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Scientific Reports Jan 2021Reproductive ageing in females is defined by a progressive decline in follicle number and oocyte quality. This is a natural process that leads to the loss of fertility...
Reproductive ageing in females is defined by a progressive decline in follicle number and oocyte quality. This is a natural process that leads to the loss of fertility and ovarian function, cycle irregularity and eventually menopause or reproductive senescence. The factors that underlie the natural depletion of follicles throughout reproductive life are poorly characterised. It has been proposed that inflammatory processes and fibrosis might contribute to ovarian ageing. To further investigate this possibility, we evaluated key markers of inflammation and immune cell populations in the ovaries of 2, 6, 12 and 18-month-old C57BL/6 female mice. We report that the decrease in follicle numbers over the reproductive lifespan was associated with an increase in the intra-ovarian percentage of CD4 + T cells, B cells and macrophages. Serum concentration and intra-ovarian mRNA levels of several pro-inflammatory cytokines, including IL-1α/β, TNF-α, IL-6, and inflammasome genes ASC and NLRP3, were significantly increased with age. Fibrosis levels, as determined by picrosirius red staining for collagen I and III, were unchanged up to 18 months of age. Collectively, these data suggest that inflammation could be one of the mechanisms responsible for the age-related regulation of follicle number, but the role of fibrosis is unclear. Further studies are now required to determine if there is a causative relationship between inflammation and follicle depletion as females age.
Topics: Aging; Animals; Female; Fertility; Inflammation; Mice; Mice, Inbred C57BL; Ovarian Follicle
PubMed: 33432051
DOI: 10.1038/s41598-020-79488-4 -
International Journal of Biological... 2019Autophagy is a mechanism that exists in all eukaryotes under a variety of physiological and pathological conditions. In the mammalian ovaries, less than 1% of follicles... (Review)
Review
Autophagy is a mechanism that exists in all eukaryotes under a variety of physiological and pathological conditions. In the mammalian ovaries, less than 1% of follicles ovulate, whereas the remaining 99% undergo follicular atresia. Autophagy and apoptosis have been previously found to be involved in the regulation of both primordial follicular development as well as atresia. The relationship between autophagy, follicular development, and atresia have been summarized in this review with the aim to obtain a more comprehensive understanding of the role played by autophagy in follicular development and atresia.
Topics: Animals; Apoptosis; Autophagy; Female; Granulosa Cells; Humans; Ovarian Follicle; Ovary
PubMed: 30906205
DOI: 10.7150/ijbs.30369 -
International Journal of Molecular... Jun 2020Each follicle represents the basic functional unit of the ovary. From its very initial stage of development, the follicle consists of an oocyte surrounded by somatic... (Review)
Review
Each follicle represents the basic functional unit of the ovary. From its very initial stage of development, the follicle consists of an oocyte surrounded by somatic cells. The oocyte grows and matures to become fertilizable and the somatic cells proliferate and differentiate into the major suppliers of steroid sex hormones as well as generators of other local regulators. The process by which a follicle forms, proceeds through several growing stages, develops to eventually release the mature oocyte, and turns into a corpus luteum (CL) is known as "folliculogenesis". The task of this review is to define the different stages of folliculogenesis culminating at ovulation and CL formation, and to summarize the most recent information regarding the newly identified factors that regulate the specific stages of this highly intricated process. This information comprises of either novel regulators involved in ovarian biology, such as , Phoenixin/GPR73, C1QTNF, and α-SNAP, or recently identified members of signaling pathways previously reported in this context, namely PKB/Akt, HIPPO, and Notch.
Topics: Animals; Female; Gonadal Steroid Hormones; Humans; Oogenesis; Ovarian Follicle; Ovulation; Signal Transduction
PubMed: 32604954
DOI: 10.3390/ijms21124565 -
Nature Communications Jul 2019The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression,...
The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression, ensuring ovarian tissue homeostasis, remain elusive. We have performed single-cell RNA-sequencing using human adult ovaries to provide a map of the molecular signature of growing and regressing follicular populations. We have identified different types of granulosa and theca cells and detected local production of components of the complement system by (atretic) theca cells and stromal cells. We also have detected a mixture of adaptive and innate immune cells, as well as several types of endothelial and smooth muscle cells to aid the remodeling process. Our results highlight the relevance of mapping whole adult organs at the single-cell level and reflect ongoing efforts to map the human body. The association between complement system and follicular remodeling may provide key insights in reproductive biology and (in)fertility.
