A single-cell atlas of the aging mouse ovary

Nature Aging, Journal Year: 2024, Volume and Issue: 4(1), P. 145 - 162

Published: Jan. 10, 2024

Abstract Ovarian aging leads to diminished fertility, dysregulated endocrine signaling and increased chronic disease burden. These effects begin emerge long before follicular exhaustion. Female humans experience a sharp decline in fertility around 35 years of age, which corresponds declines oocyte quality. Despite growing body work, the field lacks comprehensive cellular map transcriptomic changes mouse ovary identify early drivers ovarian decline. To fill this gap we performed single-cell RNA sequencing on tissue from young (3-month-old) reproductively aged (9-month-old) mice. Our analysis revealed doubling immune cells ovary, with lymphocyte proportions increasing most, was confirmed by flow cytometry. We also found an age-related downregulation collagenase pathways stromal fibroblasts, rises fibrosis. Follicular displayed stress-response, immunogenic fibrotic pathway inductions aging. This report provides critical insights into mechanisms responsible for phenotypes. The data can be explored interactively via Shiny-based web application.

Language: Английский

---

A single-cell atlas of the cycling murine ovary

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Oct. 7, 2022

The estrous cycle is regulated by rhythmic endocrine interactions of the nervous and reproductive systems, which coordinate hormonal ovulatory functions ovary. Folliculogenesis follicle progression require orchestrated response a variety cell types to allow maturation its sequela, ovulation, corpus luteum formation, wound repair. Little known about state dynamics ovary during paracrine factors that help this process. Herein, we used single-cell RNA sequencing evaluate transcriptome >34,000 cells adult mouse describe transcriptional changes occur across normal other states build comprehensive dynamic atlas murine ovarian states.

Language: Английский

---

Effects of Gonadotropin‐Releasing Hormone Analogues on Ovarian Function and Embryogenesis: A Cyclophosphamide‐Induced Mouse Model Study

BJOG An International Journal of Obstetrics & Gynaecology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

ABSTRACT Objective To clarify the protective effects of gonadotropin‐releasing hormone analogues (GnRHas) on cyclophosphamide (CTX)‐induced oocyte number loss and development potential damage. Design Mice model study. Setting Laboratory‐based animal study conducted in controlled research facilities. Population Female C57/BL6 mice subjected to CTX‐induced ovarian Methods The GnRHa CTX were evaluated terms hormones, count slices, established three‐dimensional–constructed ovaries, vitro fertilisation, RNA sequencing microinjection. Main Outcome Measures main outcome measures oocytes intact mouse ovaries quality, using three‐dimensional (3D) tissue‐clearing methods, oxidative stress markers (reactive oxygen species [ROS] malondialdehyde [MDT]), mitochondrial function (ATP levels), embryogenesis rates at two‐cell, four‐cell blastocyst stages. Results In mice, pretreatment did not protect endocrine changes, but protected slice counting. A technique, CUBIC (Clear, Unobstructed Body Imaging Cocktails), was a suitable method for clearing, 3D counting validated with accuracy 105.22% ± 3.48%. By this method, also found (597 28 vs. 222 15, p < 0.0001), which may be mediated by upregulated anti‐Müllerian (AMH) levels inhibiting primordial follicle approved culture ovaries. increased retrieved (19.4 2.1 15.0 1.6, 0.0001) developmental ability (65.0 4.6 48.1 4.2 blastocyst, 0.0001). revealed downregulated pathways exogenous drug metabolism, cytochrome P450, detection adenosine triphosphate (ATP), MDA ROS levels. up‐expression Cox17 (cytochrome c oxidase copper chaperone 17) after confirmed PCR microinjection si from mice. Conclusions associated reduced improved embryogenesis, likely AMH upregulation.

