Biology subjects

Muter, J.

Publications and source records attributed to Muter, J..

10 recordsLinked to original sources

bioRxiv2026

Whole slide image analysis of the endometrial decidual reaction reveals multiscale perturbations associated with miscarriage

The inflammatory decidual reaction renders the cycling endometrium transiently permissive for embryo implantation before transforming it into the decidua, the maternal bed accommodating the fetal placenta during pregnancy. Disruptions in decidual tissue remodeling are linked to miscarriage and other pregnancy disorders. However, endometrial assessment is hampered by a lack of affordable technologies capable of mapping the spatiotemporal dysregulation of this dynamic and complex tissue. Employing a graph neural network on whole slide images of 493 CD56-immunostained endometrial samples, Endometronome was developed as a deep learning tool to spatially track the decidual reaction and provide accurate estimates of marker gene expression. When applied to 2,690 additional biopsies, this model consistently identified morphological correlates of prior miscarriage burden, a proxy for future risk. Further, a morphological signature indicative of metabolic glandular impairment discriminated between clinical miscarriage presentations. These findings illustrate how advanced imaging analysis of routine histology can transform miscarriage prevention strategies.

pathology↗

bioRxiv2026

DCAFA: Differential Community Abundance and Feature Analysis for Histological Images

Histological images are composed of diverse local structures such as cells, glands, or tissue patches, whose organisation and relative abundance reflect underlying biological processes. While most computational approaches focus on analysing individual features, many clinically relevant signals arise from changes in the composition of these structures rather than isolated measurements. This motivates the need for explicitly modelling how groups of similar instances vary across samples and relate to outcomes. We present DCAFA (Differential Community Abundance and Feature Attribution Analysis), a regression-based framework for analysing hierarchical biomedical data through both compositional and feature-level perspectives. DCAFA groups instances into latent communities representing recurring morphological or phenotypic patterns, and then performs two complementary analyses: (i) community composition analysis, which identifies groups that are enriched or depleted across outcomes, and (ii) feature attribution analysis, which quantifies how instance-level features relate to outcomes directly or within specific communities. Both use generalised linear and mixed-effects models, enabling covariate adjustment and inference through effect sizes, confidence intervals, and false discovery rate control. We demonstrate the utility of DCAFA across multiple biomedical settings, including endometrial histopathology, spatial transcriptomics, multiplex immunofluorescence imaging, and predefined cell-type analyses in colorectal cancer. These examples identify interpretable compositional shifts and context-specific feature associations that are not captured by conventional feature-based approaches. By unifying differential abundance testing and feature attribution within a single statistical framework, DCAFA serves as an openly available toolbox that provides a practical and interpretable means of linking tissue composition with clinical or molecular outcomes in biomedical imaging data. Code available at: https://github.com/wgrgwrght/DCAFA

bioinformatics↗

bioRxiv2026

GOTFlow: Learning Directed Population Transitions from Cross-Sectional Biomedical Data with Optimal Transport

MotivationMany biological and clinical processes are dynamic, yet most datasets are cross-sectional, capturing populations at discrete states rather than tracking individuals over time. This makes it difficult to quantify how populations change across developmental, physiological, or disease-associated conditions. Existing trajectory and transport-based methods often rely on fixed feature spaces, assumptions tailored to transcriptomic time-course data, or approximately linear progression, limiting their ability to model heterogeneous and unbalanced transitions across diverse biomedical modalities. Flexible methods are needed that can infer directed population-level change from cross-sectional data while retaining biological interpretability. ResultsWe present GOTFlow, a framework for learning directed population transitions from cross-sectional biomedical data using graph-constrained optimal transport in a learned latent space. GOTFlow integrates representation learning with unbalanced optimal transport to jointly estimate embeddings and transport couplings between biological states. This enables hypothesis-driven modelling of progression structures while accommodating non-linear geometry, branching relationships, and changes in population mass. From the inferred transport plans, GOTFlow derives interpretable summaries of dynamics, including drift vectors quantifying transitions, and feature-level transported changes that highlight molecular drivers of progression. In synthetic data, GOTFlow recovered known transitions with strong agreement between inferred and ground-truth drifts. Across three biological applications, endometrial remodelling, breast cancer risk progression, and prion disease, GOTFlow identified state-to-state transitions and biologically meaningful feature shifts reflecting impaired decidualisation, increasing cancer risk, and neurodegenerative progression. These results establish GOTFlow as a general and interpretable framework for analysing directed population dynamics from cross-sectional data. AvailabilityCode available at: https://github.com/wgrgwrght/GOTFlow

bioinformatics↗

bioRxiv2025

An evolutionarily conserved microRNA, miR-185, regulates key pathways that may contribute to implantation failure.

