Newly Identified Regulators of Ovarian Folliculogenesis and Ovulation

Gershon, Eran; Dekel, Nava

doi:10.3390/ijms21124565

Cited by 116 publications

(77 citation statements)

References 123 publications

(150 reference statements)

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“…These phenomena suggested that PCOS may be a chronic low-grade inflammatory disease (5). The low-grade chronic inflammation in PCOS patients is mainly attributed to accumulated visceral fat (2,4), in which adipocytes undergo necrosis after hypoxia and gather many inflammatory cells to produce numerous inflammatory cytokines (6,7). Therefore, chronic low-grade inflammation plays an irreplaceable role in PCOS progression.…”

Section: Introductionmentioning

confidence: 99%

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The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment

Líu

Fan

et al. 2021

Front. Immunol.

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BackgroundHormones and immune imbalance are critical factors in polycystic ovary syndrome (PCOS). The alternation of immune microenvironment of oocytes may play a significant role in infertility of PCOS patients.ObjectiveThis study explores the role of follicular fluid microenvironment change in inflammatory pathways activation of granulosa cells (GCs) in PCOS women infertility.MethodsWe enrolled 27 PCOS patients and 30 controls aged 22 to 38 years who underwent IVF and collected their luteinized granulosa cells (LGCs). Meanwhile, a granulosa-like tumor cell line (KGN) as a cell-model assisted this study. Key inflammatory markers in human ovarian GCs and follicular fluid were detected by RT-qPCR, Western blotting, or ELISA. The KGN cells were treated with follicle supernatant mixed with normal medium to simulate the microenvironment of GCs in PCOS patients, and the inflammation indicators were observed. The assembly of NLRP3 inflammasomes was detected by immunofluorescence techniques. Dihydroethidium assay and EdU proliferation assay were used to detect ROS and cell proliferation by flow cytometry.ResultsCompared with normal controls (n = 19), IL-1β (P = 0.0005) and IL-18 (P = 0.021) in the follicular fluid of PCOS patients (n = 20) were significantly increased. The NF-κB pathway was activated, and NLRP3 inflammasome was formatted in ovarian GCs of PCOS patients. We also found that inflammation of KGN cells was activated with LPS irritation or stimulated by follicular fluid from PCOS patients. Finally, we found that intracellular inflammation process damaged mitochondrial structure and function, which induced oxidative stress, affected cellular metabolism, and impaired cell proliferation.ConclusionInflammatory microenvironment alteration in the follicular fluid of PCOS patients leads to activated inflammatory pathway in GCs, serving as a crucial factor that causes adverse symptoms in patients. This study provides a novel mechanism in the inflammatory process of PCOS.

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Section: Introductionmentioning

confidence: 99%

“…The follicle is the basic functional unit of oocyte generation and development, it induces human germ cell maturation and ovulation (7,8). GCs control meiosis in mammalian follicles before ovulation (9,10).…”

Section: Introductionmentioning

confidence: 99%

The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment

Líu

Fan

et al. 2021

Front. Immunol.

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“…The Hippo pathway is critical in folliculogenesis and ovarian function by regulating follicle activation and survival, and ovarian cells proliferation (21). The key molecules of the Hippo pathway, including Large tumor suppressor 1/2 (LATS1/2), Mammalian Ste20-like kinases 1/2 (MST1/2), Yes-associated protein (YAP), PDZ-binding motif (TAZ), and TEA domain transcription factor (TEAD), play a critical regulatory function in the cytoplasm of GCs (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Improve Ovarian Function and Proliferation of Premature Ovarian Insufficiency by Regulating the Hippo Signaling Pathway

Zhang

Zheng

et al. 2021

Front. Endocrinol.

