Oocyte-secreted factors strongly stimulate sFRP4 expression in human cumulus cells
Oocyte-secreted factors strongly stimulate sFRP4 expression in human cumulus cells
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DOI：
10.1093/molehr/gaab031
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发表时间：
2021-04-26
影响因子：
4
通讯作者：
Stocco, Carlos
中科院分区：
文献类型：
--
作者：
Esfandyari, Sahar;Winston, Nicola J.;Stocco, Carlos
分泌型卷曲相关蛋白4（SFRP 4）属于可溶性卵巢表达蛋白家族，参与雌性生殖，特别是在啮齿动物中。在人类中，SFRP 4在卵丘细胞（CC）中高度表达。然而，在CC中刺激SFRP 4的机制尚未被研究。我们推测，卵母细胞分泌的因子，如生长分化因子9（GDF 9）和骨形态发生蛋白15（BMP 15）参与SFRP 4的调节。从经历生育力治疗的患者收集人CC，并在FSH或媒介物存在下用GDF 9或BMP 15或其组合治疗。与未处理的细胞相比，FSH处理显著降低SFRP 4 mRNA水平。然而，在FSH存在或不存在的情况下，SFRP 4 mRNA水平以浓度依赖性方式被GDF 9加BMP 15显著增加。GDF 9加BMP 15的组合还显著增加了SFRP 4蛋白水平并降低了β-连环蛋白/T细胞因子应答启动子的活性。GDF 9加BMP 15抑制FSH对类固醇生成急性调节蛋白和LH/hCG受体的刺激，而SFRP 4处理则阻断FSH对这些基因的刺激作用。证据表明，GDF 9和BMP 15协同作用以刺激SFRP 4表达，并表明SFRP 4介导人CC中卵母细胞的抗黄体化作用。
Secreted frizzled-related protein-4 (SFRP4) belongs to a family of soluble ovarian-expressed proteins that participate in female reproduction, particularly in rodents. In humans, SFRP4 is highly expressed in cumulus cells (CCs). However, the mechanisms that stimulate SFRP4 in CCs have not been examined. We hypothesise that oocyte-secreted factors such as growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are involved in the regulation of SFRP4. Human CCs were collected from patients undergoing fertility treatments and treated with GDF9 or BMP15 or their combination in the presence of FSH or vehicle. FSH treatment significantly decreased SFRP4 mRNA levels when compared with non-treated cells. However, SFRP4 mRNA levels were increased significantly by GDF9 plus BMP15 in a concentration-dependent manner in the presence or absence of FSH. The combination of GDF9 plus BMP15 also increased SFRP4 protein levels and decreased the activity of the beta-catenin/T cell factor-responsive promoter significantly. GDF9 plus BMP15 inhibited steroidogenic acute regulatory protein and LH/hCG receptor stimulation by FSH, while treatment with SFRP4 blocked the stimulatory effect of FSH on these genes. The evidence demonstrates that GDF9 and BMP15 act in coordination to stimulate SFRP4 expression and suggests that SFRP4 mediates the anti-luteinising effects of the oocyte in human CCs.