Sarah A. Robertson

In this study, we show that maternal Treg cell deficiency in early pregnancy leads to altered maternal cardiac structure and organ homeostasis in the early postpartum period. These findings imply that in addition to regulating pregnancy immune and vascular adaptation, Treg cells are also critical for maternal postpartum cardiovascular recovery.

Background: Pregnancy complications such as preeclampsia and fetal growth restriction are caused by compromised placentation associated with impaired maternal cardiovascular and immune adaptation to pregnancy, but the pathophysiological pathways underlying these impairments are not fully defined. C1q (complement component 1q) plays a central role in immune cell recruitment, functional regulation, and immune tolerance. In this study, we investigated the impact of maternal C1q deficiency on maternal uterine and systemic cardiovascular parameters in pregnancy. Methods: C1q null mutant ( C1qa ^−/− ) and C57BL/6 wild‐type control female mice were mated with BALB/c males. Cardiovascular adaptations were investigated by echocardiography and wire myography, as well as uterine artery ultrasound and decidual spiral artery assessment. Results: C1qa ^−/− dams exhibited increased fetal loss (↑3.6‐fold; P =0.011) and late gestation fetal growth restriction, notably among male fetuses ( P =0.002). Mesenteric arteries from C1qa ^−/− dams displayed heightened vasoconstriction ex vivo (area under the curve ↑34%; P =0.018). In midpregnancy, C1qa ^−/− dams exhibited uterine artery dysfunction (resistance index ↑23%; P =0.014), defective decidual spiral artery remodeling (vessel wall thickness: ↑16%; P =0.010), and reduced decidual perivascular macrophages surrounding spiral arteries (↓28%; P =0.050) compared with control dams. Conclusions: These findings indicate that maternal C1q deficiency disrupts key cardiovascular adaptations to pregnancy, likely contributing to poor fetal outcomes via impaired maternal hemodynamics and constrained placental function. This study identifies maternal C1q as a critical regulator of pregnancy‐induced vascular adaptation and supports mounting evidence for C1q relevance in pregnancy complications involving placental insufficiency.

Lipidic nanoparticles (LNPs) hold strong potential for cervicovaginal drug delivery, yet their behaviour in complex mucosal environments remains poorly understood, limiting rational design. Here, we systematically investigate five LNP formulations spanning lamellar (Lα) and non-lamellar (cubic and hexagonal) mesophases to establish composition-structure-function relationships under biologically relevant conditions. Using small-angle X-ray scattering, cryo-TEM, proteomics, flow cytometry, confocal microscopy, and cytotoxicity assays, we evaluate physicochemical properties, protein corona formation, cellular uptake, and structural dynamics in simulated vaginal fluid (SVF). Lipid composition emerged as the dominant determinant of nanoparticle behaviour, governing protein corona composition, cytotoxicity, and cellular internalisation, superseding contributions from nanostructure or surface stabilisation. Monoolein-based systems exhibited high protein affinity and enriched corona formation, whereas PEGylated lamellar liposomes showed reduced protein binding and high cellular uptake (>91%) with minimal cytotoxicity. In contrast, phytantriol formulations displayed pronounced toxicity and limited adaptive behaviour. Mucin modulated cellular uptake in a concentration-dependent manner, suppressing internalisation at low doses while enhancing uptake at higher concentrations for non-lamellar systems, indicating an active regulatory role in nanoparticle-cell interactions. In physiologically relevant environments, lipid composition also dictated structural responses: phytantriol-based LNPs remained structurally stable across pH 4.1-7.8, whereas monoolein/oleic acid systems underwent pH and ion dependent transitions that altered internal geometry and are expected to influence release behaviour. Collectively, these results demonstrate that nanoparticle identity and function in mucosal environments are defined by the interplay between lipid composition, protein adsorption, and environmental conditions. This work establishes design principles for cervicovaginal drug delivery, highlighting the need to integrate composition, interfacial behaviour, and environmental responsiveness to achieve effective mucosal nanocarriers.

Preparation of spermatozoa with optimal developmental competence remains a challenge in assisted reproduction. Conventional techniques based on sperm motility and morphology fail to adequately remove sperm with DNA damage. Here, we report development of a microfluidic device with a functionalized surface, inspired by the physiological processes of immune cell‐mediated sperm selection in the female reproductive tract. A plasma‐polymerized polyoxazoline (PPOx) film is applied to glass channel slides by deposition of 2‐methyl‐2‐oxazoline, to establish a stable, biocompatible interface confirmed by X‐ray Photoelectron Spectroscopy (XPS), ellipsometry, and sperm culture assays. To selectively eliminate pre‐apoptotic and apoptotic spermatozoa wherein DNA damage is common, anti‐phosphatidylserine (Anti‐PS) antibody is immobilized to the PPOx‐coated surface proximal to the channel slide inlet, while the sperm chemoattractant progesterone is adsorbed near the outlet. To optimize selective functionality, the surface topography is tailored by covalent immobilization of gold nanoparticles and addition of microchannels. Sperm recovered after processing whole liquified semen consistently exhibit high motility and morphology, and low apoptosis‐associated membrane damage, with <1% showing DNA fragmentation. Compared with conventional swim‐up or other microfluidic approaches, the device yields sperm with improved quality, offering a simple one‐step sperm selection strategy with potential for application in human and animal assisted reproduction.

