Abnormal aggregation of myeloid-derived suppressor cells in a mouse model of cyclophosphamide-induced premature ovarian failure

Abstract

Oocytes are extremely sensitive to radiation and chemotherapy, and premature ovarian failure (POF) is one of the side effects of anti-tumor therapy. The pathogenesis of POF is very complex and still not fully elucidated. A mouse POF model was established after 14 days of cyclophosphamide injection. POF mice presented ovarian atrophy, destroyed follicular structure, a reduction in the number of primordial and mature follicles, and an decrease in the number of corpora luteal along with increased level of follicle-stimulating hormone (FSH), decreased levels of estradiol (E2), and anti-Mullerian hormone (AMH). Additionally, the proportion of bone marrow myeloid-derived suppressor cells (MDSCs) in peripheral blood, spleen, and ovarian tissue increased. MDSCs were mainly distributed around follicles and corpora luteal. Levels of mTOR and p-mTOR increased in ovarian tissue and inhibition of mTOR with rapamycin reduced the aggregation of MDSCs in peripheral blood, spleen, and ovarian tissue. This investigation sheds new light on the modulatory role of mTOR and demonstrates that an increase in MDSC number may play a key role in the pathological reaction during POF. Inhibition of mTOR and reduction of MDSCs in the ovary may represent a novel strategy for the treatment of POF.

摘要

卵母细胞对放疗和化疗极其敏感, 卵巢早衰(POF)是抗肿瘤治疗的副作用之一。POF的发病机制十分复杂, 至今尚未完全阐明。通过注射环磷酰胺14天建立POF小鼠模型。POF小鼠卵巢萎缩, 卵泡结构破坏, 原始卵泡和成熟卵泡数量减少, 黄体数量减少, 卵泡刺激素(FSH)水平升高, 雌二醇(E2)水平降低, 抗苗勒氏激素(AMH)水平降低。此外, 骨髓来源的抑制性细胞(MDSCs)在外周血、脾脏和卵巢组织中的比例增加。MDSCs主要分布在卵泡和黄体周围。卵巢组织中mTOR和p-mTOR水平升高, 雷帕霉素通过抑制mTOR可抑制外周血、脾脏和卵巢组织中MDSCs的聚集。本研究对mTOR的调节作用有了新的认识并表明MDSC数目的增加可能在POF发病机制中起重要作用。卵巢中mTOR的抑制和MDSCs的减少可能为POF的治疗提供新的策略。

The Chinese abstracts are translated by Prof. Dr. Xiangyan Ruan and her team: Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China.

Keywords:

• Premature ovarian failure
• endocrine system diseases
• ovarian diseases
• myeloid-derived suppressor cells
• mTOR

Acknowledgements

We would like to thank Prof. Songwen Ju (Central Laboratory of Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China) for his suggestions on the revision of this manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study was funded by the Introduction Project of Suzhou Clinical Medicine Expert Team, the fund of the Talents of Jiangsu 333 Project, the fund of Gusu Key Health Talents, the Youth Science Fund Project of the National Natural Science Foundaton of China, the Youth Science Fund Project of the Natural Science Foundaton of Jiangsu Province, Suzhou Key Laboratory of Male Reproduction Research, Jiangsu Key Youth Medical Talents.