BMP15 Prevents Cumulus Cell Apoptosis Through CCL2 and FBN1 in Porcine Ovaries

Zhai, Bo; Liu, Huiyu; Xu, Li; Dai, Li-Shang; Gao, Yan; Li, Changhong; Zhang, Lianjiang; Ding, Yu; Yu, Xiaofeng; Zhang, Jiabao

doi:10.1159/000354435

Cited by 45 publications

(33 citation statements)

References 31 publications

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“…BMP15 can significantly inhibit cumulus cell apoptosis and promote their proliferation by inducing the expression of hyaluronidase 2 (HAS2), pentraxin 3 (PTX3) and prostaglandin synthase 2 (PTGS2) to optimize the oocyte microenvironment and drive oocyte maturation and ovulation [5-8]. GDF9 also has a similar function to that of BMP15 and can inhibit the expression of the LH/CG receptor (LHCGR) and KIT ligand in cumulus cells, inducing the expression of cumulus cell proliferation-related genes and promoting oocyte maturation and ovulation [9-11].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…As an oocyte-secreted factor, BMP15 serves a crucial role in follicular growth and oocyte quality, which is underexpressed in PCOS patients. Adding BMP15 to cultures significantly reduced the apoptosis of granulosa cells (9,(28)(29)(30). Therefore, it is of value to investigate the effect of BMP15 on the apoptosis of granulosa cells in PCOS (11,12,31).…”

Section: Discussionmentioning

confidence: 99%

Abnormal expression levels of BMP15/Smad1 are associated with granulosa cell apoptosis in patients with polycystic ovary syndrome

Cui¹,

Xuan

Wu³

et al. 2017

Molecular Medicine Reports

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Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects reproductive dysfunction and metabolism in women of childbearing age. An increasing number of studies have suggested that the bone morphogenetic protein 15 (BMP15) signalling pathway serves an important role in the pathogenesis of PCOS; however, the full mechanism remains unknown. The present study revealed that intrinsic follicular dysplasia may be associated with regulation disorders of ovarian granulosa cell apoptosis. Compared with the control group, body mass index, luteinising hormone and testosterone levels were significantly increased (P<0.05). The percentage of S phase cells was significantly higher, cells in G2/M phase cells was significantly lower, and cells undergoing apoptosis was significantly higher in the PCOS group compared with the control group (P<0.05). The expression levels of B‑cell lymphoma 2 was significantly decreased in granulosa cells of PCOS group, whereas the expression of caspase‑3 was higher than the control group (P<0.05). The rate of apoptosis of granulosa cells was measured by a terminal deoxynucleotide transferase dUTP nick‑end labelling assay. The relative mRNA expression levels of BMP receptor 2 and SMAD1 were significantly decreased in granulosa cells in the PCOS group compared with the control (P<0.05). In addition, the expression of BMP15 in follicular fluid and Smad1 in granulosa cells was significantly decreased in the PCOS group compared with the control (P<0.05). The data suggested that the BMP15/Smad1 signalling pathway may be involved in granulosa cell apoptosis, and may be a target for clinical treatment for PCOS.

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“…BMP15 is one of the TGFB family members, which is a well-known oocyte-secreted growth factor that acts on cumulus cells to regulate multiple functions, such as the proliferation, expansion, and apoptosis of cumulus cells (Sudiman et al, 2014). Previous high-throughput sequencing results from our group demonstrated that BMP15 increased FAT1 mRNA (Zhai et al, 2013). Studies have demonstrated that the FAT1 gene encodes a v-3 fatty acid desaturase enzyme that converts v-6 to v-3 polyunsaturated fatty acids (PUFAs) and thus increases v-6/v-3 ratio (Chen et al, 2013a,b).…”

Section: Introductionmentioning

confidence: 96%

The possible FAT1‐mediated apoptotic pathways in porcine cumulus cells

Sun

et al. 2016

Cell Biology International

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Porcine cumulus cells are localized around oocytes and act as a specific type of granulosa that plays essential roles in the development and maturation of oocytes, the development and atresia of follicles, and the development of embryos. Studies of FAT1 have demonstrated its functions in cell-cell contact, actin dynamics, and cell growth suppression. To understand whether the FAT1 gene affects the apoptosis of porcine cumulus cells and to elucidate the mechanism of this potential action, FAT1 was knocked down using RNA interference. The lack of FAT1 resulted in stable expression of CTNNB, enhanced expression of cleaved CASP3, but decreased the BCL2/BAX ratios at both the mRNA and protein levels. These results indicated that FAT1 inhibited porcine cumulus cell apoptosis via different pathways. Taken together, these data provide new insights into the mechanisms of the association between FAT1 and porcine cumulus cell apoptosis.

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BMP15 Prevents Cumulus Cell Apoptosis Through CCL2 and FBN1 in Porcine Ovaries

Cited by 45 publications

References 31 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

Abnormal expression levels of BMP15/Smad1 are associated with granulosa cell apoptosis in patients with polycystic ovary syndrome

The possible FAT1‐mediated apoptotic pathways in porcine cumulus cells

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