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Proceedings of the National Academy of... Jan 2024Ovulation is essential for reproductive success, yet the underlying cellular and molecular mechanisms are far from clear. Here, we applied high-resolution spatiotemporal...
Ovulation is essential for reproductive success, yet the underlying cellular and molecular mechanisms are far from clear. Here, we applied high-resolution spatiotemporal transcriptomics to map out cell type- and ovulation stage-specific molecular programs as function of time during follicle maturation and ovulation in mice. Our analysis revealed dynamic molecular transitions within granulosa cell types that occur in tight coordination with mesenchymal cell proliferation. We identified molecular markers for the emerging cumulus cell fate during the preantral-to-antral transition. We describe transcriptional programs that respond rapidly to ovulation stimulation and those associated with follicle rupture, highlighting the prominent roles of apoptotic and metabolic pathways during the final stages of follicle maturation. We further report stage-specific oocyte-cumulus cell interactions and diverging molecular differentiation in follicles approaching ovulation. Collectively, this study provides insights into the cellular and molecular processes that regulate mouse ovarian follicle maturation and ovulation with important implications for advancing therapeutic strategies in reproductive medicine.
Topics: Female; Animals; Mice; Ovary; Ovulation; Ovarian Follicle; Reproduction; Granulosa Cells; Ascomycota
PubMed: 38252830
DOI: 10.1073/pnas.2317418121 -
Journal of Translational Medicine Apr 2024Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder that can lead to female infertility. Lipid metabolomics and proteomics are the new...
BACKGROUND
Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder that can lead to female infertility. Lipid metabolomics and proteomics are the new disciplines in systems biology aimed to discover metabolic pathway changes in diseases and diagnosis of biomarkers. This study aims to reveal the features of PCOS to explore its pathogenesis at the protein and metabolic level.
METHODS
We collected follicular fluid samples and granulosa cells of women with PCOS and normal women who underwent in vitro fertilization(IVF) and embryo transfer were recruited. The samples were for the lipidomic study and the proteomic study based on the latest metabolomics and proteomics research platform.
RESULTS
Lipid metabolomic analysis revealed abnormal metabolism of glycerides, glycerophospholipids, and sphingomyelin in the FF of PCOS. Differential lipids were strongly linked with the rate of high-quality embryos. In total, 144 differentially expressed proteins were screened in ovarian granulosa cells in women with PCOS compared to controls. Go functional enrichment analysis showed that differential proteins were associated with blood coagulation and lead to follicular development disorders.
CONCLUSION
The results showed that the differential lipid metabolites and proteins in PCOS were closely related to follicle quality,which can be potential biomarkers for oocyte maturation and ART outcomes.
Topics: Female; Humans; Polycystic Ovary Syndrome; Follicular Fluid; Proteomics; Biomarkers; Lipids
PubMed: 38632610
DOI: 10.1186/s12967-024-05167-x -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Dec 2023Melatonin,an endocrine hormone synthesized by the pineal gland,plays an important role in the reproduction.The growth and development of follicles is the basis of female... (Review)
Review
Melatonin,an endocrine hormone synthesized by the pineal gland,plays an important role in the reproduction.The growth and development of follicles is the basis of female mammalian fertility.Follicles have a high concentration of melatonin.Melatonin receptors exist on ovarian granulosa cells,follicle cells,and oocytes.It regulates the growth and development of these cells and the maturation and atresia of follicles,affecting female fertility.This paper reviews the protective effects and regulatory mechanisms of melatonin on the development of ovarian follicles,granulosa cells,and oocytes and makes an outlook on the therapeutic potential of melatonin for ovarian injury,underpinning the clinical application of melatonin in the future.
Topics: Animals; Female; Melatonin; Ovarian Follicle; Oocytes; Granulosa Cells; Mammals
PubMed: 38173113
DOI: 10.3881/j.issn.1000-503X.15473 -
Aging Cell Nov 2023Reproductive aging is associated with ovulatory defects. Age-related ovarian fibrosis partially contributes to this phenotype as short-term treatment with anti-fibrotic...
Reproductive aging is associated with ovulatory defects. Age-related ovarian fibrosis partially contributes to this phenotype as short-term treatment with anti-fibrotic compounds improves ovulation in reproductively old mice. However, age-dependent changes that are intrinsic to the follicle may also be relevant. In this study, we used a mouse model to demonstrate that reproductive aging is associated with impaired cumulus expansion which is accompanied by altered morphokinetic behavior of cumulus cells as assessed by time-lapse microscopy. The extracellular matrix integrity of expanded cumulus-oocyte complexes is compromised with advanced age as evidenced by increased penetration of fluorescent nanoparticles in a particle exclusion assay and larger open spaces on scanning electron microscopy. Reduced hyaluronan (HA) levels, decreased expression of genes encoding HA-associated proteins (e.g., Ptx3 and Tnfaip6), and increased expression of inflammatory genes and matrix metalloproteinases underlie this loss of matrix integrity. Importantly, HA levels are decreased with age in follicular fluid of women, indicative of conserved reproductive aging mechanisms. These findings provide novel mechanistic insights into how defects in cumulus expansion contribute to age-related infertility and may serve as a target to extend reproductive longevity.