Topics: Adult; Base Sequence; Endothelial Cells; Female; Granulosa Cells; Humans; Myocytes, Smooth Muscle; Ovarian Follicle; Ovulation; Sequence Analysis, RNA; Theca Cells; Uterus
PubMed: 31320652
DOI: 10.1038/s41467-019-11036-9 -
PLoS Biology Dec 2020Primordial follicle assembly in the mouse occurs during perinatal ages and largely determines the ovarian reserve that will be available to support the reproductive life...
Primordial follicle assembly in the mouse occurs during perinatal ages and largely determines the ovarian reserve that will be available to support the reproductive life span. The development of primordial follicles is controlled by a complex network of interactions between oocytes and ovarian somatic cells that remain poorly understood. In the present research, using single-cell RNA sequencing performed over a time series on murine ovaries, coupled with several bioinformatics analyses, the complete dynamic genetic programs of germ and granulosa cells from E16.5 to postnatal day (PD) 3 were reported. Along with confirming the previously reported expression of genes by germ cells and granulosa cells, our analyses identified 5 distinct cell clusters associated with germ cells and 6 with granulosa cells. Consequently, several new genes expressed at significant levels at each investigated stage were assigned. By building single-cell pseudotemporal trajectories, 3 states and 1 branch point of fate transition for the germ cells were revealed, as well as for the granulosa cells. Moreover, Gene Ontology (GO) term enrichment enabled identification of the biological process most represented in germ cells and granulosa cells or common to both cell types at each specific stage, and the interactions of germ cells and granulosa cells basing on known and novel pathway were presented. Finally, by using single-cell regulatory network inference and clustering (SCENIC) algorithm, we were able to establish a network of regulons that can be postulated as likely candidates for sustaining germ cell-specific transcription programs throughout the period of investigation. Above all, this study provides the whole transcriptome landscape of ovarian cells and unearths new insights during primordial follicle assembly in mice.
Topics: Animals; Female; Gene Expression Regulation, Developmental; Germ Cells; Granulosa Cells; Mice; Mice, Inbred C57BL; Oocytes; Ovarian Follicle; Ovary; Pregnancy; Single-Cell Analysis; Transcriptome
PubMed: 33351795
DOI: 10.1371/journal.pbio.3001025 -
Proceedings of the National Academy of... Aug 2020We sequenced more than 52,500 single cells from embryonic day 11.5 (E11.5) postembryonic day 5 (P5) gonads and performed lineage tracing to analyze primordial follicles...
We sequenced more than 52,500 single cells from embryonic day 11.5 (E11.5) postembryonic day 5 (P5) gonads and performed lineage tracing to analyze primordial follicles and wave 1 medullar follicles during mouse fetal and perinatal oogenesis. Germ cells clustered into six meiotic substages, as well as dying/nurse cells. Wnt-expressing bipotential precursors already present at E11.5 are followed at each developmental stage by two groups of ovarian pregranulosa (PG) cells. One PG group, bipotential pregranulosa (BPG) cells, derives directly from bipotential precursors, expresses Foxl2 early, and associates with cysts throughout the ovary by E12.5. A second PG group, epithelial pregranulosa (EPG) cells, arises in the ovarian surface epithelium, ingresses cortically by E12.5 or earlier, expresses Lgr5, but delays robust Foxl2 expression until after birth. By E19.5, EPG cells predominate in the cortex and differentiate into granulosa cells of quiescent primordial follicles. In contrast, medullar BPG cells differentiate along a distinct pathway to become wave 1 granulosa cells. Reflecting their separate somatic cellular lineages, second wave follicles were ablated by diptheria toxin treatment of Lgr5-DTR-EGFP mice at E16.5 while first wave follicles developed normally and supported fertility. These studies provide insights into ovarian somatic cells and a resource to study the development, physiology, and evolutionary conservation of mammalian ovarian follicles.
