Therapeutic effect and underlying mechanism of cell therapy on cyclophosphamide-induced premature ovarian insufficiency mouse model
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ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Songying Zhang
PROVIDER: PXD064540 | iProX | Sat May 31 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Premature ovarian insufficiency (POI) is a disease featured by early menopause before 40 years of age, accompanied by an elevation of follicle-stimulating hormone (FSH). Though POI affects many aspects of women’s health, its major causes remain unknown. Many clinical studies have shown that POI patients are generally underweight, indicating a potential correlation between POI and metabolic disorders. To understand the pathogenesis of POI, we performed metabolomics analysis on serum and identified branch chain amino acid (BCAA) insufficiency related metabolic disorders in two independent cohorts from two clinics. A low BCAA diet phenotypically reproduced the metabolic, endocrine, ovarian, and reproductive changes of POI in young C57 B6 mice. A mechanism study revealed that the BCAA insufficiency induced POI is associated with abnormal activation of the ceramide-ROS axis and consequent impairment of ovarian granulosa cell function. Significantly, dietary supplement of BCAA prevented the development of ROS-induced POI in female mice. The results of this pathogenic study will lead to the development of specific therapies for POI.
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Project description:Premature ovarian insufficiency (POI) is defined as a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 (secondary amenorrhea) with hypergonadotropism and hypoestrogenism. Premature ovarian insufficiency has few known genetic causes but in familial cases a genetic link is often suspected. A large consanguineous family with three female affected with POI was investigated. All samples including 3 affected and 5 unaffecd underwent whole genome SNP genotyping using Affymetric Axiom_GW_Hu_SNP array. Linkage analysis was carried out using HomozygosityMapper and Allegro softwares.Linkage analysis mapped the disease phenotype to long arm of chromosome 20. Sequence data analysis of potential candidate genes failed to detect any pathogenic variant.
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Project description:Premature ovarian insufficiency (POI) refers to the severe decline and failure of ovarian function in women before the age of 40, and current treatment methods have significant limitations. In order to screen miRNAs with good anti-apoptotic effect, we used high-throughput sequencing technology to study the differences in exosomal miRNA expression profiles from human follicular fluid between patients with POI and patients with normal ovarian reserve.
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Project description:Premature ovarian insufficiency (POI) is defined as a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 (secondary amenorrhea) with hypergonadotropism and hypoestrogenism. Premature ovarian insufficiency has few known genetic causes but in familial cases a genetic link is often suspected. A large consanguineous family with three female affected with POI was investigated. All samples including 3 affected and 5 unaffecd underwent whole genome SNP genotyping using Affymetric Axiom_GW_Hu_SNP array. Linkage analysis was carried out using HomozygosityMapper and Allegro softwares.Linkage analysis mapped the disease phenotype to long arm of chromosome 20. Sequence data analysis of potential candidate genes failed to detect any pathogenic variant. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples. DNA of eight individuals including three affected subjects was used for homozygosity mapping. Genotyping was performed using the Affymetrix Axiom_GW_Hu_SNP array. Briefly, 250 ng genomic DNA was digested with Digestion Master Mix containing 2 µl NE buffer 2 (10X), 0.5 µl BSA (100X; 10 mg/ml) and 1 µl Nsp1. Digested DNA sample was ligated to Nsp1 adaptor using T4 DNA ligase and amplified by 2 µl of TITANIUM Taq DNA polymerase (50X) and 100 µM PCR primer. PCR products were purified on a Clean-Up plate (Clontech Lab, Madison, USA) and eluted by RB buffer. Purified PCR products were fragmented using Fragmentation Reagent (0.05U/µl DNase 1) for 35 minutes at 37°C followed by labeling of fragmented samples with Labeling Master Mix (30 mM GeneChip DNA Labeling Reagent, 30 U/µl Terminal Deoxynucleotidyl Transferase) for 4 hours at 37°C. Labeled samples were hybridized to Axiom_GW_Hu_SNP array by mixing the sample with Hybridization Master Mix, denatured on thermoblock and loaded on to Array. Array was then placed in a hybridization oven (GeneChip Hybridization Oven 640, USA) for 16-18 hours. After hybridization, array was washed and stained on an automated Fluidic Station 450 followed by scanning on GeneChip Scanner 3000 7G using GeneChip Operating Software (GCOS).
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Project description:Premature ovarian insufficiency (POI) is a disease featured by early menopause before 40 years of age, accompanied by an elevation of follicle-stimulating hormone (FSH). Though POI affects many aspects of women’s health, its major causes remain unknown. Many clinical studies have shown that POI patients are generally underweight, indicating a potential correlation between POI and metabolic disorders. To understand the pathogenesis of POI, we performed metabolomics analysis on serum and identified branch chain amino acid (BCAA) insufficiency related metabolic disorders in two independent cohorts from two clinics. A low BCAA diet phenotypically reproduced the metabolic, endocrine, ovarian, and reproductive changes of POI in young C57 B6 mice. A mechanism study revealed that the BCAA insufficiency induced POI is associated with abnormal activation of the ceramide-ROS axis and consequent impairment of ovarian granulosa cell function. Significantly, dietary supplement of BCAA prevented the development of ROS-induced POI in female mice. The results of this pathogenic study will lead to the development of specific therapies for POI.
