Biology subjects

Stener-Victorin, E.

Publications and source records attributed to Stener-Victorin, E..

9 recordsLinked to original sources

bioRxiv2026

An integrated multimodal pan-organ atlas of the female reproductive system across the lifespan contextualises gynaecological pathologies

Single cell transcriptomics has transformed our knowledge of reproductive tissues, yet studies remain largely organ-specific and temporally limited, leaving an incomplete picture of how cell types are distributed across the reproductive system over a lifetime. Gynaecological conditions affect more than one in four females and frequently span multiple organs and life stages. To advance our understanding and treatment of these conditions, an integrated cellular reference is essential. Here we present the Human Female Reproductive System Cell Atlas v1: a single-cell transcriptomic resource integrating more than 2M cells across the ovary, fallopian tube, uterus, cervix and vagina over the lifespan and menstrual cycle, further integrated with spatial transcriptomics and chromatin accessibility profiling to define 210 cell types through community-based annotation. Cross-organ integration resolves shared and organ-specific cellular states, identifying uterine-specific perivascular populations lining uterine spiral arteries, hypoxia-sensing type 3 innate lymphoid cells (ILC3s) enriched in the uterus, and lipid-associated macrophages with distinct subsets in each reproductive organ, including a previously undescribed population shared between the uterus and fallopian tube. Cross-organ integration enables detection of ectopic epithelial populations in otherwise healthy donors, including endometrial-like cells within a paediatric ovary consistent with early endometriosis. Integration with genome-wide association studies (GWAS) reveals that risk variants for major gynecological conditions act in mesenchymal cell states defined by specific transcriptional programmes and spatial or temporal context - for instance, heavy menstrual bleeding risk is enriched in basal fibroblasts (SFRP5) of the regenerative endometrial compartment. An integrated chromatin accessibility atlas provides peak-to-gene maps across reproductive cell types, enabling nomination of disease effector genes and providing the first regulatory evidence linking a Polyendocrine Metabolic Ovarian Syndrome (PMOS) risk locus to INHBB in granulosa cells. Together, this resource establishes a cellular and molecular framework for reproductive biology and the pathogenesis of neglected gynaecological conditions.

Cell Biology↗

bioRxiv2026

Cell type-resolved transcriptomic map of skeletal muscle in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with skeletal muscle insulin resistance, fibrosis, and lipotoxicity, yet the cellular origins remain unknown. Here, we present a comprehensive cellular atlas of skeletal muscle from hyperinsulinemic and hyperandrogenic women with PCOS and controls of similar age, weight, and BMI. Analysis of 72,247 nuclei from 19 biopsies revealed cell-type-specific dysregulation in PCOS, with fiber-type-specific metabolic impairment, converging with pro-fibrotic reprogramming of fibro-adipogenic progenitors (FAPs) and enhanced FAP-myofiber crosstalk, characterized by enhanced collagen and laminin signaling. Metformin intervention for 16-weeks selectively reversed PCOS-associated transcriptional dysregulation in FAPs, revealing heterogeneous cellular responses in skeletal muscle. In vitro, PCOS myotubes retained metabolic dysfunction, yet show normalized glucose responsiveness, indicating plasticity despite metabolic memory. Systemic hyperinsulinemia and hyperandrogenemia correlated with transcriptional signatures in muscle fibers and FAPs, linking endocrine imbalance to pro-fibrotic remodeling. These findings identify novel therapeutic targets beyond conventional insulin-sensitizing approaches. Highlights- First single-nuclei atlas of human skeletal muscle in women with PCOS - FAPs subpopulations display activated pro-fibrotic phenotype - Metformin selectively targets distinct cell populations - Hyperinsulinemia and hyperandrogenemia correlate with transcriptional signatures of skeletal muscle fibers and FAPs

physiology↗

bioRxiv2026

Hypoadiponectinemia does not enhance anxiety-like behaviour in a lean PCOS-like mouse model

