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Valerie J Grant and Lawrence W Chamley

Although controversial, growing evidence from evolutionary biology suggests that the mammalian mother may have a role in influencing the sex of her offspring. However, there is competing information on the molecular mechanisms by which such influence could be manifested. The new initiatives are based on hypotheses from evolutionary biology: the ‘good condition’ hypothesis, which suggests that post conception, higher levels of maternal glucose may differentially promote the development of male embryos; and the ‘maternal dominance’ hypothesis, which proposes that before conception, higher follicular testosterone may influence the development of the ovum so that it emerges already adapted to receive an X- or a Y-chromosome-bearing spermatozoon. Now, it seems these hypothesised mechanisms could be operating in synchrony, each complementing and reinforcing the other. On the other hand, there are continuing problems in identifying a precise sequence of mechanisms as evidenced from research in sperm-sorting. Research on high-fat diets and the sex ratio in polytocous species may indicate important differences in proximate mechanisms for sex allocation between polytocous and monotocous mammals.

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Priyadarshini Pantham, Vikki M Abrahams, and Lawrence W Chamley


Anti-phospholipid antibodies (aPL) are autoantibodies that are associated with thrombosis and a range of pregnancy complications including recurrent pregnancy loss and pre-eclampsia. The three clinically relevant, well-characterized aPL are anti-cardiolipin antibodies, lupus anticoagulant and anti-beta-2-glycoprotein I (β2GPI) antibodies. aPL do not bind directly to phospholipids but instead bind to a plasma-binding ‘cofactor’. The most extensively studied cofactor is β2GPI, whose role in pregnancy is not fully elucidated. Although the pathogenicity of aPL in recurrent pregnancy loss is well established in humans and animal models, the association of aPL with infertility does not appear to be causative. aPL may exert their detrimental effects during pregnancy by directly binding trophoblast cells of the placenta, altering trophoblast signalling, proliferation, invasion and secretion of hormones and cytokines, and by increasing apoptosis. Heparin is commonly used to treat pregnant women with aPL; however, as thrombotic events do not occur in the placentae of all women with aPL, it may exert a protective effect by preventing the binding of aPL to β2GPI or by acting through non-thrombotic pathways. The aim of this review is to present evidence summarizing the current understanding of this field.

Free access

Joanna L James, Peter R Stone, and Lawrence W Chamley

It is commonly accepted that a single pool of villous cytotrophoblasts are precursors of both syncytiotrophoblast and extravillous trophoblasts during the first trimester. Here we present evidence that these two trophoblast subpopulations arise from separate progenitors that have different survival characteristics when studied in villous explant cultures. Dual staining with chloromethylfluorescin diacetate and ethidium bromide revealed degeneration of the syncytiotrophoblast by non-apoptotic mechanisms within 4 h of culture. The syncytiotrophoblast had regenerated within 48 h but at this point the vast majority of the cytotrophoblast and cells of the mesenchymal core were dead. Despite this extensive cytotrophoblast death, explants are able to produce extravillous trophoblast outgrowth for up to 3 weeks in culture. We believe that the villous cytotrophoblasts in the tips of anchoring villi are resistant to the factors that cause the death of the majority of villous cytotrophoblasts in culture. We speculate that as early as 8 weeks of gestation there are two separate villous cytotrophoblast populations, one committed to differentiate into syncytiotrophoblast and the second committed to the extravillous differentiation pathway

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Mancy Tong, Qi Chen, Joanna L James, Michelle R Wise, Peter R Stone, and Lawrence W Chamley

Throughout human gestation, the placenta extrudes vast quantities of extracellular vesicles (EVs) of different sizes into the maternal circulation. Although multinucleated macro-vesicles are known to become trapped in the maternal lungs and do not enter the peripheral circulation, the maternal organs and cells that smaller placental micro-vesicles interact with in vivo remain unknown. This study aimed to characterise the interaction between placental micro-vesicles and endothelial cells in vitro and to elucidate which organs placental micro-vesicles localise to in vivo. Placental macro- and micro-vesicles were isolated from cultured human first trimester placental explants by sequential centrifugation and exposed to human microvascular endothelial cells for up to 72 h. In vivo, placental macro- and micro-vesicles were administered to both non-pregnant and pregnant CD1 mice, and after two or 30 min or 24 h, organs were imaged on an IVIS Kinetic Imager. Placental EVs rapidly interacted with endothelial cells via phagocytic and clathrin-mediated endocytic processes in vitro, with over 60% of maximal interaction being achieved by 30 min of exposure. In vivo, placental macro-vesicles were localised exclusively to the lungs regardless of time of exposure, whereas micro-vesicles were localised to the lungs, liver and kidneys, with different distribution patterns depending on the length of exposure and whether the mouse was pregnant or not. The fact that placental EVs can rapidly interact with endothelial cells and localise to different organs in vivo supports that different size fractions of placental EVs are likely to have different downstream effects on foeto–maternal communication.