Language: Английский

---

Anti-Mullerian hormone attenuates both cyclophosphamide-induced damage and PI3K signalling activation, while rapamycin attenuates only PI3K signalling activation, in human ovarian cortex in vitro

Human Reproduction, Journal Year: 2023, Volume and Issue: 39(2), P. 382 - 392

Published: Dec. 9, 2023

Abstract STUDY QUESTION What are the effects of cyclophosphamide exposure on human ovary and can anti-Mullerian hormone (AMH) rapamycin protect against these? SUMMARY ANSWER Exposure to compromises health primordial transitional follicles in ovarian cortex upregulates PI3K signalling, indicating both direct damage increased follicular activation; AMH attenuates these chemotherapy-induced effects, while only signalling upregulation. WHAT IS KNOWN ALREADY Studies primarily rodents demonstrate that causes or follicle pool is depleted through excessive initiation growth. This activation mediated via upregulated and/or reduced local levels production due lost growing follicles. Furthermore, rodent data show promise regarding potential benefits inhibitors/protectants alongside chemotherapy treatment preserve female fertility, there no information about for this humans. DESIGN, SIZE, DURATION Fresh cortical biopsies were obtained from 17 healthy women aged 21–41 years (mean ± SD: 31.8 4.9 years) at elective caesarean section. Biopsies cut into small fragments cultured 24 h with either vehicle alone (DMSO), active metabolite 4-hydroperoxycyclophosphamide (4-HC) alone, 4-HC + 4-HC+AMH. Two doses investigated, 0.2 2 μM separate experiments, using seven (aged 27–41) six 21–34), respectively. four 28–38) used investigate effect only. PARTICIPANTS/MATERIALS, SETTING, METHODS Histological analysis tissue was undertaken staging assessment. Western blotting immunostaining assess by measuring phosphorylation AKT phosphorylated FOXO3A staining intensity, MAIN RESULTS AND THE ROLE OF CHANCE dose caused an increase proportion unhealthy (P &lt; 0.0001, doses) 0.01 low P high dose) compared vehicle. significantly approximately half investigated 0.0001), had protective Culture health. Activation following demonstrated showing non-growing oocytes. Treatment experiments culture (both intensity) across investigated. LIMITATIONS, REASONS FOR CAUTION These vitro studies may not replicate vivo exposures. longer experiment durations needed determine whether observed translate irreparable deficits WIDER IMPLICATIONS FINDINGS provide a solid foundation which explore efficacy protecting gonadotoxic chemotherapies. Future work will require consideration sustained protectants ensure agents do impair developmental competence oocytes lead survival accumulated DNA damage, could have adverse consequences offspring. FUNDING/COMPETING INTEREST(S) supported grants TENOVUS Scotland, Academy Medical Sciences (to R.R.), Research Council (G1100357 R.A.A., MR/N022556/1 MRC Centre Reproductive Health), Merck Serono UK R.A.A.). R.R., H.L.S., N.S., E.E.T. declare conflicts interest. R.A.A. reports personal fees Roche Diagnostics Ferring Pharmaceuticals, IBSA outside submitted work. TRIAL REGISTRATION NUMBER N/A.

Language: Английский

---

Comprehensive Review of In Vitro Human Follicle Development for Fertility Restoration: Recent Achievements, Current Challenges, and Future Optimization Strategies

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(6), P. 1791 - 1791

Published: March 20, 2024

Ovarian tissue cryopreservation (OTC) and subsequent transplantation (OTT) is a fertility preservation technique widely offered to prepubertal girls young fertile women who need undergo oncological treatment but are at high risk of infertility. However, OTT not considered safe in patients with certain diseases like leukemia, Burkitt’s lymphoma, ovarian cancer because the associated malignant cell reintroduction. In vitro follicle development has therefore emerged as promising means obtaining mature metaphase II (MII) oocytes from primordial (PMF) pool contained within cryopreserved tissue, without for transplantation. Despite its significant potential, this novel approach remains highly challenging, it requires replication intricate process intraovarian folliculogenesis. Recent advances multi-step culture (IVC) systems, tailored specific needs each stage, have demonstrated feasibility generating early-stage human follicles. While progress been made, there still room improvement terms efficiency productivity, long way go before IVC can be implemented clinical setting. This comprehensive review outlines most improvements recent years, current limitations, future optimization strategies.

