Cumulus Cell-Expressed Type I Interferons Induce Cumulus Expansion in Mice1

Jang, You-Jee; Park, Jae-Il; Moon, Won‐Jin; Dam, Phuong T M; Cho, Moon-Kyoung; Chun, Sang-Young

doi:10.1095/biolreprod.114.122770

Cited by 18 publications

(11 citation statements)

References 29 publications

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“…In the in vitro COCs culture experiments, cumulus cell proliferation and expansion had important effects on oocyte maturation and quality, whereas PTX3, HAS2 and PTGS2 are important genes that affected cumulus cell proliferation [29, 30]. This study showed that miR-375 could regulate the expression levels of PTX3, HAS2 and PTGS2 through its target genes.…”

Section: Discussionmentioning

confidence: 96%

Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

Liu¹,

Yuan²,

Chen³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), which are secreted by oocytes, are important regulators of follicular growth and development and ovarian function. These two factors can regulate the proliferation and apoptosis of cumulus cells via modulation of the Smad signaling pathway. Studies have shown that BMP15 and GDF9 can affect the level of miR-375, whereas the target gene of miR-375 is BMPR2, the type II receptor of BMP15 and GDF9. However, whether or how the BMP15/ GDF9-miR-375-BMPR2 pathway affects the proliferation and apoptosis of bovine cumulus cells through regulation of the Smad signaling pathway remains unclear. Methods: In this study, cumulus cells were first obtained from cumulus-oocyte complexes (COCs). Appropriate concentrations of BMP15 and GDF9 were added during the in vitro culture process. Cell Counting Kit-8 (CCK-8) analyses and flow cytometry were used to determine the effects of BMP15/GDF9 on bovine cumulus cells proliferation and apoptosis. Subsequently, miR-375 mimics, miR-375 inhibitor and BMPR2 siRNA were synthesized and used for transfection experiments. Western Blot analysis was used to detect changes before and after transfection in the expression levels of the BMP15/GDF9 type I receptors ALK4, ALK5 and ALK6; the phosphorylation levels of Smad2/3 and Smad1/5/8, which are key signaling pathway proteins downstream of BMP15/GDF9; the expression levels of PTX3, HAS2 and PTGS2, which are key genes involved in cumulus cells proliferation; and Bcl2/Bax, which are genes involved in apoptosis. Results: The addition of 100 ng/mL BMP15 or 200 ng/mL GDF9 or the combined addition of 50 ng/mL BMP15 and 100 ng/mL GDF9 effectively inhibited bovine cumulus cell apoptosis and promoted cell proliferation. BMP15/GDF9 negatively regulated miR-375 expression and positively regulated BMPR2 expression. High levels of miR-375 and inhibition of BMPR2 resulted in increased expression of ALK4 and decreased expression of PTX3, HAS2 and PTGS2, whereas miR-375 inhibition resulted in the opposite results. BMP15 and GDF9 significantly activated the levels of p-Smad2/3 and p-Smad1/5/8, whereas miR-375 inhibited the levels of p-Smad2/3 and p-Smad1/5/8 by negatively regulating BMPR2 and also led to apoptosis. Conclusion: BMP15 and GDF9 have synergistic effects and can act through miR-375 to affect the expression levels of type I receptor ALK4 and type II receptor BMPR2 and the activation of Smad signaling pathway, which subsequently affected the proliferation, spread and apoptosis of cumulus cells.

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Section: Discussionmentioning

confidence: 96%

Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

Liu¹,

Yuan²,

Chen³

et al. 2018

Cell Physiol Biochem

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“…The reduced expression of GJA1 in CCs after oocyte maturation is beneficial (Edry et al 2006) because it is related to cumulus expansion and decreased diffusion of cAMP and cGMP from the CCs to the oocyte, which is followed by the end of meiotic arrest and extrusion of the first polar body (Shao et al 2015). Conversely, PTGS2 is the key enzyme in prostaglandin E biosynthesis and is also involved in regulation of CC expansion during the ovulatory process in mice (Davis et al 1999;Jang et al 2015). In the present study, Ptgs2 mRNA transcripts were upregulated in CCs after oocyte maturation, as described previously for cattle (Nuttinck et al 2002), mice (Shao et al 2015) and humans (Feuerstein et al 2007;Wathlet et al 2011).…”

Section: Discussionmentioning

confidence: 99%

In vivo and in vitro maturation of rabbit oocytes differently affects the gene expression profile, mitochondrial distribution, apoptosis and early embryo development

Arias-Álvarez

García-García

López-Tello

et al. 2017

Reprod. Fertil. Dev.

