ORCID Profile
0000-0002-3757-4177
Current Organisation
The University of Auckland
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Publisher: Springer Science and Business Media LLC
Date: 03-07-2017
DOI: 10.1038/S41598-017-04776-5
Abstract: Homeobox genes regulate embryonic and placental development, and are widely expressed in the human placenta, but their regulatory control by DNA methylation is unclear. DNA methylation analysis was performed on human placentae from first, second and third trimesters to determine methylation patterns of homeobox gene promoters across gestation. Most homeobox genes were hypo-methylated throughout gestation, suggesting that DNA methylation is not the primary mechanism involved in regulating HOX genes expression in the placenta. Nevertheless, several genes showed variable methylation patterns across gestation, with a general trend towards an increase in methylation over gestation. Three genes ( TLX1, HOXA10 and DLX5 ) showed inverse gains of methylation with decreasing mRNA expression throughout pregnancy, supporting a role for DNA methylation in their regulation. Proteins encoded by these genes were primarily localised to the syncytiotrophoblast layer, and showed decreased expression later in gestation. siRNA mediated downregulation of DLX5 , TLX1 and HOXA10 in primary term villous cytotrophoblast resulted in decreased proliferation and increased expression of differentiation markers, including ERVW-1 . Our data suggest that loss of DLX5, TLX1 and HOXA10 expression in late gestation is required for proper placental differentiation and function.
Publisher: The Royal Society
Date: 16-08-2019
Abstract: The ability of the baby to receive nutrients and oxygen in utero depends on the healthy development of the placenta. For maternal blood to adequately perfuse the placenta, it dramatically alters the arteries in the uterus that supply it with nutrient-rich blood right from the start of pregnancy. Placental cells (trophoblasts) invade both into the tissue of the uterus and into the maternal blood vessels nearest to the site of implantation (the spiral arteries (SAs)) and transform these allowing a relatively high and steady flow of nutrient-rich blood to perfuse the placenta. Trophoblasts also form plugs that occlude SAs, preventing maternal blood flow to the placenta until the late first trimester, at which point these plugs dislodge or disintegrate. Here we present an agent-based model of trophoblast migration within plugged SAs to tease apart the impact of chemical signals and mechanical factors on trophoblast behaviour. The model supports our previous in vitro hypothesis that plugging of the maternal arteries in early pregnancy can act to promote trophoblast invasion by providing a ‘low flow’ environment and extends our understanding by suggesting ‘weak spots’ in plug structure can lead to plug degeneration, allowing increased blood flow through the materno-fetal circulation.
Publisher: Springer Science and Business Media LLC
Date: 03-12-2021
Publisher: Cold Spring Harbor Laboratory
Date: 15-06-2022
DOI: 10.1101/2022.06.12.495853
Abstract: The surface of the placenta is lined by a single multinucleated cell, the syncytiotrophoblast, which forms a functional barrier between maternal and fetal blood in pregnancy. The placenta plays a critical role in healthy fetal development and over the course of pregnancy forms a complex branching tree-like structure which bathes in maternal blood and serves a vital exchange function. It has been suggested that the structure of the placenta may evolve, in part, under the influence of the shear stress exerted by maternal blood flow over its surface, with the syncytiotrophoblast having a role in mechanosensing. However, data describing the mechano-sensitive nature of this cell, particularly in early gestation, is lacking. In this study we show that the syncytiotrophoblast expresses six proteins that have been related to shear sensing, and this expression is higher in the first trimester than at term. This suggests shear on the sycytiotrophoblast as an important factor influencing placental morphogenesis early in pregnancy. We then predict shear stress felt by the syncytiotrophoblast in first trimester and term placental tissue using a combination of porous medium modelling and explicit simulations of blood flow in realistic geometries derived from microCT imaging. Our models predict that typical shear stress on first-trimester tissue is higher than at term, supporting the feasibility of this mechanical stimulus as an important driver of healthy placental development.