Topics: Animals; Cell Differentiation; Cell Lineage; Female; Forkhead Box Protein L2; Granulosa Cells; Mice; Ovarian Follicle; Pregnancy; Receptors, G-Protein-Coupled
PubMed: 32759216
DOI: 10.1073/pnas.2005570117 -
Journal of Assisted Reproduction and... Mar 2016Cells are able to produce and release different types of vesicles, such as microvesicles and exosomes, in the extracellular microenvironment. According to the scientific... (Review)
Review
Cells are able to produce and release different types of vesicles, such as microvesicles and exosomes, in the extracellular microenvironment. According to the scientific community, both microvesicles and exosomes are able to take on and transfer different macromolecules from and to other cells, and in this way, they can influence the recipient cell function. Among the different macromolecule cargos, the most studied are microRNAs. MicroRNAs are a large family of non-coding RNAs involved in the regulation of gene expression. They control every cellular process and their altered regulation is involved in human diseases. Their presence in mammalian follicular fluid has been recently demonstrated, and here, they are enclosed within microvesicles and exosomes or they can also be associated to protein complexes. The presence of microvesicles and exosomes carrying microRNAs in follicular fluid could represent an alternative mechanism of autocrine and paracrine communication inside the ovarian follicle. The outcomes from these studies could be important in basic reproductive research but could also be useful for clinical application. In fact, the characterization of extracellular vesicles in follicular fluid could improve reproductive disease diagnosis and provide biomarkers of oocyte quality in ART (Assisted Reproductive Treatment).
Topics: Animals; Cell Communication; Exosomes; Extracellular Vesicles; Female; Follicular Fluid; Humans; MicroRNAs; Ovarian Follicle; Signal Transduction
PubMed: 26814471
DOI: 10.1007/s10815-016-0657-9 -
Seminars in Reproductive Medicine Jul 2015Inflammation is a biologic process that mediates tissue effects including vasodilation, hyperemia, edema, collagenolysis, and cell proliferation through complex... (Review)
Review
Inflammation is a biologic process that mediates tissue effects including vasodilation, hyperemia, edema, collagenolysis, and cell proliferation through complex immunologic pathways. In regard to the ovary, inflammation has key physiologic roles in ovarian folliculogenesis and ovulation. On the other hand, inflammatory processes are subject to underlying pathology and, if pushed, proinflammatory conditions may have a negative impact on ovarian follicular dynamics. Obesity and polycystic ovary syndrome (PCOS) serve as examples of conditions associated with chronic endogenous production of low-grade proinflammatory cytokines. Both conditions negatively impact ovarian folliculogenesis and ovulation. The pages that follow summarize the role of inflammation in normal ovarian follicular dynamics and evidence for its role in mediating the negative effects of obesity and PCOS on ovarian follicular dynamics. The review concludes with a summary supporting a role for lifestyle factors that favorably impact inflammatory process involved in obesity and PCOS to improve ovarian function.
Topics: Female; Humans; Inflammation; Obesity; Ovarian Follicle; Polycystic Ovary Syndrome
PubMed: 26132931
DOI: 10.1055/s-0035-1554928 -
Fertility and Sterility May 2013The removal and cryostorage of ovarian cortical biopsies is now offered as a fertility preservation option for young women. The only available option to restore... (Comparative Study)
Comparative Study Review
The removal and cryostorage of ovarian cortical biopsies is now offered as a fertility preservation option for young women. The only available option to restore fertility using this tissue is by transplantation, which may not be possible for all patients. The full potential of this tissue to restore fertility could be achieved by the development of in vitro systems that support oocyte development from the most immature stages to maturation. The techniques of in vitro growth (IVG) combined with in vitro maturation (IVM) are being developed with human tissue, but comparing different systems has been difficult because of the scarcity of tissue so nonhuman primates are being used as model systems. There are many challenges to developing a complete culture system that would support human oocyte development, and this review outlines the approaches being taken by several groups using tissue from women and nonhuman primate models to support each of the stages of oocyte development.
Topics: Animals; Female; Humans; Macaca mulatta; Oocytes; Ovarian Follicle; Papio; Tissue Culture Techniques
PubMed: 23635350
DOI: 10.1016/j.fertnstert.2013.03.043 -
Journal of Assisted Reproduction and... Mar 2021Extracellular vesicles (EVs) are nano-sized membrane bound complexes that have been identified as a mean for intercellular communication between cells and tissues both... (Review)
Review
Extracellular vesicles (EVs) are nano-sized membrane bound complexes that have been identified as a mean for intercellular communication between cells and tissues both in physiological and pathological conditions. These vesicles contain numerous molecules involved in signal transduction including microRNAs, mRNAs, DNA, proteins, lipids, and cytokines and can affect the behavior of recipient cells. Female reproduction is dependent on extremely fine-tuned endocrine regulation, and EVs may represent an added layer that contributes to this regulation. This narrative review article provides an update on the research of the role of EVs in female reproduction including folliculogenesis, fertilization, embryo quality, and implantation. We also highlight potential pitfalls in typical EV studies and discuss gaps in the current literature.
Topics: Embryo Implantation; Extracellular Vesicles; Female; Humans; Ovarian Follicle; Reproduction
PubMed: 33471231
DOI: 10.1007/s10815-020-02048-2