BACKGROUND: Male fertility investigation is currently limited to semen analysis. However, the origins of abnormal sperm parameters are not well-understood, and normal sperm do not assure fertility in men. Improved pathophysiological and prognostic insight might be achieved utilising additional measures of male reproductive tract function. Cytokine and chemokine levels in seminal plasma (SP) may be relevant, but evidence on their clinical significance is unclear. The utility of measuring SP cytokines remains uncertain, and no consensus exists on which cytokines are most informative. OBJECTIVE AND RATIONALE: To perform a systematic review and meta-analysis on the association between fertility status and concentration of seminal plasma cytokines in men. The sixth edition of the WHO laboratory manual for the examination and processing of human semen raises the prospect of evaluating cytokines in SP as part of an extended examination. We performed a systematic search and meta-analysis to assess whether the current literature is sufficient to identify cytokines present in human SP that exhibit a relationship with fertility status in men. SEARCH METHODS: We searched PubMed, Web of Science, Scopus, and Embase from inception until April 2025, using keywords pertaining to seminal fluid and cytokines, restricted to humans and the English language. Original data with values reported as concentration of cytokines in SP of men clearly defined as infertile, compared to a discernible population of fertile/normozoospermic healthy control men, were included. A total of 5737 studies were identified, with 2737 duplicates removed. Title and abstract screening were performed for 3000 studies, then 291 studies underwent full-text screening, and 68 studies progressed to quality assessment using the NHLBI-NIH quality assessment tool and 52 studies underwent data extraction. OUTCOMES: We identified 52 research articles published from 1993 to 2025 that quantified at least one cytokine in the seminal plasma of 8153 men, after 19 studies of poor quality and/or containing serious flaws were excluded. Data on 30 cytokines in the SP of healthy control and infertile men were extracted and included in narrative synthesis. Compared to fertile controls, infertile men had elevated concentrations of IL6 (SMD 0.39, 95% CI; 0.14–0.64, I2 = 80.7%), TNFA (SMD 0.13, 95% CI; 0.00–0.25, I2 = 4.3%), and CXCL8 (SMD 0.24, 95% CI; 0.06–0.43, I2 = 0.0%) in seminal plasma. IL6 reported a high degree of heterogeneity between studies, whilst CXCL8 and TNFA reported low heterogeneity. No significant moderator effects due to study quality or composition of the control cohort were identified. WIDER IMPLICATIONS: With one in six couples experiencing infertility worldwide and a male factor identified as a primary or contributing cause in up to 50% of cases, there is a strong imperative to develop a better understanding of the pathophysiology of male infertility. This analysis identifies an association between infertility and elevated SP IL6, CXCL8, and TNFA, but whether these pro-inflammatory cytokines reflect events affecting fertility or are simply markers of transient inflammation and/or cofactors of fertility status remains to be determined. Greater precision in quantifying seminal plasma cytokines will be attained, and additional informative cytokines may be identified, by utilising standardised technical approaches in future studies. REGISTRATION NUMBER: CRD42023398438.

Declining reproductive health and fertility are global public health issues affecting an estimated 15% of reproductive-aged couples worldwide. The reasons for declining fertility are complex. However, a male contribution is thought to occur in ∼50% of infertile couples. Deficits in sperm number and/or function are undeniably a major cause of infertility, but compelling evidence suggests that additional factors in the male ejaculate also play an influential and underappreciated role. In this review, we focus specifically on extracellular vesicles within human seminal plasma and explore their emerging roles in reproduction and fertility. These seminal extracellular vesicles (SEVs) are nano-sized membrane structures secreted by various cell lineages in virtually all regions of the male reproductive tract and exert key roles in intercellular communication. Consideration is given to the well-characterized effects of SEVs in supporting sperm as they transit through the female reproductive tract and their ability to modulate the immune environment within the female reproductive tract. Building on these important roles, we also detail the emerging links between dysregulated SEV production and male fertility status, and highlight the potential utility of leveraging these vesicles to improve fertility and reproductive outcomes in infertile couples. Altogether, this review highlights how expanding knowledge of SEVs provides a new perspective on the complexity of seminal fluid physiology and the underlying aetiology of male infertility.

When seminal fluid is delivered into the female reproductive tract by natural mating or artificial insemination, seminal fluid components elicit biological responses from female tract cells and tissues. This “male to female seminal fluid signaling” affects the chances of conception and pregnancy, depending on the balance of signals in the seminal fluid – which can vary in relation to the genetics and physiological state of individual males. Seminal plasma is instrumental in eliciting female responses, and sperm also contribute. Signaling agents include cytokines and prostaglandins synthesized in the seminal vesicles and other male accessory glands, delivered to the female tract in soluble form, as cargo of seminal extracellular vesicles, or in association with sperm. These agents modulate oviduct and endometrium secretions, and activate immune cell recruitment and gene expression changes in female reproductive tissues, that in turn initiate an adaptive immune response to semen and the conceptus. Collectively these effects can exert either permissive or inhibitory consequences for conception, embryo development, and receptivity to implantation. Extensive studies show seminal fluid effects in porcine, equine, bovine, ovine and canine species, with variations between species due to the site of seminal fluid deposition and female reproductive tract anatomy. Greater insight into the biological function and molecular basis of seminal fluid effects in females has potential applications in novel treatments and management practices to support optimal reproductive outcomes in domestic, livestock and endangered animal species.