Publisher: American Physiological Society
Date: 10-2023
DOI: 10.1152/AJPHEART.00205.2023
Abstract: Fetal growth throughout pregnancy relies on delivery of an increasing volume of maternal blood to the placenta. To facilitate this, the uterine vascular network adapts structurally and functionally, resulting in wider blood vessels with decreased flow-mediated reactivity. Impaired remodeling of the rate-limiting uterine radial arteries has been associated with fetal growth restriction. However, the mechanisms underlying normal or pathological radial artery remodeling are poorly understood. Here, we used pressure myography to determine the roles of haemodynamic (resistance, flow rate, shear stress) and paracrine (β-estradiol, progesterone, placental growth factor (PlGF), vascular endothelial growth factor) factors on rat radial artery reactivity. We show that β-estradiol, progesterone, and PlGF attenuate flow-mediated constriction of radial arteries from non-pregnant rats, allowing them to withstand higher flow rates in a similar manner to pregnant vessels. This effect was partly mediated by nitric oxide (NO) production. To better understand how the combination of paracrine factors and shear stress may impact human radial artery remodeling in the first half of gestation, computational models of uterine haemodynamics, incorporating physiological parameters for trophoblast plugging and spiral artery remodeling, were used to predict shear stress in the upstream radial arteries across the first half of pregnancy. Human microvascular endothelial cells subjected to these predicted shear stresses demonstrated higher NO production when paracrine factors were added. This suggests that synergistic effects of paracrine and haemodynamic factors induce uterine vascular remodeling, and that alterations in this balance could impair radial artery adaptation, limiting blood flow to the placenta and negatively impacting fetal growth.
Publisher: Wiley
Date: 03-08-2021
DOI: 10.1002/WSBM.1502
Abstract: In pregnancy, fetal growth is supported by its placenta. In turn, the placenta is nourished by maternal blood, delivered from the uterus, in which the vasculature is dramatically transformed to deliver this blood an ever increasing volume throughout gestation. A healthy pregnancy is thus dependent on the development of both the placental and maternal circulations, but also the interface where these physically separate circulations come in close proximity to exchange gases and nutrients between mum and baby. As the system continually evolves during pregnancy, our understanding of normal vascular anatomy, and how this impacts placental exchange function is limited. Understanding this is key to improve our ability to understand, predict, and detect pregnancy pathologies, but presents a number of challenges, due to the inaccessibility of the pregnant uterus to invasive measurements, and limitations in the resolution of imaging modalities safe for use in pregnancy. Computational approaches provide an opportunity to gain new insights into normal and abnormal pregnancy, by connecting observed anatomical changes from high‐resolution imaging to function, and providing metrics that can be observed by routine clinical ultrasound. Such advanced modeling brings with it challenges to scale detailed anatomical models to reflect organ level function. This suggests pathways for future research to provide models that provide both physiological insights into pregnancy health, but also are simple enough to guide clinical focus. We the review evolution of computational approaches to understanding the physiology and pathophysiology of pregnancy in the uterus, placenta, and beyond focusing on both opportunities and challenges. This article is categorized under: Reproductive System Diseases Computational Models
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.PLACENTA.2021.08.049
Abstract: Adequate development of the feto-placental circulation is critical for placental exchange function and healthy fetal growth. Understanding the structure of this circulation and how it informs fetal outcomes is important both in the human placenta, and the rodent, a purported comparative experimental model. Vascular casting and micro-CT imaging approaches enable detailed quantification of the complex vascular relationships in the feto-circulation, and provide detailed data to parameterise in silico models. Here, to assist researchers to apply these technically challenging methods we provide detailed approaches to cast and image 1) human placentas at the cotyledon-level, and 2) whole rodent placentas.
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1016/J.PLACENTA.2021.10.013
Abstract: Career trajectories in science are often unpredictable, with many early and mid-career researchers working multiple successive fixed-term contracts, and physically relocating to take up employment opportunities. Whilst this can provide exciting opportunities to change research direction, acquire new skills, and see the world, the precarity of this scenario is also a significant cause of anxiety for many, and can have a negative impact on their ability to maintain career momentum and trajectory, access institutional financial benefits, or make long term career or financial plans. Here, we build on a pair of workshops held at the 2021 International Federation of Placenta Associations annual conference to discuss two key areas important to help early career researchers navigate their careers - building an academic profile, and the financial ramifications of academic careers.