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In vivo-matured cumulus-oocyte complexes are valuable models in which to assess potential biomarkers of rabbit oocyte quality that contribute to enhanced IVM systems. In the present study we compared some gene markers of oocytes and cumulus cells (CCs) from immature, in vivo-matured and IVM oocytes. Moreover, apoptosis in CCs, nuclear maturation, mitochondrial reallocation and the developmental potential of oocytes after IVF were assessed. In relation to cumulus expansion, gene expression of gap junction protein, alpha 1, 43 kDa (Gja1) and prostaglandin-endoperoxide synthase 2 (Ptgs2) was significantly lower in CCs after in vivo maturation than IVM. In addition, there were differences in gene expression after in vivo maturation versus IVM in both oocytes and CCs for genes related to cell cycle regulation and apoptosis (V-Akt murine thymoma viral oncogene homologue 1 (Akt1), tumour protein 53 (Tp53), caspase 3, apoptosis-related cysteine protease (Casp3)), oxidative response (superoxide dismutase 2, mitochondrial (Sod2)) and metabolism (glucose-6-phosphate dehydrogenase (G6pd), glyceraldehyde-3-phosphate dehydrogenase (Gapdh)). In vivo-matured CCs had a lower apoptosis rate than IVM and immature CCs. Meiotic progression, mitochondrial migration to the periphery and developmental competence were higher for in vivo-matured than IVM oocytes. In conclusion, differences in oocyte developmental capacity after IVM or in vivo maturation are accompanied by significant changes in transcript abundance in oocytes and their surrounding CCs, meiotic rate, mitochondrial distribution and apoptotic index. Some of the genes investigated, such as Gja1, could be potential biomarkers for oocyte developmental competence in the rabbit model, helping improve in vitro culture systems in these species.

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“…Human and bovine granulosa cells express TLR1-9 (Zhou et al 2009, Price and Sheldon 2013. Similarly, murine cumulus cells express TLR2 and TLR4, and activation of these pattern recognition receptors induces events associated with ovulation such as cumulus expansion (Shimada et al 2006, Shimada et al 2008, Jang et al 2015. Furthermore, endocrine regulation of TLRs was evident in bovine and murine granulosa cells using FSH or EGF (Shimada et al 2006, Shimada et al 2008, Price and Sheldon 2013.…”

Section: Innate Immunity In the Ovarymentioning

confidence: 99%

Innate immunity and the sensing of infection, damage and danger in the female genital tract

Sheldon

Owens

Turner

2017

Journal of Reproductive Immunology

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Tissue homeostasis in the female genital tract is challenged by infection, damage, and even physiological events during reproductive cycles. We propose that the evolutionarily ancient system of innate immunity is sufficient to sense and respond to danger in the non-pregnant female genital tract. Innate immunity produces a rapidly inducible, non-specific response when cells sense danger. Here we provide a primer on innate immunity and discuss what is known about how danger signals are sensed in the endometrium and ovary, the impact of inflammatory responses on reproduction, and how endocrinology and innate immunity are integrated. Endometrial epithelial and stromal cells, and ovarian granulosa cells express pattern recognition receptors, similar to cells of the innate immune system. These pattern recognition receptors, such as the Toll-like receptors, bind pathogen-associated or damage-associated molecular patterns. Activation of pattern recognition receptors leads to inflammation, recruitment of immune cells from the peripheral circulation, and phagocytosis. Although the inflammatory response helps maintain or restore endometrial health, there may also be negative consequences for fertility, including perturbation of oocyte competence. The intensity of the inflammatory response reflects the balance between the level of danger and the systems that regulate innate immunity, including the endocrine environment. Understanding innate immunity is important because disease and inappropriate inflammatory responses in the endometrium or ovary cause infertility.

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Cumulus Cell-Expressed Type I Interferons Induce Cumulus Expansion in Mice1

Cited by 18 publications

References 29 publications

Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

In vivo and in vitro maturation of rabbit oocytes differently affects the gene expression profile, mitochondrial distribution, apoptosis and early embryo development

Innate immunity and the sensing of infection, damage and danger in the female genital tract

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