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BackgroundPremature ovarian insufficiency (POI) is associated with severe physical damage and psychological burden on women. Transplantation of exosomes is an encouraging regenerative medicine method, which has the potential for restoring ovarian functions on POI with high efficiency. This study aims at evaluating the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) on ovarian dysfunction of POI and the role of Hippo pathway in this exosome-mediated treatment.MethodsPOI mice models were established through intraperitoneal injection of cyclophosphamide. Subsequently, transplantation of hUCMSC-Exos was conducted to administer POI mice. Ovaries and plasma of these mice models were harvested after two weeks of treatment. Ovarian morphology and follicle number were assessed by hematoxylin and eosin staining. Moreover, ELISA was used to detect hormone levels, which are related to ovarian function in serum. To assess the recovery of reproductive ability, we recorded the rate of pregnancy, the amount of offspring, and the time of birth in different groups. To explore the underlying mechanisms of exosome-mediated treatment for ovarian function recovery, the proliferation of ovarian cells in vivo was detected by immunohistochemistry and immunofluorescence staining. Additionally, we conducted EdU and CCK-8 assays to assess the proliferative ability of ovarian granulosa cells (GCs) that were cultured in vitro. Western blot analysis was conducted to estimate the proteins levels of Hippo- and proliferation-associated molecules in vivo and in vitro.ResultsAfter transplantation of hUCMSC-Exos, the ovarian function-related hormone levels and the number of ovarian follicles returned to nearly normal degrees. Meanwhile, there was a significant improvement in reproductive outcomes after exosomal treatment. Furthermore, the improvement of ovarian function and proliferation was associated with the regulation of Hippo pathway. In vitro, co-culture with exosomes significantly elevated the proliferation of ovarian GCs by regulating Hippo pathway. However, the positive effects on the proliferation of GCs were significantly depressed when key Hippo pathway molecule was inhibited.ConclusionThis study suggested that hUCMSC-Exos promoted ovarian functions and proliferation by regulating the Hippo pathway. Therefore, exosomal transplantation could be a promising and efficient clinical therapy for POI in the near future.

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“…It has been reported that decreased levels of Cyp11a1 or Cyp19a1 disrupt the development of antral and Graafian follicles (Gershon and Dekel, 2020). The reduced level of Gata4 expression in Erβ null GCs may contribute to reduced GC proliferation and theca cell recruitment, which would impair the maturation of follicles to the preovulatory stage (Bennett et al, 2013;Efimenko et al, 2013;LaVoie, 2014).…”

Section: Discussionmentioning

confidence: 99%

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

Chakravarthi

Borosha

Ghosh

et al. 2020

Preprint

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Follicle development beyond the preantral stage is dependent on gonadotropins. FSH signaling is crucial for the advancement of preantral follicles to the antral stage, and LH signaling is essential for further maturation of preovulatory follicles. Estrogen is intricately tied to gonadotropin signaling during the advanced stages of folliculogenesis. We observed that Erβnull ovarian follicles fail to develop beyond the antral stage, even after exogenous gonadotropin stimulation. As ERβ is primarily expressed in the granulosa cells (GCs), we explored the gonadotropin-regulated GC genes that induce maturation of antral follicles. Synchronized follicle development was induced by administration of exogenous gonadotropins to wildtype 4-wk-old female rats. The GC transcriptome was analyzed via RNA-sequencing before and after gonadotropin stimulation. An Erβnull mutant model that fails to show follicle maturation was also included in order to identify the ERβ-regulated genes involved at this step. We observed that specific groups of genes were differentially expressed in response to PMSG or hCG administration in wildtype rats. While some of the PMSG or hCG-induced genes showed a similar expression pattern in Erβnull GCs, a subset of PMSG- or hCG-induced genes showed a differential expression in Erβnull GCs. These latter ERβ-regulated genes included previously known FSH or LH target genes including Lhcgr, Cyp11a1, Cyp19a1, Pgr, Runx2, Egfr, Kiss1, and Ptgs2, which are involved in follicle development, oocyte maturation, and ovulation. We also identified novel ERβ-regulated genes including Jaml, Galnt6, Znf750, Dusp9, Wnt16, and Mageb16 that failed to respond to gonadotropin stimulation in Erβnull GCs. Our findings indicate that the gonadotropin-induced spatiotemporal pattern of gene expression is essential for ovarian follicle maturation beyond the antral stage. However, expression of a subset of those gonadotropin-induced genes is dependent on transcriptional regulation by ERβ.

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Newly Identified Regulators of Ovarian Folliculogenesis and Ovulation

Cited by 116 publications

References 123 publications

The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment

The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment

Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Improve Ovarian Function and Proliferation of Premature Ovarian Insufficiency by Regulating the Hippo Signaling Pathway

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

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