Publisher: Oxford University Press (OUP)
Date: 28-06-2018
Abstract: How does trophoblast plugging impact utero-placental haemodynamics? Physiological trophoblast plug structures are dense enough to restrict flow of oxygenated blood to the intervillous space (IVS) in the first trimester, and result in a shear stress environment upstream of the plugs that promotes spiral artery remodelling. Trophoblast plugging of the uterine spiral arteries is thought to be the dominant factor restricting the flow of oxygenated maternal blood to the placenta in the first trimester of pregnancy. However, the extent of plugging, the timing of plug break up, and the impact of plug structure on pregnancy outcomes is debated. A computational model of the uterine radial and spiral arteries, incorporating arteriovenous anastomoses was developed. The model was parameterized with our own histological data and previous literature descriptions of the dimensions of the spiral arteries, and the structural properties (porosity) of trophoblast plugs. Structural data were acquired from the literature, and supplemented by images of the spiral arteries acquired by standard thin-section 2D immunohistochemistry, and whole mount immunohistochemistry imaged in 3D by micro-CT. Computational models were solved using Matlab software, via custom written scripts. We confirm that physiological lengths (>0.1 mm) and porosities (0.2-0.6) of trophoblast plugs are sufficient to restrict the flow of oxygenated maternal blood flow to the placental surface. Trophoblast plugs also have important haemodynamic consequences upstream in the spiral arteries by generating shear stress conditions of <2 dyne/cm2 that promote trophoblast-induced spiral artery remodelling. Structural changes in plugs as they dislodge are likely to result in rapid increases in blood flow to the IVS, and it is likely at this stage of gestation that the major source of resistance in the utero-placental circulation transitions from the spiral arteries to the radial arteries, which then act as a the 'rate-limiting' step to IVS flow. Structural descriptions of the spiral arteries, radial arteries and trophoblast plugs largely rely on 2D histological sections, or historical measurements. Increased focus on quantitatively assessing the 3D structure of the uterine arteries using more modern imaging technologies in the future will strengthen model predictions. Our work suggests that trophoblast plugs play a previously under-appreciated role in regulating spiral artery remodelling in the first trimester of human pregnancy. This creates the possibility that inadequate trophoblast plugging in the first trimester may contribute to the inadequate artery remodelling observed in pregnancy pathologies such as pre-ecl sia. The incorporation of arteriovenous anastomoses in our model highlights the important influence that shunted blood can play in utero-placental haemodynamics, and together with the emerging role of radial arteries in regulating blood flow to the placenta, the influence of arteriovenous anastomoses on radial artery haemodynamics in normal and pathological pregnancies warrants further investigation. This research was supported by a Royal Society of New Zealand Marsden Fund award (13-UOA-032). A.R.C. is supported by a Royal Society of New Zealand Rutherford Discovery Fellowship (14-UOA-019). R.S. was supported by a Gravida (National Centre for Growth and Development) postgraduate scholarship. The authors have no conflicts of interest. N/A.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.PLACENTA.2016.08.001
Abstract: Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialised topics. At the 2015 IFPA annual meeting there were 12 themed workshops, three of which are summarized in this report. These workshops related to various aspects of placental biology and collectively covered areas of obesity and the placenta, stem cells of the feto-maternal interface, and placental immunobiology and infection.
