Biology subjects

Cleal, J. K.

Publications and source records attributed to Cleal, J. K..

7 recordsLinked to original sources

bioRxiv2026

Endometrial transcriptomic and ciliation analysis after scratch shows no signature linked to live birth following IVF

ObjectiveTo determine whether endometrial scratch induces differences in transcriptomic profiles or epithelial cell ciliation in the endometrium at the window of implantation that associate with live birth following IVF. DesignSecondary analysis of 50 matched endometrial biopsies collected within a randomised controlled trial evaluating the clinical effectiveness of endometrial scratch before first-time IVF. SettingEndometrial biopsy samples were obtained from women attending the Jessop Wing of Sheffield Teaching Hospitals. Population or SampleWomen undergoing first-time IVF who received an endometrial scratch in the preceding cycle at the window of implantation (6-10 days after LH surge). MethodsEndometrial biopsies were molecularly dated using transcriptomic menstrual-cycle staging algorithms. Bulk RNA sequencing was analysed using DESeq2 with FDR correction, and principal component analysis (PCA) assessed clustering patterns. Epithelial cell ciliation was quantified using immunohistochemistry and an automated Python-based image analysis pipeline. Main Outcome MeasuresDifferential endometrial gene expression between women with and without live birth after IVF; percentage coverage of ciliated epithelial cells in luminal and glandular regions. ResultsTranscriptomic dating confirmed no differences in menstrual-cycle timing between live-birth and no-live-birth groups. No significant differential gene expression was detected (log2FC >2, FDR <0.05), and PCA showed no clustering by pregnancy outcome. Ciliation coverage did not differ between outcome groups or between glandular and luminal surfaces. ConclusionsWhen implantation timing is precisely defined, endometrial scratch does not produce detectable transcriptomic changes or alterations in epithelial ciliation that distinguish women who achieve live birth after IVF. FundingWellbeing of Women RG2147; Wessex Medical Research; Rosetrees Trust (PGS23/100171).

physiology↗

bioRxiv2026

Evidence for independent retroviral syncytin-like Env endogenization in non-placental chondrichthyans

Viviparity and placentation are remarkable examples of convergent evolution across vertebrates. The evolution of the uniquely intimate mammalian placenta has been associated with the repeated independent capture of fusogenic retroviral Env proteins, called syncytins. Research into syncytin capture has therefore been predominantly focused on resolving their central role in mammalian placentation. As such, the presence of syncytin-like Env proteins outside of mammals, and their role in non-placental physiological contexts, remain much less understood. We expanded this understanding by systematically surveying genomes from 36 chondrichthyan species (sharks, rays, skates, and chimaeras), which display a wide range of independently evolved placental and non-placental reproductive strategies, for the presence of syncytin-like Env genes. We identified 295 candidate syncytin-like Env proteins from 16 chondrichthyan species, with a subset displaying conserved fusogenic domains, structural homology with known syncytins, and genomic signatures of endogenization. Using transcriptomic data from the model catshark Scyliorhinus canicula, we found that syncytin-like Env genes are transcriptionally active in diverse adult tissue types. Using two closely related species of Squalus (spiny dogfish), we present evidence that endogenized Env genes are syntenically conserved, indicative of vertical transmission from a common ancestor before species divergence. Notably, we detected no candidates in any placental shark genome, suggesting that syncytin-like Env capture is not a feature of shark placentation. Our findings expand the known phylogenetic breadth and functional scope of syncytin-like Env protein endogenization beyond mammalian placentation, providing a solid foundation for future investigations into the wider role of retroviral capture in vertebrate biology and evolution.

evolutionary biology↗

bioRxiv2024

Changes in the cellular composition of the endometrium during the implantation window are associated with recurrent pregnancy loss