Recurrent implantation failure (RIF) is defined after three or more good quality embryo transfers following in vitro fertilisation without a successful pregnancy outcome. Many factors contribute to RIF however, the endometrial contribution remains unclear. Previous work by our group has identified a micro-RNA (miRNA) miR-185-5p as conserved across placental mammal irrespective of implantation strategies. We tested the hypothesis that miR-185-5p and the pathways it regulates, may be disrupted in the endometria of women with RIF. A human endometrial epithelial cells line (Ishikawa cells) was transfected with mimics or inhibitors for miR-185-5p for 24 (for implantation assay) or 48 hr (for proteomic analysis) along with non-targeting controls. There was a significant different in percentage attachment of BeWoW spheroids to cells transfected with miR-185-5p mimic compared to inhibitor (P<0.05). Transfection of epithelial cells with miR-185-5p altered expression of 1450 (mimic alone) and 509 (inhibitor alone) proteins respective of which, 146 were modified by both. Comparison of predicted targets of miR-185-5p, proteins modified by this study, and key endometrial genes from the literature determined genes and proteins associated with CNP family were further investigated in biopsies from individuals with (n=10) and without RIF (n=9) with CSNK1D expression significantly lower (p<0.05) in individuals with RIF. Collectively these data demonstrate that miR-185-5p modifies pathways that are important for successful implantation in humans.

cell biology↗

bioRxiv2024

Stalling of the endometrial decidual reaction determines the recurrence risk of miscarriage risk

In each menstrual cycle, progesterone acting on estrogen-primed endometrium elicits an inflammatory decidual reaction, rendering it poised for embryo implantation and transformation into the decidua of pregnancy. Here, we show that the sequential functions of the decidual reaction - implantation and decidualization - pivot on the time-sensitive loss of progesterone-resistant stromal cells that form a transient implantation niche and reciprocal expansion of progesterone-responsive pre-decidual cells. In parallel, proliferation and differentiation increase the abundance of immunotolerant uterine natural killer (uNK) cells. Examination of pre-pregnancy endometrial biopsies from 924 women revealed that the frequency of cycles culminating in a blunted or stalled decidual reaction closely aligns with the age-independent recurrence risk of miscarriage. Further, analysis of 632 biopsies obtained in different cycles from 316 women indicated that prior miscarriages disrupt intercycle endometrial homeostasis, an observation supported by modelling the impacts of prolonged decidual inflammation in three-dimensional endometrial assembloids. Although stalling of the decidual reaction is often accompanied by a poor expansion of immunotolerant uNK cells, miscarriages do not impact intercycle uNK cell dynamics. Our findings indicate that intrinsic uterine mechanisms hardwire the recurrence risk of miscarriage, underscoring the need for pre-pregnancy diagnostics and therapeutics. One Sentence SummaryThe frequency of menstrual cycles culminating in a suboptimal decidual reaction determines the recurrence risk of miscarriage.

physiology↗

bioRxiv2023

Dynamic chromatin remodeling in cycling human endometrium at single cell level

Estrogen-dependent proliferation followed by progesterone-dependent differentiation of the endometrium culminates in a short implantation window. We performed single cell ATAC-seq on endometrial samples obtained across the menstrual cycle to investigate the regulation of temporal gene networks that control embryo implantation. We identified uniquely accessible chromatin regions in all major cellular constituents of the endometrium, delineated temporal patterns of coordinated chromatin remodeling in epithelial and stromal cells, and gained mechanistic insights into the emergence of a receptive state through integrated analysis of enriched transcription factor (TF) binding sites in dynamic chromatin regions, ChIP-seq analyses, and gene expression data. We demonstrate that the implantation window coincides with pervasive cooption of transposable elements (TE) into the regulatory chromatin landscape of decidualizing cells and expression of TE-derived transcripts in a spatially defined manner. Our data constitute the first comprehensive map of the chromatin changes that control TF activities in cycling endometrium at cellular resolution.

genomics↗

bioRxiv2020

Involvement of uterine natural killer cells in the natural selection of human embryos at implantation.