Publisher: ASME International
Date: 20-03-2017
DOI: 10.1115/1.4036145
Abstract: Spiral arteries (SAs) lie at the interface between the uterus and placenta, and supply nutrients to the placental surface. Maternal blood circulation is separated from the fetal circulation by structures called villous trees. SAs are transformed in early pregnancy from tightly coiled vessels to large high-capacity channels, which is believed to facilitate an increased maternal blood flow throughout pregnancy with minimal increase in velocity, preventing damage to delicate villous trees. Significant maternal blood flow velocities have been theorized in the space surrounding the villi (the intervillous space, IVS), particularly when SA conversion is inadequate, but have only recently been visualized reliably using pulsed wave Doppler ultrasonography. Here, we present a computational model of blood flow from SA openings, allowing prediction of IVS properties based on jet length. We show that jets of flow observed by ultrasound are likely correlated with increased IVS porosity near the SA mouth and propose that observed mega-jets (flow penetrating more than half the placental thickness) are only possible when SAs open to regions of the placenta with very sparse villous structures. We postulate that IVS tissue density must decrease at the SA mouth through gestation, supporting the hypothesis that blood flow from SAs influences villous tree development.
Publisher: Oxford University Press (OUP)
Date: 20-12-2017
Abstract: What is the association between placental formyl peptide receptor 2 (FPR2) and trophoblast and endothelial functions in pregnancies affected by foetal growth restriction (FGR)? Reduced FPR2 placental expression in idiopathic FGR results in significantly altered trophoblast differentiation and endothelial function in vitro. FGR is associated with placental insufficiency, where defective trophoblast and endothelial functions contribute to reduced feto-placental growth. The expression of FPR2 in placental tissues from human pregnancies complicated with FGR was compared to that in gestation-matched uncomplicated control pregnancies (n = 25 from each group). Fpr2 expression was also determined in placental tissues obtained from a murine model of FGR (n = 4). The functional role of FPR2 in primary trophoblasts and endothelial cells in vitro was assessed in erse assays in a time-dependent manner. Placentae from third-trimester pregnancies complicated by idiopathic FGR (n = 25) and those from gestation-matched pregnancies with appropriately grown infants as controls (n = 25) were collected at gestation 27-40 weeks. Placental tissues were also collected from a spontaneous CBA/CaH × DBA/2 J murine model of FGR. Placental FPR2/Fpr2 mRNA expression was determined by real-time PCR, while protein expression was examined by immunoblotting and immunohistochemistry. siRNA transfection was used to silence FPR2 expression in primary trophoblasts and in human umbilical vein endothelial cells (HUVEC), and the quantitation of cytokines, chemokines and apoptosis was performed following a cDNA array analyses. Functional effects of trophoblast differentiation were measured using HCGB/β-hCG and syncytin-2 expression as well as markers of apoptosis, tumour protein 53 (TP53), caspase 8, B cell lymphoma 2 (BCL2) and BCL associated X (BAX). Endothelial function was assessed by proliferation, network formation and permeability assays. Placental FPR2/Fpr2 expression was significantly decreased in FGR placentae (n = 25, P < 0.05) as well as in murine FGR placentae compared to controls (n = 4, P < 0.05). FPR2 siRNA (siFPR2) in term trophoblasts significantly increased differentiation markers, HCGB and syncytin-2 cytokines, interleukin (IL)-6, CXCL8 and apoptotic markers, TP53, caspase 8 and BAX, but significantly reduced the expression of the chemokines CXCL12 and its receptors CXCR4 and CXCR7 CXCL16 and its receptor, CXCR6 and cytokine, IL-10, compared with control siRNA (siCONT). Treatment of HUVECs with siFPR2 significantly reduced proliferation and endothelial tube formation, but significantly increased permeability of HUVECs. N/A. Reduced expression of placental FPR2/Fpr2 was observed in the third trimester at delivery after development of FGR, suggesting that FPR2 is associated with FGR pregnancies. However, there is a possibility that the decreased placental FPR2 observed in FGR may be a consequence rather than a cause of FGR, although our in vitro functional analyses using primary trophoblasts and endothelial cells suggest that FPR2 may have a direct or indirect regulatory role on trophoblast differentiation and endothelial function in FGR. This is the first study linking placental FPR2 expression with changes in the trophoblast and endothelial functions that may explain the placental insufficiency observed in FGR. P.M. and P.R.E. received funding from the Australian Institute of Musculoskeletal Science, Western Health, St. Albans, Victoria 3021, Australia. M.L. is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC Grant no. 1047025). Monash Health is supported by the Victorian Government's Operational Infrastructure Support Programme. The authors declare that there is no conflict of interest in publishing this work.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.JTBI.2016.06.037
