955 research outputs found

    A stochastic model for early placental development

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    In the human, placental structure is closely related to placental function and consequent pregnancy outcome. Studies have noted abnormal placental shape in small-for-gestational age infants which extends to increased lifetime risk of cardiovascular disease. The origins and determinants of placental shape are incompletely under-stood and are difficult to study in vivo. In this paper we model the early development of the placenta in the human, based on the hypothesis that this is driven by dynamics dominated by a chemo-attractant effect emanating from proximal spiral arteries in the decidua. We derive and explore a two-dimensional stochastic model for these events, and investigate the effects of loss of spiral arteries in regions near to the cord insertion on the shape of the placenta. This model demonstrates that placental shape is highly variable and disruption of spiral arteries can exert profound effects on placental shape, particularly if this disruption is close to the cord insertion. Thus, placental shape reflects the underlying maternal vascular bed. Abnormal placental shape may reflect an abnormal uterine environment, which predisposes to pregnancy complications

    Current model systems for the study of preeclampsia

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    Preeclampsia (PE) is a pregnancy complex disease, distinguished by high blood pressure and proteinuria, diagnosed after the 20th gestation week. Depending on the values of blood pressure, urine protein concentrations, symptomatology, and onset of disease there is a wide range of phenotypes, from mild forms developing predominantly at the end of pregnancy to severe forms developing in the early stage of pregnancy. In the worst cases severe forms of PE could lead to systemic endothelial dysfunction, eclampsia, and maternal and/or fetal death. Worldwide the fetal morbidity and mortality related to PE is calculated to be around 8% of the total pregnancies. PE still being an enigma regarding its etiology and pathophysiology, in general a deficient trophoblast invasion during placentation at first stage of pregnancy, in combination with maternal conditions are accepted as a cause of endothelial dysfunction, inflammatory alterations and appearance of symptoms. Depending on the PE multifactorial origin, several in vitro, in vivo,andin silico models have been used to evaluate the PE pathophysiology as well as to identify or test biomarkers predicting, diagnosing or prognosing the syndrome. This review focuses on the most common models used for the study of PE, including those related to placental development, abnormal trophoblast invasion, uteroplacental ischemia, angiogenesis, oxygen deregulation, and immune response to maternal–fetal interactions. The advances in mathematical and computational modeling of metabolic network behavior, gene prioritization, the protein–protein interaction network, the genetics of PE, and the PE prediction/classification are discussed. Finally, the potential of these models to enable understanding of PE pathogenesis and to evaluate new preventative and therapeutic approaches in the management of PE are also highlighted

    The transcriptomic evolution of mammalian pregnancy:gene expression innovations in endometrial stromal fibroblasts

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    The endometrial stromal fibroblast (ESF) is a cell type present in the uterine lining of therian mammals. In the stem lineage of eutherian mammals, ESF acquired the ability to differentiate into decidual cells in order to allow embryo implantation. We call the latter cell type “neo-ESF” in contrast to “paleo-ESF” which is homologous to eutherian ESF but is not able to decidualize. In this study, we compare the transcriptomes of ESF from six therian species: Opossum (Monodelphis domestica; paleo-ESF), mink, rat, rabbit, human (all neo-ESF), and cow (secondarily nondecidualizing neo-ESF). We find evidence for strong stabilizing selection on transcriptome composition suggesting that the expression of approximately 5,600 genes is maintained by natural selection. The evolution of neo-ESF from paleo-ESF involved the following gene expression changes: Loss of expression of genes related to inflammation and immune response, lower expression of genes opposing tissue invasion, increased markers for proliferation as well as the recruitment of FOXM1, a key gene transiently expressed during decidualization. Signaling pathways also evolve rapidly and continue to evolve within eutherian lineages. In the bovine lineage, where invasiveness and decidualization were secondarily lost, we see a re-expression of genes found in opossum, most prominently WISP2, and a loss of gene expression related to angiogenesis. The data from this and previous studies support a scenario, where the proinflammatory paleo-ESF was reprogrammed to express anti-inflammatory genes in response to the inflammatory stimulus coming from the implanting conceptus and thus paving the way for extended, trans-cyclic gestation