Polycystic ovary syndrome (PCOS) is characterized by reproductive and metabolic disturbances and is associated with increased symptoms of anxiety and depression. Circulating adiponectin, an insulin-sensitizing adipokine, is reduced in women with PCOS, and low adiponectin has been linked to impaired mental health, particularly in females. We investigated whether low serum adiponectin is associated with impaired mental health in women with PCOS and whether adiponectin deficiency exacerbates anxiety-like behaviour in a PCOS-like mouse model. Serum adiponectin was measured in women with (n=179) and without PCOS (n=228), stratified by body mass index (BMI). Health-related quality of life was assessed using the SF-36, generating physical and mental component scores. In parallel, the prenatal androgenization (PNA) PCOS-like mouse model was combined with adiponectin-deficient mice (APNhet) to assess the impact of reduced adiponectin on anxiety-like behaviour with and without prenatal androgen exposure. Women with PCOS had lower total and high molecular weight adiponectin levels compared with controls. Adiponectin positively correlated with mental component scores in women with BMI <30, but not in those with obesity. Free testosterone was inversely correlated with adiponectin. In mice, PNA induced anxiety-like behaviour, however, reduced adiponectin did not exacerbate this phenotype. Although APNhet PNA mice showed 65% lower serum adiponectin levels and reproductive dysfunction, they displayed improved metabolic function. Unlike women with PCOS, adult PNA mice were not hyperandrogenic. These findings suggest that adiponectin is associated with mental health in non-obese women, but reduced adiponectin alone does not induce anxiety-like behaviour in the absence of hyperandrogenism. The differing patterns observed across BMI categories, as well as between the human cohort and experimental data, underscore the complexity of the mechanisms underlying mental health disturbances in PCOS.

animal behavior and cognition↗

bioRxiv2026

Implantation failure linked to altered uterine NK cells in PCOS-like mice

Uterine NK (uNK) cells are essential for reproductive function, yet little is known how they are affected in polycystic ovary syndrome (PCOS), despite the strong association between PCOS and reproductive complications. We demonstrate that implantation failure coincides with distinct phenotypic alterations of uNK cells in a PCOS-like mouse model. Hyperandrogenism caused an increased influx of conventional NK (cNK) cells into the uterus, which contributed to an augmented uNK cell population, while tissue-resident NK (trNK) cells remained unchanged. Notably, CD69+ trNK cells were reduced and seemingly compensated by an upregulated expression of CD69 on cNK cells in the uterus. The maturation of uNK cells was disrupted and plausibly linked to an inability of cNK cells to convert into trNK cells. The inhibited maturation was associated with a reduced expression of the inhibitory receptor NKG2A, demonstrating an impaired education of uNK cells. This disruption of uNK cells could contribute to endometrial dysfunction and may be an underlying factor to reproductive comorbidities such as implantation failure, miscarriage and pre-eclampsia in PCOS.

immunology↗

bioRxiv2025

Decoding human placental cellular and molecular responses to maternal obesity and fetal growth

Maternal obesity increases risk of large-for-gestational-age (LGA) births and subsequent cardiometabolic disorders in offspring. To identify placental signatures associated with these outcomes, we performed single-nucleus RNAseq on placentas from women with obesity delivering appropriate-for-gestational-age (AGA) or LGA infants, compared to normal-weight controls. In maternal obesity, regardless of fetal growth, syncytiotrophoblasts showed upregulated hypoxia and TNF- signaling, while cytotrophoblasts exhibited downregulated receptor tyrosine kinase signaling. However, only in LGA placentas, villous non-trophoblasts displayed upregulated TNF- signaling and inflammatory responses. Notably, Hofbauer cells in LGA placentas presented transcriptional alterations in immunometabolism-related genes and functioned as main signaling senders via SPP1. Importantly, we recapitulated syncytiotrophoblast responses to maternal obesity using a novel microfluidic organoids-on-a-chip co-culture. These findings reveal distinct transcriptional responses of placental cell types to maternal obesity and fetal growth, highlighting potential intervention pathways to mitigate future disease risks.