Abstract: The placenta is critical to fetal health during pregnancy as it supplies oxygen and nutrients to maintain life. It has a complex structure, and alterations to this structure across spatial scales are associated with several pregnancy complications, including intrauterine growth restriction (IUGR). The relationship between placental structure and its efficiency as an oxygen exchanger is not well understood in normal or pathological pregnancies. Here we present a computational framework that predicts oxygen transport in the placenta which accounts for blood and oxygen transport in the space around a placental functional unit (the villous tree). The model includes the well-defined branching structure of the largest villous tree branches, as well as a smoothed representation of the small terminal villi that comprise the placenta's gas exchange interfaces. The model demonstrates that oxygen exchange is sensitive to villous tree geometry, including the villous branch length and volume, which are seen to change in IUGR. This is because, to be an efficient exchanger, the architecture of the villous tree must provide a balance between maximising the surface area available for exchange, and the opposing condition of allowing sufficient maternal blood flow to penetrate into the space surrounding the tree. The model also predicts an optimum oxygen exchange when the branch angle is 24 °, as villous branches and TBs are spread out sufficiently to channel maternal blood flow deep into the placental tissue for oxygen exchange without being shunted directly into the DVs. Without concurrent change in the branch length and angles, the model predicts that the number of branching generations has a small influence on oxygen exchange. The modelling framework is presented in 2D for simplicity but is extendible to 3D or to incorporate the high-resolution imaging data that is currently evolving to better quantify placental structure.
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.PLACENTA.2021.07.290
Abstract: Placental structures at the nano-, micro-, and macro scale each play important roles in contributing to its function. As such, quantifying the dynamic way in which placental structure evolves during pregnancy is critical to both clinical diagnosis of pregnancy disorders, and mechanistic understanding of their pathophysiology. Imaging the placenta, both exvivo and invivo, can provide a wealth of structural and/or functional information. This review outlines how imaging across modalities and spatial scales can ultimately come together to improve our understanding of normal and pathological pregnancies. We discuss how imaging technologies are evolving to provide new insights into placental physiology across disciplines, and how advanced computational algorithms can be used alongside state-of-the-art imaging to obtain a holistic view of placental structure and its associated functions to improve our understanding of placental function in health and disease.
Publisher: The Royal Society
Date: 06-04-2015
Abstract: The placenta provides all the nutrients required for the fetus through pregnancy. It develops dynamically, and, to avoid rejection of the fetus, there is no mixing of fetal and maternal blood rather, the branched placental villi ‘bathe’ in blood supplied from the uterine arteries. Within the villi, the feto–placental vasculature also develops a complex branching structure in order to maximize exchange between the placental and maternal circulations. To understand the development of the placenta, we must translate functional information across spatial scales including the interaction between macro- and micro-scale haemodynamics and account for the effects of a dynamically and rapidly changing structure through the time course of pregnancy. Here, we present steps towards an anatomically based and multiscale approach to modelling the feto–placental circulation. We assess the effect of the location of cord insertion on feto–placental blood flow resistance and flow heterogeneity and show that, although cord insertion does not appear to directly influence feto–placental resistance, the heterogeneity of flow in the placenta is predicted to increase from a 19.4% coefficient of variation with central cord insertion to 23.3% when the cord is inserted 2 cm from the edge of the placenta. Model geometries with spheroidal and ellipsoidal shapes, but the same volume, showed no significant differences in flow resistance or heterogeneity, implying that normal asymmetry in shape does not affect placental efficiency. However, the size and number of small capillary vessels is predicted to have a large effect on feto–placental resistance and flow heterogeneity. Using this new model as an ex le, we highlight the importance of taking an integrated multi-disciplinary and multiscale approach to understand development of the placenta.