Topics: Humans; Female; Mice; Animals; Hyaluronic Acid; Ovarian Follicle; Oocytes; Ovary; Extracellular Matrix
PubMed: 37850336
DOI: 10.1111/acel.14004 -
Reproductive Biology and Endocrinology... Dec 2023Survival rates of young women undergoing cancer treatment have substantially improved, with a focus on post-treatment quality of life. Ovarian tissue transplantation... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Survival rates of young women undergoing cancer treatment have substantially improved, with a focus on post-treatment quality of life. Ovarian tissue transplantation (OTT) is a viable option to preserve fertility; however, there is no consensus on the optimal transplantation site. Most studies on OTT are nonrandomized controlled trials with limited sample sizes and uncontrolled statistical analyses, leaving the question of which transplant site yields the highest chance of achieving a live birth unanswered.
OBJECTIVE
This meta-analysis aimed to assess the effect of different ovarian transplant sites on postoperative reproductive outcomes.
METHODS
We adhered to the PRISMA Reporting Items for Systematic Reviews and Meta-Analyses recommendations. Systematic searches were conducted in PubMed, Embase, Web of Science, and the Cochrane Library from inception to September 17, 2023. The inclusion criteria were as follows: (1) women who underwent OTT with a desire for future childbirth, and (2) reports of specific transplant sites and corresponding pregnancy outcomes. The exclusion criteria included the inability to isolate or extract relevant outcome data, case reports, non-original or duplicate data, and articles not written in English.
RESULTS
Twelve studies (201 women) were included in the meta-analysis of cumulative live birth rates (CLBR) after OTT. The CLBR, which encompasses both spontaneous pregnancies and those achieved through assisted reproductive technology (ART) following OTT to the ovarian site, was 21% (95% CI: 6-40, I: 52.81%, random effect). For transplantation to the pelvic site, the live birth rate was 30% (95% CI: 20-40, I: 0.00%, fixed effect). Combining transplantation to both the pelvic and ovarian sites resulted in a live birth rate of 23% (95% CI: 11-36, I: 0.00%, fixed effect). Notably, heterotopic OTT yielded a live birth rate of 3% (95% CI: 0-17, I: 0.00%, fixed effect).
CONCLUSION
Pregnancy outcomes were not significantly different after orthotopic ovarian transplantation, and pregnancy and live birth rates after orthotopic OTT were significantly higher than those after ectopic transplantation.
REGISTRATION NUMBER
INPLASY202390008.
Topics: Pregnancy; Female; Humans; Quality of Life; Ovary; Reproductive Techniques, Assisted; Pregnancy Outcome; Pregnancy, Multiple; Live Birth; Pregnancy Rate
PubMed: 38087312
DOI: 10.1186/s12958-023-01167-6 -
Stem Cell Research & Therapy Apr 2024Studies have shown that chemotherapy and radiotherapy can cause premature ovarian failure and loss of fertility in female cancer patients. Ovarian cortex...
BACKGROUND
Studies have shown that chemotherapy and radiotherapy can cause premature ovarian failure and loss of fertility in female cancer patients. Ovarian cortex cryopreservation is a good choice to preserve female fertility before cancer treatment. Following the remission of the disease, the thawed ovarian tissue can be transplanted back and restore fertility of the patient. However, there is a risk to reintroduce cancer cells in the body and leads to the recurrence of cancer. Given the low success rate of current in vitro culture techniques for obtaining mature oocytes from primordial follicles, an artificial ovary with primordial follicles may be a good way to solve this problem.
METHODS
In the study, we established an artificial ovary model based on the participation of mesenchymal stem cells (MSCs) to evaluate the effect of MSCs on follicular development and oocyte maturation. P2.5 mouse ovaries were digested into single cell suspensions and mixed with bone marrow derived mesenchymal stem cells (BM-MSCs) at a 1:1 ratio. The reconstituted ovarian model was then generated by using phytohemagglutinin. The phenotype and mechanism studies were explored by follicle counting, immunohistochemistry, immunofluorescence, in vitro maturation (IVM), in vitro fertilization (IVF), real-time quantitative polymerase chain reaction (RT-PCR), and Terminal-deoxynucleotidyl transferase mediated nick end labeling(TUNEL) assay.