Recurrent pregnancy loss (RPL) affects 1-2% of women trying to conceive, yet in many cases the causes remain unclear. Endometrial function is central to the establishment and maintenance of pregnancy, and endometrial dysfunction may underlie RPL. A greater understanding of the endometrial cell populations and their interactions in women with and without RPL may identify markers of endometrial receptivity and the likelihood of pregnancy success. Single cell RNA sequencing was performed on RPL (n = 3) and control (n = 4) endometrial biopsies collected at days 21-24 of the menstrual cycle, the window of implantation. 10,022 cells were clustered and nine major individual cell types were characterised. Further analysis identified six distinct endometrial stromal cell (EnSCs) and three natural killer (NK) cell sub-populations. In RPL, there were changes in the abundance of specific endometrial stromal and NK cell subpopulations with associated differences in cellular communication between the cell types related to the Wnt pathway and angiogenesis. This is consistent with NK cell signalling orchestrating the difference in abundance of stromal cells and regulating processes needed for successful implantation. These changes in RPL endometrium provide further evidence for an endometrial cause of RPL and identify specific mechanisms for future study.

genomics↗

bioRxiv2022

Regulation of human trophoblast gene expression by endogenous retroviruses

The placenta is a fast-evolving organ with large morphological and histological differences across eutherians, but the genetic changes driving placental evolution have not been fully elucidated. Transposable elements, through their capacity to quickly generate genetic variation and affect host gene regulation, may have helped to define species-specific trophoblast gene expression programmes. Here, we assessed the contribution of transposable elements to human trophoblast gene expression as enhancers or promoters. Using epigenomic data from primary human trophoblast and trophoblast stem cell lines, we identified multiple endogenous retrovirus families with regulatory potential that lie close to genes with preferential expression in trophoblast. These largely primate-specific elements are associated with inter-species gene expression differences, and are bound by transcription factors with key roles in placental development. Using genetic editing we demonstrated that several elements act as transcriptional enhancers of important placental genes, such as CSF1R and PSG5. We also identified an LTR10A element that regulates ENG expression, affecting secretion of soluble ENG, with potential implications for preeclampsia. Our data show that transposons have made important contributions to human trophoblast gene regulation, and suggest that their activity may affect pregnancy outcomes.

genetics↗

bioRxiv2022

3D Visualisation of trans-syncytial nanopores provides a pathway for paracellular diffusion across the human placental syncytiotrophoblast

The placental syncytiotrophoblast, a syncytium without cell-cell junctions, is the primary barrier between the mother and the fetus. Despite no apparent anatomical pathway for paracellular diffusion of solutes across the syncytiotrophoblast size-dependent paracellular diffusion is observed. Here we report data demonstrating that the syncytiotrophoblast is punctuated by trans-syncytial nanopores (TSNs). These membrane-bound TSNs directly connect the maternal and fetal facing sides of the syncytiotrophoblast, providing a pathway for paracellular diffusion between the mother and fetus. Mathematical modelling of TSN permeability based on their 3D geometry suggests that 10-37 million TSNs per cm3 of placental tissue could explain experimentally observed placental paracellular diffusion. TSNs may mediate physiological hydrostatic and osmotic pressure homeostasis between the maternal and fetal circulations but also expose the fetus to pharmaceuticals, environmental pollutants and nanoparticles.

physiology↗

bioRxiv2021

PAEP and cilia gene splicing changes in endometrial glands during the implantation window in women with recurrent pregnancy loss

Endometrial glands are essential for fertility, consisting of ciliated and secretory cells that facilitate a suitable uterine environment for embryo implantation. This study sought to determine whether an endometrial gland specific transcriptome and splicing profile are altered in women with recurrent pregnancy loss. Our data provide a comprehensive catalogue of cilia and PAEP gene isoforms and relative exon usage in endometrial glands. We report a previously unannotated endometrial gland cilia transcript GALNT11 and its susceptibility to exon skipping. Key endometrial receptivity gene transcripts are also reported to change in endometrial glands of women with recurrent pregnancy loss. The endometrial gland cilia and PAEP targets identified in this study could be used to identify a perturbed endometrium, isolate causes of recurrent pregnancy loss and develop targeted therapies in personalised medicine.

developmental biology↗

bioRxiv2021

Placental uptake and metabolism as determinants of pregnancy vitamin D status

Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.

physiology↗