BDNF secreted by mesenchymal stem cells improves the quality and development potential of aged oocytes by activating the ERK1/2 signaling pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1099639 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28642685_1.fastq.gz | Fastqsanger.gz | |||
| SRR28642685_2.fastq.gz | Fastqsanger.gz | |||
| SRR28642686_1.fastq.gz | Fastqsanger.gz | |||
| SRR28642686_2.fastq.gz | Fastqsanger.gz | |||
| SRR28642687_1.fastq.gz | Fastqsanger.gz |
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Project description:Decreased oocyte quality is a major determinant of age-associated fertility decline which lacks an effective treatment strategy. The secretome of mesenchymal stem cells (MSC-sec) contains various bioactive factors and has the potential to improve oocyte quality. In this study, MSC-sec treatment significantly increased first polar body emission, improved spindle assembly, reduced aneuploidy rate, and promoted maternal mRNA degradation in aged mouse oocytes, whereas the addition of BDNF antibody blocked the effects of MSC-sec. Furthermore, BDNF treatment alone also improved the oocyte quality from aged mice. Mechanistically, both MSC-sec and BDNF activated the ERK1/2 signaling pathway to increase the expression of DAZL and BTG4 in aged oocytes. Furthermore, injection of MSC-sec or BDNF into aged mouse ovaries significantly improved oocyte quality and early embryonic development. Finally, we demonstrated that BDNF treatment increased both the fertilization rate and blastocyst formation of aged human oocytes. Our study identified BDNF as the functional component of MSC-sec to improve the quality and development potential of aged oocytes by activating the ERK1/2 signaling pathway, suggesting that BDNF has the potential to mitigate age-related decline in oocyte quality.
2025-04-02 | GSE263864 | GEO
Project description:The decline in oocyte quality is a limiting factor of female fertility; however, strategies to maintain the oocyte quality of aged women are not available. In this study, we showed that growth hormone (GH) supplementation in vivo not only alleviated the decline in oocyte number caused by aging, but also improved the quality and developmental potential of aged oocytes. Strikingly, GH supplementation reduced aneuploidy in aged oocytes. Proteomic analysis indicated that the ERK1/2 pathway was involved in the reduction in aneuploidy rate of aged oocytes, as confirmed both in vivo and in vitro. In addition, JAK2 might be involved in the regulation of ERK1/2 by GH in aged oocytes. Collectively, our findings revealed that GH supplementation protects oocytes from aging-related aneuploidy and enhances the quality of aged oocytes, and could be used to improve the outcome of assisted reproduction in aged women.
2023-07-20 | PXD039147 | Pride
Project description:Female reproductive aging is characterized by the decline in oocytes quality and developmental potentials, but the underlying mechanisms remain insufficiently investigated. In this study, we analyze the transcriptomes of individual oocytes from young and aged mice, identifying a distinct group of aged oocytes, which display morphological abnormalities, such as fragmentation and darkened cytoplasm. These defective aged oocytes show a global shrink in gene expression, with yet a notable expression increase in mitochondrial RNA. Further gene expression analysis indicates that these defective oocytes exhibit typical features of programmed cell death (PCD), and functional assays demonstrate that those oocytes are specifically subject to both apoptosis and ferroptosis. Blocking the PCD pathways largely reverses the defective morphology. Interestingly, the expression of tissue-type plasminogen activator (tPA, or Plat) decreases with age, and even becomes undetectable in defective oocytes. Loss of Plat expression in oocytes downregulates Erk1/2 pathway activity, closely resembling the effects observed in Erk1/2 deficiency. Combining with tPA-interactome assay, it is suggested that Plat functions as an upstream regulator of Erk1/2 pathway activity, likely through Erk1/2 phosphorylation. Supplementing exogenous tPA in oocyte cultures reduces defect rate and therefore improves oocyte quality. Collectively, our findings highlight Plat as a pivotal factor in protecting aged mouse oocytes from PCD, with potential implications for developing better clinical strategies to enhance oocyte quality in aging females.