RESULTS
Our study found that the addition of BM-MSCs to the reconstituted ovary can enhance the survival of oocytes and promote the growth and development of follicles. After transplanting the reconstituted ovaries under kidney capsules of the recipient mice, we observed normal folliculogenesis and oocyte maturation. Interestingly, we found that BM-MSCs did not contribute to the formation of follicles in ovarian aggregation, nor did they undergo proliferation during follicle growth. Instead, the cells were found to be located around growing follicles in the reconstituted ovary. When theca cells were labeled with CYP17a1, we found some overlapped staining with green fluorescent protein(GFP)-labeled BM-MSCs. The results suggest that BM-MSCs may participate in directing the differentiation of theca layer in the reconstituted ovary.
CONCLUSIONS
The presence of BM-MSCs in the artificial ovary was found to promote the survival of ovarian cells, as well as facilitate follicle formation and development. Since the cells didn't proliferate in the reconstituted ovary, this discovery suggests a potential new and safe method for the application of MSCs in clinical fertility preservation by enhancing the success rate of cryo-thawed ovarian tissues after transplantation.
Topics: Female; Animals; Mesenchymal Stem Cells; Mice; Ovary; Oocytes; Mesenchymal Stem Cell Transplantation; Ovarian Follicle
PubMed: 38650029
DOI: 10.1186/s13287-024-03718-z -
International Journal of Molecular... Nov 2023Granulosa cells are crucial for the establishment and maintenance of bidirectional communication among oocytes. Various intercellular material exchange modes, including... (Review)
Review
Granulosa cells are crucial for the establishment and maintenance of bidirectional communication among oocytes. Various intercellular material exchange modes, including paracrine and gap junction, are used between them to achieve the efficient delivery of granulosa cell structural components, energy substrates, and signaling molecules to oocytes. Glucose metabolism and lipid metabolism are two basic energy metabolism pathways in granulosa cells; these are involved in the normal development of oocytes. Pyruvate, produced by granulosa cell glycolysis, is an important energy substrate for oocyte development. Granulosa cells regulate changes in intrafollicular hormone levels through the processing of steroid hormones to control the development process of oocytes. This article reviews the material exchange between oocytes and granulosa cells and expounds the significance of granulosa cells in the development of oocytes through both glucose metabolism and lipid metabolism. In addition, we discuss the effects of glucose and lipid metabolism on oocytes under pathological conditions and explore its relationship to polycystic ovary syndrome (PCOS). A series of changes were found in the endogenous molecules and ncRNAs that are related to glucose and lipid metabolism in granulosa cells under PCOS conditions. These findings provide a new therapeutic target for patients with PCOS; additionally, there is potential for improving the fertility of patients with PCOS and the clinical outcomes of assisted reproduction.
Topics: Female; Humans; Polycystic Ovary Syndrome; Lipid Metabolism; Glucose; Oocytes; Granulosa Cells
PubMed: 38003436
DOI: 10.3390/ijms242216247 -
Gynecological Endocrinology : the... Dec 2023Among the natural polyphenolic compounds, resveratrol (RES) is known for reducing the effects of declining reproductive power through resisting senility, anti-oxidant...
AIM
Among the natural polyphenolic compounds, resveratrol (RES) is known for reducing the effects of declining reproductive power through resisting senility, anti-oxidant and anti-inflammatory, while the molecular mechanism of RES in human ovaries is unclear. We aimed to evaluate the most likely mechanisms of RES against apoptosis induced by HO in human ovary granulosa cells.
METHODS
Ovarian granulosa cells from infertile women (≤35 years old) were collected. Those patients defined as polycystic ovary syndrome (PCOS), poor ovarian responder (POR) and Endometriosis were excluded. Then they were randomly divided into control group, model group and the treatment group. Cellular apoptosis was analyzed by flow cytometer method. The related protein and mRNA expressions were detected by western blot and RT-PCR.
RESULTS
Apoptosis rates of the treatment group containing RES with concentrations of 1 μM and 10 μM were significantly decreased ( < 0.001). Western blot results demonstrated that the proteins levels of transforming growth factor-β (TGF-β), Bax and Caspase 9 were decreased, and Bcl-2 was increased under RES treatment, while the protein levels of Caspase 8, Caspase 3, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) expressed no significant difference. The results by RT-PCR of follicle and ovarian development related mRNA factors were consistent with that of western blot assay.
CONCLUSION
In conclusion, the present study provides the evidence that RES may affects apoptotic factors to protect human ovarian state.
Topics: Female; Humans; Adult; Ovary; Resveratrol; Infertility, Female; Hydrogen Peroxide; Granulosa Cells; Polycystic Ovary Syndrome; Apoptosis; RNA, Messenger
PubMed: 36824010
DOI: 10.1080/09513590.2023.2181652 -
Phytomedicine : International Journal... Jun 2024Polycystic ovary syndrome is a metabolic and hormonal disorder that is closely linked to oxidative stress. Within individuals diagnosed with PCOS, changes occur in the...