developmental biology↗

bioRxiv2024

Androgens modulate the immune profile in a mouse model of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with a low-grade inflammation, but it is unknown how hyperandrogenism, the hallmark of PCOS, affects the immune system. Using a well-established PCOS-like mouse model, we demonstrate that androgen exposure affects immune cell populations in reproductive, metabolic, and immunological tissues differently in a site-specific manner. Co-treatment with flutamide, an androgen receptor antagonist, prevents most of these alterations, demonstrating that these effects are mediated through androgen receptor activation. Dihydrotestosterone (DHT)-exposed mice display a drastically reduced eosinophil population in uterus compared to controls, coupled with lower levels of eotaxin (CCL11), suggesting a reduced recruitment from blood. Decreased frequencies of eosinophils were also seen in visceral adipose tissue (VAT). A higher expression level of CD69, a marker of activation or tissue residency, was consistently found on natural killer (NK) cells in all analyzed tissues. However, a higher frequency of NK cells and elevated levels of IFN-{gamma} and TNF- were only seen in uteri of androgen-exposed mice, while NK cell frequencies were unaffected in all other analyzed compartments. Distinct alterations of macrophages in ovaries, uterus and VAT were also found in DHT-exposed mice and could potentially be linked to PCOS-like traits of the model. Indeed, androgen-exposed mice were insulin resistant and displayed an aberrant immune profile in VAT, albeit unaltered fat mass. Collectively, we demonstrate that hyperandrogenism causes tissue-specific alterations of immune cells in reproductive organs and VAT, which could have considerable implications on tissue function and contribute to the reduced fertility and metabolic comorbidities associated with PCOS.

immunology↗

bioRxiv2023

Dissecting the Impact of Maternal Androgen Exposure on Offspring Health through Targeting the Androgen Receptor in Developmental Programming

Women with polycystic ovary syndrome (PCOS) exhibit sustained elevation in circulating androgens during pregnancy, an independent risk factor linked to pregnancy complications and adverse neonatal outcomes. Yet, further investigation is required to understand the precise mechanisms and the impact on cell-type specific placental dysfunction. To explore these dynamics, a PCOS-like mice model was induced with continuous androgen exposure throughout pregnancy, mimicking the human-PCOS. This resulted in impaired placental and embryonic development, leading to mid-gestation lethality. Co-treatment with the androgen receptor blocker, flutamide, prevented this lethality. Comprehensive analysis using whole-genome bisulfite and RNA sequencing revealed the diminished proportion of trophoblast precursors by downregulation of Cdx2. The absence of Gcm1, Synb, and Prl3b1 further resulted in decreased numbers of syncytiotrophoblasts and sinusoidal trophoblast giant cells, leading to observed compromised placenta labyrinth formation. Importantly, human trophoblast organoids exposed to androgens exhibited analogous alterations, highlighting impaired trophoblast differentiation as a key feature in PCOS-related pregnancy complications. Remarkably, all effects were mediated through the androgen receptor pathways, as demonstrated by comparable offspring phenotypes to controls when treated with flutamide. These findings provide novel insight into the PCOS-related pregnancy complications, and potential cellular targets for future treatment.

physiology↗

bioRxiv2023

The role of B cells in immune cell activation in polycystic ovary syndrome

Variations in B cell numbers are associated with polycystic ovary syndrome (PCOS) through unknown mechanisms. Here we demonstrate that B cells are not central mediators of PCOS pathology and that their frequencies are altered as a direct effect of androgen receptor activation. Hyperandrogenic women with PCOS have increased frequencies of age-associated double-negative B memory cells and increased levels of circulating immunoglobulin M (IgM). However, the transfer of serum IgG from women into wild-type female mice induces only an increase in body weight. Furthermore, RAG1 knock-out mice, which lack mature T- and B cells, fail to develop any PCOS-like phenotype. In wild-type mice, co-treatment with flutamide, an androgen receptor antagonist, prevents not only the development of a PCOS-like phenotype but also alterations of B cell frequencies induced by dihydrotestosterone (DHT). Finally, B cell-deficient mice, when exposed to DHT, are not protected from developing a PCOS-like phenotype. These results urge further studies on B cell functions and their effects on autoimmune comorbidities highly prevalent among women with PCOS. SummaryAndrogen receptor activation alters B cell frequencies and functionality as the transfer of human PCOS IgG increase weight in female mice. Lack of B cells does not protect from the development of a PCOS phenotype, suggesting an unrecognized role for B cells in PCOS autoimmune comorbidities. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/525671v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@15802fborg.highwire.dtl.DTLVardef@12bd154org.highwire.dtl.DTLVardef@1bc14a9org.highwire.dtl.DTLVardef@f08d2b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2018

Large-Scale Genome-Wide Meta Analysis of Polycystic Ovary Syndrome Suggests Shared Genetic Architecture for Different Diagnosis Criteria.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed with different criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease indicate shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. Only one locus differed in its association by diagnostic criteria, otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or Rotterdam criteria across common variants at 13 loci.

genetics↗