Decidualizing endometrial stromal cells (EnSC) critically determine the maternal response to an implanting conceptus, triggering either menstruation-like disposal of low-fitness embryos or creating an environment that promotes further development. However, the mechanism that couples maternal recognition of low-quality embryos to tissue breakdown remains poorly understood. Recently, we demonstrated that successful transition of the cycling endometrium to a pregnancy state requires selective elimination of pro-inflammatory senescent decidual cells by activated uterine natural killer (uNK) cells. Here we report that uNK cells express CD44, the canonical hyaluronan (HA) receptor, and demonstrate that high-molecular weight HA (HMWHA) inhibits uNK cell-mediated killing of senescent decidual cells. By contrast, low-molecular weight HA (LMWHA) did not attenuate uNK cell activity in co-culture experiments. Killing of senescent decidual cells by uNK cells was also inhibited upon exposure to medium conditioned by IVF embryos that failed to implant, but not successful embryos. Embryo-mediated inhibition of uNK cell activity was reversed by recombinant hyaluronidase 2 (HYAL2), which hydrolyses HMWHA. We further report a correlation between the levels of HYAL2 secretion by human blastocysts, morphological scores, and implantation potential. Taken together, the data suggest a pivotal role for uNK cells in embryo biosensing and endometrial fate decisions at implantation.

cell biology↗

bioRxiv2020

Impact of sustained TGFβ receptor inhibition on chromatin accessibility and gene expression in cultured human endometrial MSC

Endometrial mesenchymal stem cells (eMSC) drive the extraordinary regenerative capacity of the human endometrium. Clinical application of eMSC for therapeutic purposes is hampered by spontaneous differentiation and cellular senescence upon large-scale expansion in vitro. A83-01, a selective transforming growth factor-{beta} receptor (TGF{beta}-R) inhibitor, promotes pharmacological expansion of eMSC in culture by blocking differentiation and senescence, but the underlying mechanisms are incompletely understood. In this study, we combined RNA-seq and ATAC-seq to study the impact of sustained TGF{beta}-R inhibition on gene expression and chromatin architecture of eMSC. Treatment of primary eMSC with A83-01 for 5 weeks resulted in differential expression of 1,463 genes. Gene ontology analysis showed enrichment of genes implicated in cell growth whereas extracellular matrix genes and genes involved in cell fate commitment were downregulated. ATAC-seq analysis demonstrated that sustained TGF{beta}-R inhibition results in opening and closure of 3,555 and 2,412 chromatin loci, respectively. Motif analysis revealed marked enrichment of retinoic acid receptor (RAR) binding sites, which was paralleled by the induction of RARB, encoding retinoic acid receptor beta (RAR{beta}). Selective RAR{beta} inhibition attenuated proliferation and clonogenicity of A83-01 treated eMSC. Taken together, our study provides new insights into the gene networks and genome-wide chromatin changes that underpin maintenance of an undifferentiated phenotype of eMSC in prolonged culture. Significance statementCycling human endometrium is a rich source of adult stem/progenitor cells that could be exploited for clinical purposes. Small molecules, such as A83-01, that modulate cell identity may open new avenues to maintain the functional properties of eMSC upon expansion in culture. By integrating complementary genome-wide profiling techniques, we mapped the dynamic changes in chromatin landscape and gene expression in response to prolonged A83-01 treatment of eMSC. Our findings provide new insights into the mechanisms of action of TGF{beta}-R inhibition that may lead to the development of more targeted pharmacological approaches for MSC expansion.

cell biology↗

bioRxiv2018

Reconstruction of the Decidual Pathways in Human Endometrial Cells Using Single-Cell RNA-Seq

Breakdown of the feto-maternal interface in early pregnancy causes miscarriage. The cycling endometrium becomes poised to transition to a pregnant state during the midluteal implantation window, coinciding with differentiation of stromal cells into decidual cells (DC) and emergence of senescent decidual cells (snDC). Emerging evidence suggests that DC engage uterine natural killer cells to eliminate their senescent counterparts, thus enabling formation of a robust decidual matrix in pregnancy. To examine if failure to constrain snDC during the peri-implantation window increases the risk of miscarriage, we reconstructed the decidual pathway at single-cell level in vitro and demonstrated that, without immune surveillance, secondary senescence rapidly transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identified DIO2 and SCARA5 as marker genes of a diverging decidual response in vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in luteal phase endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage.

systems biology↗

bioRxiv2017

Clearance of senescent decidual cells by uterine natural killer cells drives endometrial remodeling during the window of implantation

In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives the transient inflammatory response associated with endometrial receptivity. Further, senescent cells prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. Our findings reveal that acute decidual senescence governs endometrial rejuvenation and remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining homeostasis in cycling endometrium.

cell biology↗