BACKGROUND
Polycystic ovary syndrome is a metabolic and hormonal disorder that is closely linked to oxidative stress. Within individuals diagnosed with PCOS, changes occur in the ovaries, resulting in an excessive buildup of iron and peroxidation of lipids, both of which may be associated with the occurrence of ferroptosis. Baicalein, a flavonoid found in the roots of Scutellaria baicalensis and widely known as Chinese skullcap, is known for its anti-inflammatory and anti-ferroptotic properties, which protect against various diseases. Nevertheless, there has been no investigation into the impact of baicalein on polycystic ovary syndrome.
PURPOSE
This study aimed to correlate ferroptosis with polycystic ovary syndrome and to assess the effects of baicalein on ovarian dysfunction and placental development in pregnant patients.
STUDY DESIGN AND METHODS
Polycystic ovary syndrome was induced in a rat model through the administration of dehydroepiandrosterone, and these rats were treated with baicalein. Oxidative stress and inflammation levels were assessed in serum and ovaries, and tissue samples were collected for histological and protein analyses. Furthermore, different groups of female rats were mated with male rats to observe pregnancy outcomes and tissue samples were obtained for histological, protein, and RNA sequencing. Then, RNA sequencing of the placenta was performed to determine the key genes involved in ferroptosis negative regulation (FNR) signatures.
RESULTS
Baicalein was shown to reduce ovarian oxidative stress and pathology. Baicalein also ameliorated polycystic ovary syndrome by decreasing lipid peroxidation and chronic inflammation and modulating mitochondrial functions and ferroptosis in the ovaries. Specifically, glutathione peroxidase and ferritin heavy chain 1 were considerably downregulated in polycystic ovary syndrome gravid rats compared to their expression in the control group, and most of these differences were reversed after baicalein intervention.
CONCLUSIONS
Our findings, initially, indicated that baicalein could potentially enhance the prognosis of individuals suffering from polycystic ovary syndrome by reducing oxidative stress and ferroptosis, thus potentially influencing the formulation of a therapeutic approach to address this condition.
Topics: Polycystic Ovary Syndrome; Female; Flavanones; Ferroptosis; Animals; Oxidative Stress; Pregnancy; Placenta; Ovary; Rats; Rats, Sprague-Dawley; Scutellaria baicalensis; Disease Models, Animal; Lipid Peroxidation; Male
PubMed: 38518646
DOI: 10.1016/j.phymed.2024.155423 -
Frontiers in Endocrinology 2023The non-growing, meiotically-arrested oocytes housed within primordial follicles are exquisitely sensitive to genotoxic insults from endogenous and exogenous sources....
INTRODUCTION
The non-growing, meiotically-arrested oocytes housed within primordial follicles are exquisitely sensitive to genotoxic insults from endogenous and exogenous sources. Even a single DNA double-strand break (DSB) can trigger oocyte apoptosis, which can lead to accelerated depletion of the ovarian reserve, early loss of fertility and menopause. Therefore, repair of DNA damage is important for preserving the quality of oocytes to sustain fertility across the reproductive lifespan. This study aimed to evaluate the role of KU80 (encoded by the XRCC5 gene) - an essential component of the non-homologous end joining (NHEJ) pathway - in the repair of oocyte DNA DSBs during reproductive ageing, and following insult caused by the DNA-damaging chemotherapies cyclophosphamide and cisplatin.
METHODS
To investigate the importance of KU80 following endogenous and exogenous DNA damage, ovaries from conditional oocyte-specific knockout ( cKO) and wildtype (WT) mice that were aged or exposed to DNA damage-inducing chemotherapy were compared. Ovarian follicles and oocytes were quantified, morphologically assessed and analysed via immunohistochemistry for markers of DNA damage and apoptosis. In addition, chemotherapy exposed mice were superovulated, and the numbers and quality of mature metaphase- II (MII) oocytes were assessed.
RESULTS
The number of healthy follicles, atretic (dying) follicles, and corpora lutea were similar in Xrcc5 cKO and WT mice at PN50, PN200 and PN300. Additionally, primordial follicle number and ovulation rates were similar in young adult Xrcc5 cKO and WT mice following treatment with cyclophosphamide (75mg/kg), cisplatin (4mg/kg), or vehicle control (saline). Furthermore, KU80 was not essential for the repair of exogenously induced DNA damage in primordial follicle oocytes.
DISCUSSION
These data indicate that KU80 is not required for maintenance of the ovarian reserve, follicle development, or ovulation during maternal ageing. Similarly, this study also indicates that KU80 is not required for the repair of exogenously induced DSBs in the prophase-arrested oocytes of primordial follicles.
Topics: Animals; Female; Mice; Cisplatin; Cyclophosphamide; DNA; Oocytes; Ovarian Follicle; Prophase; Ku Autoantigen
PubMed: 37900135
DOI: 10.3389/fendo.2023.1268009