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Anna L Boss, Lawrence W Chamley, Anna E S Brooks, and Joanna L James

Placentae from pregnancies with foetal growth restriction (FGR) exhibit poor oxygen and nutrient exchange, in part due to impaired placental vascular development. Placental mesenchymal stromal cells (pMSCs) reside in a perivascular niche, where they may influence blood vessel formation/function. However, the role of pMSCs in vascular dysfunction in FGR is unclear. To elucidate the mechanisms by which pMSCs may impact placental vascularisation we compared the transcriptomes of human pMSCs isolated from FGR (<5th centile) (n = 7) and gestation-matched control placentae (n = 9) using Affymetrix microarrays. At the transcriptome level, there were no statistically significant differences between normal and FGR pMSCs; however, several genes linked to vascular function exhibited notable fold changes, and thus the dataset was used as a hypothesis-generating tool for possible dysfunction in FGR. Genes/proteins of interest were followed up by real-time PCR, western blot and immunohistochemistry. Gene expression of ADAMTS1 and FBLN2 (fibulin-2) were significantly upregulated, whilst HAS2 (hyaluronan synthase-2) was significantly downregulated, in pMSCs from FGR placentae (n = 8) relative to controls (n = 7, P  < 0.05 for all). At the protein level, significant differences in the level of fibulin-2 and hyaluronan synthase-2, but not ADAMTS1, were confirmed between pMSCs from FGR and control pregnancies by Western blot. All three proteins demonstrated perivascular expression in third-trimester placentae. Fibulin-2 maintains vessel elasticity, and its increased expression in FGR pMSCs could help explain the increased distensibility of FGR blood vessels. ADAMTS1 and hyaluronan synthase-2 regulate angiogenesis, and their differential expression by FGR pMSCs may contribute to the impaired angiogenesis in these placentae.

Free access

Yohanes N S Nursalim, Cherie Blenkiron, Katie M Groom, and Lawrence W Chamley

Trophoblasts are unique epithelial cells found only in the placenta. It has been possible to isolate and maintain human trophoblasts in in vitro culture for many decades. During this period there have been a vast array of media and supplements reported for trophoblast culture and often the reasons for using the media and specific supplements employed in any given laboratory have been lost in the ‘mists of time’. After a gradual development over many years this field has recently changed, with the publication of several reports of the isolation, growth and differentiation of human trophoblast stem or stem-like cells. This advance was made largely because of a greater understanding of the molecular pathways that control human trophoblasts and availability of media supplements that can be used to manipulate those pathways. We have searched the literature and here summarise many of the different media and supplements and describe how and why they were developed and are used to culture human trophoblasts.

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Zoe Tasma, Weilin Hou, Tanvi Damani, Kathleen Seddon, Matthew Kang, Yi Ge, David Hanlon, Fiona Hollinshead, Colin L Hisey, and Lawrence W Chamley

In brief

Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) have shown promise as off-the-shelf therapeutics; however, producing them in sufficient quantities can be challenging. In this study, MSCs were isolated from preimplantation equine embryos and used to produce EVs in two commercially available bioreactor designs.


Mesenchymal stromal cells (MSC) have recently been explored for their potential use as therapeutics in human and veterinary medicine applications, such as the treatment of endometrial inflammation and infertility. Allogeneic MSC-derived extracellular vesicles (EVs) may also provide therapeutic benefits with advantage of being an ‘off-the-shelf’ solution, provided they can be produced in large enough quantities, without contamination from bovine EVs contained in fetal bovine serum that is a common component of cell culture media. Toward this aim, we demonstrated the successful isolation and characterization of equine MSCs from preimplantation embryos. We also demonstrate that many of these lines can be propagated long-term in culture while retaining their differentiation potential and conducted a head-to-head comparison of two bioreactor systems for scalable EV production including in serum-free conditions. Based on our findings, the CELLine AD 1000 flasks enabled higher cell density cultures and significantly more EV production than the FiberCell system or conventional culture flasks. These findings will enable future isolation of equine MSCs and the scalable culture of their EVs for a wide range of applications in this rapidly growing field.