial (n = 1), prospective cohort studies (n = 5), and a cross-sectional study (n = 1). Higher circulating maternal folate and 25-hydroxyvitamin D3 concentrations, along with higher maternal dietary caffeine intakes, were associated with longer offspring telomere length, whereas higher dietary intake of carbohydrate, folate, n-3 polyunsaturated fatty acids, vitamin C, or sodium was not.ConclusionThe limited but suggestive evidence highlights the need for further research to be conducted in this area, particularly longitudinal studies involving larger cohorts of pregnant women.Systematic review registrationPROSPERO registration no. CRD42019136506

Zika virus (ZIKV) infection has emerged as a global health threat and infection of pregnant women causes intrauterine growth restriction, spontaneous abortion and microcephaly in newborns. Here we show using biologically relevant cells of neural and placental origin that following ZIKV infection, there is attenuation of the cellular innate response characterised by reduced expression of IFN-β and associated interferon stimulated genes (ISGs). One such ISG is viperin that has well documented antiviral activity against a wide range of viruses. Expression of viperin in cultured cells resulted in significant impairment of ZIKV replication, while MEFs derived from CRISPR/Cas9 derived viperin−/− mice replicated ZIKV to higher titers compared to their WT counterparts. These results suggest that ZIKV can attenuate ISG expression to avoid the cellular antiviral innate response, thus allowing the virus to replicate unchecked. Moreover, we have identified that the ISG viperin has significant anti-ZIKV activity. Further understanding of how ZIKV perturbs the ISG response and the molecular mechanisms utilised by viperin to suppress ZIKV replication will aid in our understanding of ZIKV biology, pathogenesis and possible design of novel antiviral strategies.