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Ovarian aging increases small extracellular vesicle CD81+ release in human follicular fluid and influences miRNA profiles.

ABSTRACT: Ovarian aging affects female reproductive potential and is characterized by alterations in proteins, mRNAs and non-coding RNAs inside the ovarian follicle. Ovarian somatic cells and the oocyte communicate with each other secreting different molecules into the follicular fluid, by extracellular vesicles. The cargo of follicular fluid vesicles may influence female reproductive ability; accordingly, analysis of extracellular vesicle content could provide information about the quality of the female germ cell.In order to identify the most significant deregulated microRNAs in reproductive aging, we quantified the small extracellular vesicles in human follicular fluid from older and younger women and analyzed the expression of microRNAs enclosed inside the vesicles. We found twice as many small extracellular vesicles in the follicular fluid from older women and several differentially expressed microRNAs. Correlating microRNA expression profiles with vesicle number, we selected 46 deregulated microRNAs associated with aging. Bioinformatic analyses allowed us to identify six miRNAs involved in TP53 signaling pathways. Specifically, miR-16-5p, miR214-3p and miR-449a were downregulated and miR-125b, miR-155-5p and miR-372 were upregulated, influencing vesicle release, oocyte maturation and stress response. We believe that this approach allowed us to identify a battery of microRNAs strictly related to female reproductive aging.

SUBMITTER: Battaglia R

PROVIDER: S-EPMC7343446 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Ovarian aging increases small extracellular vesicle CD81<sup>+</sup> release in human follicular fluid and influences miRNA profiles.

Battaglia Rosalia R Musumeci Paolo P Ragusa Marco M Barbagallo Davide D Scalia Marina M Zimbone Massimo M Lo Faro Josè Maria JM Borzì Placido P Scollo Paolo P Purrello Michele M Vento Elena Maria EM Di Pietro Cinzia C

Aging 20200617 12

Ovarian aging affects female reproductive potential and is characterized by alterations in proteins, mRNAs and non-coding RNAs inside the ovarian follicle. Ovarian somatic cells and the oocyte communicate with each other secreting different molecules into the follicular fluid, by extracellular vesicles. The cargo of follicular fluid vesicles may influence female reproductive ability; accordingly, analysis of extracellular vesicle content could provide information about the quality of the female ...[more]

PMID: 32554857

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Project description:Study questionAre phthalate metabolite concentrations in follicular fluid (FF) associated with the expression of extracellular vesicle microRNAs (EV-miRNAs)?Summary answerPhthalate metabolite concentrations are associated with the expression of EV-miRNA and their associated pathways in FFs.What is known alreadyPhthalate metabolites were recently detected in FF. Urinary phthalate metabolite concentrations alter the expression of EV-miRNAs in FF.Study design, size, durationProspective study including 105 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital.Participants/materials, setting, methodsWe assessed FF concentrations of 12 phthalate metabolites. EV-miRNAs were isolated from aliquots of the same FF, and their expression profiles were measured using a human miRNA panel. Associations between EV-miRNAs that were present in >50% of the samples and phthalate metabolites that were measured in >74% of the FF samples were tested. Genes regulated by EV-miRNAs that were found to be significantly (false discovery rate q-value < 0.1) correlated with FF-phthalates were analyzed for pathways linked with female fertility using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources and Kyoto Encyclopedia of Genes and Genomes (KEGG).Main results and the role of chanceOf 12 phthalate metabolites, 11 were measured in at least one FF sample. Mono (6-COOH-2-methylheptyl) phthalate (MCOMHP), mono-2-ethyl-5-carboxypentyl phthalate (mECPP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), mono-isobutyl phthalate (MiBP), monoethyl phthalate (MEP) and mono (7-COOH-2-methyloctyl) phthalate (MCOMOP) were detected in more than 74% of the samples. Of 754 EV-miRNAs tested, 39 were significantly associated either with MEP, MBzP, MCOMOP, MCOMHP and/or with mECPP, after adjusting for multiple testing (P < 0.05). KEGG-based pathway enrichment analysis of the genes regulated by these miRNAs showed that these EV-miRNAs may be involved in pathways related to ovary or oocyte development, maturation and fertilization.Limitations, reasons for cautionThe use of miRNA panel array limits the number of potential relevant miRNAs. Moreover, several of the phthalate metabolites examined may be biased due to internal (enzymatic activity) or external (contamination in medical interventions) causes.Wider implications of the findingsPhthalate metabolites may alter follicular EV-miRNAs profile and thus impair pathways that are involved with oocyte development, maturation and fertilization. Our results contribute to understanding of possible mechanism(s) in which endocrine disruptor chemicals interfere with female fertility.Study funding/competing interestsThis work was supported by the National Institutes of Environmental Health Sciences [Grant R21-ES024236]; and Environmental Health Fund, Israel [Grant 1301], no competing interests.Trial registration numberN/A.

