Aberrant BMP15/HIF-1α/SCF signaling pathway in human granulosa cells is involved in the PCOS related abnormal follicular development

Abstract

Aims

To investigate the regulatory mechanism of SCF expression in human GCs of PCOS related follicles.

Materials and Methods

SCF, BMP15 and HIF-1α were evaluated in human serums, follicular fluids (FFs) and GCs, which were collected from 69 PCOS patients and 74 normal ovulatory patients. KGN cell line was used in this study.

Results

Our results showed that the rate of MII oocyte and 2PN fertilization was lower in PCOS group, though PCOS patients retrieved much more oocytes. The level of BMP15 in FF and the level of SCF in serum and FF were also lower in PCOS patients. We found a weakened expression of HIF-1α and SCF in GCs from PCOS patients when compared with the non-PCOS patients. The expression of HIF-1α and SCF was significantly increased in KGN cells after treating cells with rhBMP15, however, this promotion effects of BMP15 on HIF-1α and SCF expression were obviously abolished by co-treatment with BMP-I receptor inhibitor (DM). Moreover, knock down of HIF-1α expression in KGN cells significantly reduced the expression of SCF in human GCs, in spite of activating BMP15 signaling pathway.

Conclusions

The present study suggest that BMP15 could induce SCF expression by up-regulating HIF-1α expression in human GCs, the aberrance of this signaling pathway might be involved in the PCOS related abnormal follicular development.

摘要

目的

探讨干细胞因子（SCF）在PCOS相关卵泡GCs中表达的调控机制。

材料与方法

对69例PCOS患者和74例排卵正常患者的血清、卵泡液(FFs)和颗粒细胞液（GCs）进行SCF、BMP15和HIF-1α检测。本研究采用KGN细胞系。

结果

PCOS患者获得更多的卵母细胞, 但MII卵母细胞和2PN受精率较低。PCOS患者卵泡液中BMP15水平及血清和FF中SCF水平均较低。 我们发现与非PCOS患者相比, PCOS患者GCs中HIF-1α和SCF的表达减弱。rhBMP15作用后KGN细胞HIF-1α和SCF的表达明显增加, 而BMP15对HIF-1α和SCF表达的促进作用与BMP-I受体抑制剂(DM)联合作用则明显减弱。 此外, 下调KGN细胞HIF-1α的表达, 虽然激活了BMP15信号通路, 但显著降低了人GCs中SCF的表达。

结论

BMP15可通过上调HIF-1α在GCs中的表达而诱导SCF的表达, 该信号通路的异常可能与PCOS相关的卵泡发育异常有关。

Keywords:

• SCF
• BMP15
• HIF-1α
• granulosa cells
• PCOS

关键词:

• 干细胞因子
• BMP15
• HIF-1α
• 颗粒细胞
• 多囊卵巢综合征

Author’s note

The study was approved by the Clinical Ethical Committee of Jiangxi Provincial Maternal and Child Health Hospital, and informed consents from patients were obtained before the initiation of the study.

Acknowledgments

The authors thank all the staff, nurses, and physicians at the Reproductive Medicine Center and the staff at Key Laboratory of Women’s Reproductive Health of Jiangxi Province for their support in generating this manuscript.

Disclosure statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81960271 and 81960288) and the JXHC Key Laboratory of Fertility Preservation, the Major Research and Development Project of Science and Technology Department of Jiangxi Province (20203BBGL73140).