2025-09-13 | GSE281294 | GEO
Project description:Plat safeguards aged mouse oocytes against programmed cell death through activating the Erk1/2 pathway
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Project description:Proto-oncogenic receptor tyrosine kinase (KIT) ligand (KITL) secreted by granulosa cells and its receptor KIT on oocytes are crucial for primordial follicle formation and activation, and follicular development. In the present study, ZnSO4 decreased the number of primordial and growing follicles in cultured neonatal mouse ovaries when KITL-KIT signaling was inhibited by ISCK03. ZnSO4 also significantly increased the mRNA and protein levels of Zrt/Irt-like protein 6 (ZIP6, a zinc importer) and zinc levels in the oocytes of cultured neonatal mouse ovaries in the presence of ISCK03, suggesting that the increase of ZIP6 levels results in zinc overload in the oocytes of cultured neonatal mouse ovaries. Further experiments indicated that zinc overload resulted in oocyte apoptosis in cultured neonatal mouse ovaries via oxidative stress-driven dual mechanisms: irreversible DNA damage in the nucleus and autophagic flux blockade in the cytoplasm of oocytes. Moreover, intraperitoneal injection of ZnSO4 and ISCK03 significantly increased ZIP6 expression, DNA damage, autophagic flux blockade, and apoptosis of oocytes in neonatal mice. Taken together, these findings indicate that granulosa cell-secreted KITL is involved in maintaining zinc homeostasis in the oocytes of neonatal mouse ovaries. This study not only reveals a novel function of granulosa cells in supporting oocyte homeostasis, but also provides a theoretical basis for identifying individuals susceptible to zinc dyshomeostasis caused by the impaired KITL-KIT signaling.
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Project description:Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions selectively eliminate senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors as selectively capable of triggering apoptosis of senescent, but not proliferating, human fibroblasts. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF function supported an autocrine function for TrkB and BDNF, and the increased expression of BCL2L2 through ERK5, downstream of BDNF-TrkB, favored senescent cell survival. Strikingly, treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. Our results suggest that the SASP factor BDNF promotes cell survival by activating TrkB and is a promising therapeutic target to reduce the senescent cell burden.
2022-09-20 | GSE190998 | GEO
Project description:MDGA2 is an excitatory synaptic suppressor and its mutations have been associated with autism spectrum disorder (ASD). However, the detailed physiological function of MDGA2 and the mechanism underlying MDGA2 deficiency-caused ASD has yet to be elucidated. Herein, we not only confirm that Mdga2+/- mice exhibit increased excitatory synapse transmission and ASD-like behaviors, but also identify aberrant BDNF/TrkB signaling activation in these mice. We demonstrate that MDGA2 interacts with TrkB through its MAM domain, thereby competing the binding of BDNF to TrkB. Both loss of MDGA2 and the ASD-associated MDGA2 V930I mutation promote the BDNF/TrkB signaling activity. Importantly, we demonstrate that inhibiting the BDNF/TrkB signaling by both small molecular compound and MDGA2-derived peptide can attenuate the increase of AMPA receptor-mediated excitatory synaptic activity and social deficits in MDGA2 deficient mice. These results highlight a novel MDGA2-BDNF/TrkB-dependent mechanism underlying the synaptic function regulation, which may become a therapeutic target for ASD.
2025-02-06 | PXD050810 | Pride
Project description:Advanced maternal age, defined as 35 years or older, is associated with a decline in both ovarian reserve and oocyte quality, which leads to the female infertility, pregnancy loss, fetal anomalies, stillbirth, and obstetric complications. At present, the effective approaches to counteract the maternal age-related decay of oocyte quality are still not fully determined. Here, we report that in vivo supplementation of nicotinamide mononucleotide (NMN) efficaciously ameliorates the quality of oocytes from naturally aged mice by recovering nicotinamide adenine dinucleotide (NAD + ) levels in oocytes. NMN supplementation increases the number of antral follicles, ovulated oocytes and matured oocytes from aged mice. Specifically, NMN supplementation maintains the normal spindle/chromosome structure and dynamics of cortical granule component ovastacin to ensure the meiotic competency and fertilization ability of aged oocytes. Moreover, single cell transcriptome analysis shows that the beneficial effect of NMN on the aged oocytes is mediated by the restoration of the mitochondrial function, thereby reducing the accumulated ROS to suppress the occurrence of apoptosis. To sum up, our data reveal that supplementation of NMN is a feasible approach to prevent oocyte quality from advanced maternal age-related deterioration, contributing to improve the reproductive outcome of aged women and the assisted reproductive technology.