Project description:Bone metastasis represents one of the most deleterious clinical consequences arising in the context of many solid tumors. Severe osteolysis results from tumor cell colonization of the bone compartment, a process which entails reciprocal exchange of soluble signals between tumor cells and their osseous microenvironment. Recent evidence indicates that tumor-intrinsic miRNAs are pleiotropic regulators of gene expression. But they are also frequently released in exosome-like vesicles (ELV). Yet the functional relevance of the transference of tumor-derived ELV and their miRNA cargo to the extracellular milieu during osseous colonization is unknown. Comparative transcriptomic profiling using an in vivo murine model of bone metastasis identified a repressed miRNA signature associated with high prometastatic activity. Forced expression of single miRNAs identified miR-192 that markedly appeased osseous metastasis in vivo, as shown by X-ray, bioluminescence imaging and microCT scans. Histological examination of metastatic lesions revealed impaired tumor-induced angiogenesis in vivo, an effect that was associated in vitro with decreased hallmarks of angiogenesis. Isolation and characterization of ELV by flow cytometry, Western blot analysis, transmission electron microscopy and nanoparticle tracking analysis revealed the ELV cargo enrichment in miR-192. Consistent with these findings, fluorescent labeled miR-192-enriched-ELV showed the in vitro transfer and release of miR-192 in target endothelial cells and abrogation of the angiogenic program by repression of proangiogenic IL-8, ICAM and CXCL1. Moreover, in vivo infusion of fluorescent labeled ELV efficiently targeted cells of the osseous compartment. Furthermore, treatment with miR-192 enriched ELV in a model of in vivo bone metastasis pre-conditioned osseous milieu and impaired tumor-induced angiogenesis, thereby reducing the metastatic burden and tumor colonization. Changes in the miRNA-cargo content within ELV represent a novel mechanism heavily influencing bone metastatic colonization, which is most likely relevant in other target organs. Mechanistic mimicry of this phenomenon by synthetic nanoparticles could eventually emerge as a novel therapeutic approach.

Project description:Ovarian follicular fluid (FF) comprises a dynamic milieu whose composition alters under seasonal variation, influencing follicle development and oocyte developmental competence. Various cell subtypes (e.g. granulosa, theca, and cumulus) produce cell-secreted nanoparticles, coined extracellular vesicles (EVs), which contain bioactive regulatory molecules such as microRNAs (miRNAs) known to mediate intrafollicular communication through various forms of signaling and information transfer. Markedly, the hallmark feature of EVs transferring cellular knowledge propagates their appealing nature as direct indicators of cellular status, albeit homeostasis, dysfunction, or disease. Photoperiod alterations influencing the regulatory content of FF-EVs as downstream modifiers remain largely unknown, particularly in seasonal breeding animals. Here, we aimed to unpack the impacts of seasonal variation on the miRNA expression profiles of FF-EVs in the mare. Equine pre-ovulatory follicles were monitored and aspirated using ultrasound-guided transvaginal techniques to obtain follicular fluids during non-breeding (spring anovulatory, SAN) and breeding seasons (spring ovulatory, SOV; summer, SUM; and fall ovulatory, FOV). 97 miRNAs were found to be differentially expressed between groups. Pairwise comparisons revealed specific clusters, including six miRNAs involved in the spring transition (miR-149-200b-206-221-328-615) and many others dysregulated during that of the summer (miR-143-192451- 302b-100, and let 7c), the peak time point for breeding. Bioinformatic analyses led to unveiling significant enrichments in various biological functions, such as transcription factor activity, transcription and transcription regulation, nucleic acid binding, sequence-specific DNA binding, p53 signaling, and post-translational modifications. Ultimately, the miRNA content of seasonally divergent FF-EVs poses as potentially relevant indicators of intrafollicular mechanisms directing seasonal transitions and their functional regulatory roles in the pre-ovulatory stage, governing subsequent ovulation.

Dataset Information

Ovarian aging increases small extracellular vesicle CD81+ release in human follicular fluid and influences miRNA profiles.

Publications

Ovarian aging increases small extracellular vesicle CD81<sup>+</sup> release in human follicular fluid and influences miRNA profiles.

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