Language: Английский

---

Durable contraception in the female domestic cat using viral-vectored delivery of a feline anti-Müllerian hormone transgene

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 6, 2023

Abstract Eighty percent of the estimated 600 million domestic cats in world are free-roaming. These typically experience suboptimal welfare and inflict high levels predation on wildlife. Additionally, euthanasia healthy animals overpopulated shelters raises ethical considerations. While surgical sterilization is mainstay pet population control, there a need for efficient, safe, cost-effective permanent contraception alternatives. Herein, we report evidence that single intramuscular treatment with an adeno-associated viral vector delivering anti-Müllerian hormone transgene produces long-term cat. Treated females followed over two years, during which expression, anti-transgene antibodies, reproductive hormones monitored. Mating behavior success measured mating studies. Here show ectopic expression does not impair sex steroids nor estrous cycling, but prevents breeding-induced ovulation, resulting safe durable female

Language: Английский

---

Steroidogenic factor 1 (SF-1; Nr5a1 ) regulates the formation of the ovarian reserve

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(32)

Published: July 26, 2023

The ovarian follicle reserve, formed pre- or perinatally, comprises all oocytes for lifetime reproduction. Depletion of this reserve results in infertility. Steroidogenic factor 1 (SF-1; Nr5a1 ) and liver receptor homolog (LRH-1; Nr5a2 are two orphan nuclear receptors that regulate adult endocrine function, but their role formation is unknown. We developed models conditional depletion SF-1 LRH-1 from prenatal ovaries. SF-1, not LRH-1, resulted dramatically smaller ovaries fewer primordial follicles. This was mediated by increased oocyte death, resulting inflammation Notch signaling. Major dysregulated genes were Iroquois homeobox 3 5 downstream targets involved the establishment laminin matrix oocyte-granulosa cell gap junctions. Disruptions these pathways follicles with impaired basement membrane compromised oocyte–granulosa communication networks, believed to render them more prone atresia. study identifies as a key regulator reserve.

Language: Английский

---

Cellular atlases of ovarian microenvironment alterations by diet and genetically-induced obesity

Science China Life Sciences, Journal Year: 2023, Volume and Issue: 67(1), P. 51 - 66

Published: Sept. 15, 2023

Language: Английский

---

Anti-Müllerian hormone-mediated preantral follicle atresia is a key determinant of antral follicle count in mice

Human Reproduction, Journal Year: 2022, Volume and Issue: 37(11), P. 2635 - 2645

Published: Sept. 7, 2022

Abstract STUDY QUESTION Does anti-Müllerian hormone (AMH) induce preantral follicle atresia in mice? SUMMARY ANSWER The present findings suggest that AMH-mediated only occurs early follicles before they become sensitive to FSH. WHAT IS KNOWN ALREADY Most prior studies have investigated the ability of AMH inhibit primordial activation. Our previous study showed AMH-overexpressing mice had fewer than expected after accounting for inhibition but reason this was not determined. DESIGN, SIZE, DURATION Cross-sectional—control versus transgenic/knockout mouse were carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS Studies conducted on female wild-type (Amh+/+), AMH-knockout (Amh−/−) and overexpressing (Thy1.2-AMHTg/0) a C57Bl/6J background (age: 42–120 days). counts primordial, transitioning, primary, secondary antral Amh−/− Amh+/+ mice. After confirming development speeds identical (proliferating cell nuclear antigen immunohistochemistry), ratio surviving beyond each stage folliculogenesis determined both genotypes. Evidence increased rates assessed by active caspase-3 immunohistochemistry Thy1.2-AMHTg/0 MAIN RESULTS AND THE ROLE OF CHANCE Amh −/− at 100–120 days age lower higher activation compared These counteracting effects led equivalent numbers transitioning primary Despite this, secondary, small medium indicating differing developing between Cleaved ovaries revealed high granulosa oocyte apoptosis late primary/early LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION shown one species additional research will be required determine generalizability other species. WIDER IMPLICATIONS FINDINGS This is consistent with showing these new demonstrate predominant cause suggests role conserve ovarian reserve prolong fertility, instead prevent pool from becoming too large. While may function AMH, biological purpose requires further investigation, particularly mono-ovulatory FUNDING/COMPETING INTEREST(S) funded Health Research Council New Zealand University Otago. No competing interests declare.

Language: Английский

---

Cancer-associated mesothelial cells are regulated by the anti-Müllerian hormone axis

Cell Reports, Journal Year: 2023, Volume and Issue: 42(7), P. 112730 - 112730

Published: July 1, 2023

Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, mouse human ovarian tumors, cancer express anti-Müllerian hormone (AMH) while CAMCs its receptor AMHR2, suggesting a paracrine axis. Factors secreted by induce AMHR2 expression during their reprogramming into vitro models. Overexpression of Met5a cell line is sufficient immunosuppressive cytokines factors that stimulate an AMH-dependent way. Finally, syngeneic implanted transgenic mice with Amhr2

Language: Английский

---