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Project description:Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptors Ret and Gfra1 can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expresses Bdnf. FAP-specific inactivation of Bdnf (Prrx1-Cre; Bdnf-fl/fl) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reduced Bdnf expression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs’ response to peripheral nerve injury.
2024-07-30 | GSE250436 | GEO
Project description:STUDY QUESTION: Does maternal age affect the maturated oocyte quality and the fol-lowing development after fertilization in human? SUMMARY ANSWER: Maternal age affects the quality of maturated oocytes by altering the stored mRNA levels in human, such as TOP2B. WHAT IS KNOWN ALREADY: Intracellular mRNAs in maturated oocytes are tran-scripted from the maternal genome during oogenesis and important for the zygotic genome activation (ZGA) after fertilization. Microarray data showed that maternal age affected polyadenylated transcript abundance in human oocytes. These genes are involved in in signaling pathway related to cell cycle regulation, chromosome alignment. However, which genes are the key genes affected by maternal age and important for the development after fertilization had not been reported. Therefore, single-cell RNA sequencing (scRNA-Seq) technology is employed in this study to screen the key genes affected by maternal age in human maturated oocytes. STUDY DESIGN, SIZE, DURATION: We isolated mRNA from maturated (MII) oo-cytes donated by IVF or ICSI patients (three oocytes from young (≤ 30 years) and three oocytes from advanced maternal age (≥ 40 years) patients) undergoing controlled ovarian stimulation. Thus, a total of six maturated oocytes were individually processed for scRNA-seq analysis. The key genes screened from scRNA-seq analysis are confirmed using mouse model. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients undergoing infertility treatment at the Yuhuangding Hospital of Yantai underwent ovarian stimulation with FSH and received hCG for final follicular maturation prior to ul-trasound guided oocyte retrieval. We isolated RNA, generated single cell RNA-seq librar-ies (Smart-Seq2) and sequenced by Illumina Hiseq X-ten platform with 150 bp paired-end. Bioinformatics analysis of the sequencing data was done to find the biological processes and key genes that led to the decline in the quality of oocytes with advanced maternal age. To validate the findings, we used mouse model and validated candidate genes by RT-PCR and knockdown experiments. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 1439 genes differentially expressed between older and younger women's maturated oocytes (|foldchange|>2, P < 0.05). These genes are significantly enriched with annotations related to transporter activity, cytoskeleton, oxidative stress, catalytic activity, immune function, cellular senescence and biosynthesis. The key candidate gene TOP2B was found by protein interaction network analysis, and knockdown verification on young mouse maturated oocytes showed that TOP2B was a key gene affecting the oocyte quality and disturbing early embryo development. LARGE SCALE DATA Raw data from this study can be accessed through GSE. LIMITATIONS, REASONS FOR CAUTION: The human maturated oocytes used in this study were from patients with different causes of infertility and may affect oocyte gene expression. In addition, the study was based on a lim-ited number of patients, and there are possible natural biological variance existed in human samples. WIDER IMPLICATIONS OF THE FINDINGS: For the first time, we used scRNA-seq to detect global gene transcriptome of maturated oocytes in young and older women. These results are useful to indicate the molecular mechanisms of female ovary aging and establishing a criterion to evaluate the quality of oocytes in women with advanced maternal age. STUDY FUNDING/COMPETING INTERESTS: This research was supported by the National Key Research and Development Program of China (2018YFC1004304, 2016YFA0100203), Medical and Health Science Technology Development Plan Project of Shandong Province (Grant#. 2017WS566). There are no competing interests.
2019-01-19 | GSE125300 | GEO