Publisher: American Physiological Society
Date: 07-2022
DOI: 10.1152/AJPHEART.00693.2021
Abstract: To our knowledge, this is the first data-driven computational model of autoregulation of uterine radial arteries, likely rate limiters of maternal blood flow to the placenta. The study demonstrates that uterine radial arteries behave differently from systemic vessels (higher compliance, shear-mediated constriction) and change their properties in pregnancy (higher myogenic tone, higher compliance, tolerance of higher flow rates). This pregnancy-specific mathematical model of vascular reactivity allows interrogation of the functional significance of incomplete vascular adaption in pathology.
Publisher: American Physiological Society
Date: 05-2017
DOI: 10.1152/PHYSIOL.00033.2016
Abstract: The utero-placental circulation links the maternal and fetal circulations during pregnancy, ensuring adequate gas and nutrient exchange, and consequently fetal growth. However, our understanding of this circulatory system remains incomplete. Here, we discuss how the utero-placental circulation is established, how it changes dynamically during pregnancy, and how this may impact on pregnancy success, highlighting how we may address knowledge gaps through advances in imaging and computational modeling approaches.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.PLACENTA.2021.11.004
Abstract: Early placental development lays the foundation of a healthy pregnancy, and numerous tightly regulated processes must occur for the placenta to meet the increasing nutrient and oxygen exchange requirements of the growing fetus later in gestation. Inadequacies in early placental development can result in disorders such as fetal growth restriction that do not present clinically until the second half of gestation. Indeed, growth restricted placentae exhibit impaired placental development and function, including reduced overall placental size, decreased branching of villi and the blood vessels within them, altered trophoblast function, and impaired uterine vascular remodelling, which together combine to reduce placental exchange capacity. This review explores the importance of early placental development across multiple anatomical aspects of placentation, from the stem cells and lineage hierarchies from which villous core cells and trophoblasts arise, through extravillous trophoblast invasion and spiral artery remodelling, and finally remodelling of the larger uterine vessels.
Publisher: SAGE Publications
Date: 14-09-2021
DOI: 10.1177/19476035211044822
Abstract: Mesenchymal stem/stromal cells (MSCs) are a well-established cell source for cartilage engineering, but challenges remain as differentiation often results in chondrocyte hypertrophy. Chondrogenic potential also varies with MSC source and donor age. We assessed the chondrogenic potential of first-trimester and term placental MSCs and compared their response to commonly used bone marrow MSCs (BM-MSCs). MSCs were isolated from first-trimester and term placentae. BM-MSCs were commercially obtained. Chondrogenesis was induced by micromass culture in commercial chondrogenic media for 7, 14, or 21 days. Pellets were assessed for glycosaminoglycan (GAG) content, and types I, II, and X collagen. Gene expression was profiled using Qiagen RT2 human MSC arrays. At day 0, first-trimester and term MSCs expression levels of many chondrogenic genes to BM-MSC after 21 days of culture. Only first trimester MSCs showed significant changes in chondrogenic gene expression during induction compared to day 0 undifferentiated MSCs (greater BMP4, KAT2B, and reduced GDF6 expression). Additionally, first-trimester MSCs showed significantly greater expression of ABCB1 (at days 14 and 21) and BMP4 (at days 7, 14, 21) compared with term MSCs. Both first-trimester and term pellets showed increased GAG content over time and term MSCs had significantly GAG greater compared with BM-MSCs at days 7 and 14. Type II collagen was present in all pellets but unlike BM-MSCs, type I collagen was not observed in first-trimester or term MSC pellets. These data highlight differences in BM-MSC and placental MSC chondrogenesis and demonstrate that placental MSCs may be an alternative cell source.
Publisher: Elsevier BV
Date: 06-2018
Start Date: 2023
End Date: 2026
Funder: Marsden Fund
View Funded ActivityStart Date: 2019
End Date: 2022
Funder: Marsden Fund
View Funded ActivityStart Date: 2014
End Date: 2017
Funder: Marsden Fund
View Funded Activity