Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China.
Department of Anesthesiology, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China.
Reprod Biol Endocrinol. 2022 Feb 26;20(1):39. doi: 10.1186/s12958-022-00911-8.
Premature ovarian failure (POF) is a serious problem for young women who receive chemotherapy, and its pathophysiological basis is the dysfunction of granulosa cells. According to previous reports, menstrual-derived stem cells (MenSCs) can restore ovarian function and folliculogenesis in mice with chemotherapy-induced POF. Fat mass- and obesity-associated (FTO) was reported to be associated with oocyte development and maturation. FTO was decreased in POF and may be a biomarker for the occurrence of POF. Knockdown of FTO in granulosa cells promoted cell apoptosis and inhibited proliferation. But the relationship between FTO and ovarian repair was still unclear. This study was aimed at investigating the FTO expression level and the role of FTO in the MenSCs recovering the function of injured granulosa cells.
First, cisplatin was used to establish a granulosa cell injury model. Then, the MenSCs and injured granulosa cell coculture model and POF mouse model were established in this study to explore the role of FTO. Furthermore, gain- and loss-of-function studies, small interfering RNA transfection, and meclofenamic acid (MA), a highly selective inhibitor of FTO, studies were also conducted to clarify the regulatory mechanism of FTO in granulosa cells.
MenSCs coculture could improve the function of injured granulosa cells by increasing the expression of FTO. MenSCs transplantation restored the expression of FTO in the ovaries of POF mice. Overexpression of FTO restored the injured cell proliferation and decreased apoptosis by regulating the expression of BNIP3. Down-regulation of FTO got the opposite results.
In the treatment of MenSCs, FTO has a protective effect, which could improve the viability of granulosa cells after cisplatin treatment by decreasing the expression of BNIP3. Meanwhile, FTO may provide new insight into therapeutic targets for the chemotherapy-induced POF.
卵巢早衰（POF）是接受化疗的年轻女性面临的严重问题，其病理生理基础是颗粒细胞功能障碍。据此前报道，月经来源的干细胞（MenSCs）可恢复化疗诱导的 POF 小鼠的卵巢功能和卵泡发生。脂肪量和肥胖相关（FTO）基因与卵母细胞发育和成熟有关。POF 中 FTO 减少，可能是 POF 发生的生物标志物。在颗粒细胞中敲低 FTO 可促进细胞凋亡并抑制增殖。但 FTO 与卵巢修复的关系仍不清楚。本研究旨在研究 FTO 的表达水平以及 FTO 在 MenSCs 恢复受损颗粒细胞功能中的作用。
首先，用顺铂建立颗粒细胞损伤模型。然后，本研究建立了 MenSCs 和受损颗粒细胞共培养模型和 POF 小鼠模型，以探讨 FTO 的作用。此外，还进行了 gain-和 loss-of-function 研究、小干扰 RNA 转染以及 FTO 的高度选择性抑制剂甲氯芬酸（MA）研究，以阐明 FTO 在颗粒细胞中的调节机制。
MenSCs 共培养可通过增加 FTO 的表达来改善受损颗粒细胞的功能。MenSCs 移植可恢复 POF 小鼠卵巢中 FTO 的表达。过表达 FTO 通过调节 BNIP3 的表达恢复受损细胞的增殖并减少凋亡。下调 FTO 则得到相反的结果。
在 MenSCs 治疗中，FTO 具有保护作用，可通过降低 BNIP3 的表达来改善顺铂处理后颗粒细胞的活力。同时，FTO 可能为化疗诱导的 POF 的治疗靶点提供新的见解。