    Mathematical modelling of cancer invasion : a review

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    Funding: MAJC gratefully acknowledges the support of EPSRC Grant No. EP/S030875/1 (EPSRC SofTMech∧MP Centre-to-Centre Award).A defining feature of cancer is the capability to spread locally into the surrounding tissue, with cancer cells spreading beyond any normal boundaries. Cancer invasion is a complex phenomenon involving many inter-connected processes at different spatial and temporal scales. A key component of invasion is the ability of cancer cells to alter and degrade the extracellular matrix through the secretion of matrix-degrading enzymes. Combined with excessive cell proliferation and cell migration (individual and collective), this facilitates the spread of cancer cells into the local tissue. Along with tumour-induced angiogenesis, invasion is a critical component of metastatic spread, ultimately leading to the formation of secondary tumours in other parts of the host body. In this paper we present an overview of the various mathematical models and different modelling techniques and approaches that have been developed over the past 25 years or so and which focus on various aspects of the invasive process.Postprin

    A travelling wave model to interpret a wound healing migration assay for human peritoneal mesothelial cells

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    The critical determinants of the speed of an invading cell front are not well known. We performed a "wound-healing" experiment that quantifies the migration of human peritoneal mesothelial cells over components of the extracellular matrix. Results were interpreted in terms of Fisher's equation, which includes terms for the modeling of random cell motility (diffusion) and proliferation. The model predicts that, after a short transient, the invading cell front will move as a traveling wave at constant speed. This is consistent with the experimental findings. Using the model, a relationship between the rate of cell proliferation and the diffusion coefficient was obtained. We used the model to deduce the cell diffusion coefficients under control conditions and in the presence of collagen IV and compared these with other published data. The model may be useful in analyzing the invasive capacity of cancer cells as well in predicting the efficacy of growth factors in tissue reconstruction, including the development of monolayer sheets of cells in skin engineering or the repair of injured corneas using grafts of cultured cells

    Trophoblast attachment to the endometrial epithelium elicits compartment-specific transcriptional waves in an in-vitro model

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    Implantation is a major bottleneck in human reproduction (Polanski et al., 2014). The average implantation rate for an embryo ranges from 30% to 40% (Coughlan et al., 2014). Recurrent implantation failure (RIF) is estimated to occur in approximately 4% of IVF cycles (Koot et al., 2012), although estimates vary because there are several somewhat different definitions of RIF in the literature. Implantation of the blastocyst in the receptive endometrium is a sequential process involving apposition, attachment and invasion that precedes the establishment of pregnancy (Wang and Dey, 2006). Successful implantation requires embryo competence and endometrial receptivity, both of which are dynamic and highly regulated states (Wang and Dey, 2006). In addition to genetic disorders (which are a major cause of implantation failure and miscarriage), embryo competence, quality and ultimately developmental potential depend on the embryo achieving the correct regulatory, signalling and metabolic states (Fu et al., 2009; Hourvitz et al., 2006; Lundin et al., 2001; Simon and Laufer, 2012; Sjoblom et al., 2006). A key determinant of these embryonic states is their underlying transcriptional dynamics; for instance, waves of embryonic transcriptional activation direct early development and the symmetry breaking needed for cell fate specification (Shi et al., 2015; Vassena et al., 2011).info:eu-repo/semantics/publishedVersio

    IFPA meeting 2016 workshop report I: Genomic communication, bioinformatics, trophoblast biology and transport systems

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    Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2016 there were twelve themed workshops, four of which are summarized in this report. These workshops covered innovative technologies applied to new and traditional areas of placental research: 1) genomic communication; 2) bioinformatics; 3) trophoblast biology and pathology; 4) placental transport systems

    Expression of aldehyde dehydrogenase family 1, member A3 in glycogen trophoblast cells of the murine placenta

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    Introduction: Retinoic acid (RA) signaling is a well known regulator of trophoblast differentiation and placental development, and maternal decidual cells are recognized as the source of much of this RA. We explored possible trophoblast-derived sources of RA by examining the expression of RA synthesis enzymes in the developing mouse placenta, as well as addressed potential sites of RA action by examining the ontogeny of gene expression for other RA metabolizing and receptor genes. Furthermore, we investigated the effects of endogenous RA production on trophoblast differentiation

    Ectopic Pregnancy as a Model to Identify Endometrial Genes and Signaling Pathways Important in Decidualization and Regulated by Local Trophoblast