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Project description:Premature ovarian insufficiency (POI) is a heterogeneous female disorder characterized by the loss of ovarian function before the age of 40. It represents a significant detriment to female fertility. However, the known POI-causative genes currently account for only a fraction of cases. To elucidate the genetic factors underlying POI, we conducted whole-exome sequencing on a family with three fertile POI patients and identified a deleterious missense variant in RNF111. In a subsequent replication study involving 1030 POI patients, this variant was not only confirmed but also accompanied by the discovery of three additional predicted deleterious RNF111 variants. These variants collectively account for eight cases, representing 0.78% of the study cohort. A further study involving 500 patients with diminished ovarian reserves also identified two additional RNF111 variants. Notably, RNF111 encodes an E3-ubiquitin ligase with a regulatory role in the TGF-β/BMP signaling pathway. Our analysis revealed that RNF111/RNF111 is predominantly expressed in the oocytes of mice, monkeys, and humans. To further investigate the functional implications of RNF111 variants, we generated two mouse models: one with a heterozygous missense mutation (Rnf111+/M) and another with a heterozygous null mutation (Rnf111+/−). Both mouse models exhibited impaired female fertility, characterized by reduced litter sizes and small ovarian reserve. Additionally, RNA-seq and quantitative proteomics analysis unveiled that Rnf111 haploinsufficiency led to dysregulation in female gonad development and negative regulation of the BMP signaling pathway within mouse ovaries. In conclusion, our findings strongly suggest that monoallelic deleterious variants in RNF111 can impair female fertility and induce POI in both humans and mice.
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Project description:Premature ovarian insufficiency (POI) has become a focus of many reproductive studies recently due to its long-life menopause-like symptoms in young women. It may affect up to three of a hundred women under 40 years. The possible causes include genetic diseases, infections, autoimmune disorders and iatrogenic events such as radiotherapy and chemotherapy. Recent studies investigating the regenerative dynamic potential of the ovaries demonstrate that follicular growth could be stimulated when an adequate ovarian environment is restored. This restoration can be achieved employing factors of known regenerative potential such as stem cells, or growth factors of platelet rich plasma (PRP), artificial ovary, ovarian transplantation, and mitochondrial replacement therapy. The emergence of autologous platelet-rich plasma (PRP) therapy reflects a break-through for POI patients, since the approach is the most ethical-friendly, the cheapest, the least invasive and limited adverse effects. Therefore, it has the highest potential to be applied in clinical routine practice. Nevertheless, the complex mechanism of PRP components’ on the ovary, especially in term of folliculogenesis, remains to be deciphered. Furthermore, it is necessary to clarify to what extent they impact the gene or protein targets that play important role in ovarian rejuvenation after POI. We report raw fastq data of Sprague Dawley rat models of POI in four treatment groups and one control to evaluate the effect of intraovarian injection of PRP on POI rat models. This report is a part of animal study regarding the effect of intraovarian injection of PRP on ovarian function recovery in POI rat models (unpublished study). The data collected from this study will be used to investigate how PRP induce the ovarian rejuvenation and to analyse transcriptomic changes after PRP treatment on chemotherapy-induced POI animal models.
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Project description:Premature ovarian insufficiency (POI) has recently been reported to be linked with epigenetic changes. Previous studies have focused on the regulation of individual genes associated with ovarian function through single-gene epigenetic variations, however, there is a deficiency in the comprehensive comprehension of the epigenetic profile for POI. Therefore, we conducted a multi-omics study integrating methylation, hydroxymethylation, and transcriptome sequencing analyses in cumulus cells from women with POI and their matched controls. Our results showed significantly higher global methylation and hydroxymethylation levels in POI women compared to controls. The number of hyper-methylated/hyper-hydroxymethylated regions exceeded hypo-methylated/hypo-hydroxymethylated regions in differentially methylated and hydroxymethylated regions across chromosomes and genetic elements. Methylation within genebodies remained high and exhibited a slight negative correlation with gene expression. Variation in methylation levels was notable among promoter regions, with gene expression decreasing as methylation levels increased (displaying a pronounced negative correlation). Hydroxymethylation levels in both the genebody and promoter regions remained consistently low and showed no overall association with gene expression. Furthermore, we found that changes in methylation were linked to the epigenetic age clock rather than being specifically associated with POI causative genes or ovarian function genes. Our study sheds light on critical features of POI, characterized by widespread DNA hyper-methylation and hyper-hydroxymethylation across the genome. The observed relationship between hyper/hypo-methylation and gene expression regulation may provide valuable insights for identifying potential epigenetic biomarkers and treatment targets for POI.
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