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    The endometrium in early pregnancy undergoes decidualization and functional changes induced by local trophoblast, which are not fully understood. We hypothesized that endometrium from tubal ectopic pregnancy (EP) could be interrogated to identify novel genes and pathways involved in these processes. Gestation-matched endometrium was collected from women with EP (n = 11) and intrauterine pregnancies (IUP) (n = 13). RNA was extracted from the tissue. In addition, tissues were prepared for histological analysis for degree of decidualization. We compared a) the samples from EP that were decidualized (n = 6) with non-decidualized samples (n = 5), and b) the decidualized EP (n = 6) with decidualization-matched IUP (n = 6) samples using an Affymetrix gene array platform, with Ingenuity Pathway Analysis, combined with quantitative RT-PCR. Expression of PRL and IGFBP1 was used to confirm the degree of decidualization in each group. There were no differences in PRL or IGFBP1 expression in the decidualization-matched samples but a marked reduction (P<0.001) in the non-decidualized samples. Decidualization was associated with increased expression of 428 genes including SCARA5 (181-fold), DKK1 (71-fold) and PROK1 (32-fold), and decreased expression of 230 genes including MMP-7 (35-fold) and SFRP4 (21-fold). The top canonical pathways associated with these differentially expressed genes were Natural Killer Cell and Wnt/b-Catenin signaling. Local trophoblast was associated with much less alteration of endometrial gene expression with an increase in 56 genes, including CSH1 (8-fold), and a reduction in 29 genes including CRISP3 (8-fold). The top associated canonical pathway was Antigen Presentation. The study of endometrium from tubal EP may promote novel insights into genes involved in decidualization and those influenced by factors from neighboring trophoblast. This has afforded unique information not highlighted by previous studies and adds to our understanding of the endometrium in early pregnancy

    Regulation of pregnancy-associated plasma protein A2 (PAPPA2) in a human placental trophoblast cell line (BeWo)

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    <p>Abstract</p> <p>Background</p> <p>Pregnancy-associated plasma protein A2 (PAPPA2) is an insulin-like growth factor-binding protein (IGFBP) protease expressed at high levels in the placenta and upregulated in pregnancies complicated by preeclampsia and HELLP (Hemolytic anemia, Elevated Liver enzymes, and Low Platelet count) syndrome. However, it is unclear whether elevated PAPPA2 expression causes abnormal placental development, or whether upregulation compensates for placental pathology. In the present study, we investigate whether PAPPA2 expression is affected by hypoxia, oxidative stress, syncytialization factors or substances known to affect the expression of PAPPA2's paralogue, PAPPA.</p> <p>Methods</p> <p>BeWo cells, a model of placental trophoblasts, were treated with one of the following: hypoxia (2% O2), oxidative stress (20 microM hydrogen peroxide), forskolin (10 microM and 100 microM), TGF-beta (10 and 50 ng/mL), TNF-alpha (100 ng/mL), IL-1beta (100 ng/mL) or PGE2 (1 microM). We used quantitative RT-PCR (qRT-PCR) to quantify the mRNA levels of PAPPA2, as well as those of PAPPA and ADAM12 since these proteases have similar substrates and are also highly expressed in the placenta. Where we observed significant effects on PAPPA2 mRNA levels, we tested for effects at the protein level using an in-cell Western assay.</p> <p>Results</p> <p>Hypoxia, but not oxidative stress, caused a 47-fold increase in PAPPA2 mRNA expression, while TNF-alpha resulted in a 6-fold increase, and both of these effects were confirmed at the protein level. PGE2 resulted in a 14-fold upregulation of PAPPA2 mRNA but this was not reflected at the protein level. Forskolin, TGF-beta and IL-1beta had no significant effect on PAPPA2 mRNA expression. We observed no effects of any treatment on PAPPA or ADAM12 expression.</p> <p>Conclusion</p> <p>Our study demonstrates that factors previously known to be highly expressed in preeclamptic placentae (PGE2 and TNF-alpha), contribute to the upregulation of PAPPA2. Hypoxia, known to occur in preeclamptic placentae, also increased PAPPA2 expression. These results are consistent with the hypothesis that PAPPA2 is upregulated as a consequence of placental pathology, rather than elevated PAPPA2 levels being a cause of preeclampsia.</p
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