Intrinsic differences in mTOR activity mediates lineage-specific responses to cyclophosphamide in mouse and human granulosa cells.

IF 3.8 3区 医学 Q1 REPRODUCTIVE BIOLOGY
Shiqian Xu, Yerong Ma, Yinli Zhang, Hanqi Ying, Xiaomei Tong, Weijie Yang, Yibin Pan, Yan Rong, Yangyang Dai, Songying Zhang, Peidong Han
{"title":"Intrinsic differences in mTOR activity mediates lineage-specific responses to cyclophosphamide in mouse and human granulosa cells.","authors":"Shiqian Xu, Yerong Ma, Yinli Zhang, Hanqi Ying, Xiaomei Tong, Weijie Yang, Yibin Pan, Yan Rong, Yangyang Dai, Songying Zhang, Peidong Han","doi":"10.1186/s13048-025-01627-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Cyclophosphamide (CTX) often induces oocyte and granulosa cell injury, leading to fertility loss in young female cancer survivors. Deciphering the mechanisms underlying follicular cell injury could offer novel insights into fertility preservation. Granulosa cells represent the most abundant cell type within the follicles and can be generally categorized as cumulus granulosa cells (CGCs) and mural granulosa cells (MGCs). Despite the essential roles of granulosa cells in supporting ovarian function in physiological conditions, their distinct lineage-specific responses to CTX remains elusive.</p><p><strong>Results: </strong>Here, we performed a genome-wide transcriptome analysis of murine mural and cumulus granulosa cells before and after CTX administration. Compared with MGCs, CGCs exhibited higher basal mammalian target of rapamycin (mTOR) activity and an increased DNA damage response post-injury. Pharmacological mTOR suppression or RNA interference-mediated gene silencing of Raptor, a key component of the mTORC1 complex, significantly reduced DNA damage in granulosa cells induced by 4-HC, an activated form of CTX. Notably, by examining human granulosa cells in response to 4-HC, our results uncovered a conserved role of mTOR inhibition in ovarian protection.</p><p><strong>Conclusions: </strong>Taken together, our findings reveal that intrinsic variations in mTOR activity in CGC and MGC lineages determine their differential responses to CTX. Targeting this signaling pathway may prove beneficial in mitigating CTX-induced granulosa cell apoptosis and protecting against ovarian injury.</p>","PeriodicalId":16610,"journal":{"name":"Journal of Ovarian Research","volume":"18 1","pages":"49"},"PeriodicalIF":3.8000,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895326/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Ovarian Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13048-025-01627-0","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"REPRODUCTIVE BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Cyclophosphamide (CTX) often induces oocyte and granulosa cell injury, leading to fertility loss in young female cancer survivors. Deciphering the mechanisms underlying follicular cell injury could offer novel insights into fertility preservation. Granulosa cells represent the most abundant cell type within the follicles and can be generally categorized as cumulus granulosa cells (CGCs) and mural granulosa cells (MGCs). Despite the essential roles of granulosa cells in supporting ovarian function in physiological conditions, their distinct lineage-specific responses to CTX remains elusive.

Results: Here, we performed a genome-wide transcriptome analysis of murine mural and cumulus granulosa cells before and after CTX administration. Compared with MGCs, CGCs exhibited higher basal mammalian target of rapamycin (mTOR) activity and an increased DNA damage response post-injury. Pharmacological mTOR suppression or RNA interference-mediated gene silencing of Raptor, a key component of the mTORC1 complex, significantly reduced DNA damage in granulosa cells induced by 4-HC, an activated form of CTX. Notably, by examining human granulosa cells in response to 4-HC, our results uncovered a conserved role of mTOR inhibition in ovarian protection.

Conclusions: Taken together, our findings reveal that intrinsic variations in mTOR activity in CGC and MGC lineages determine their differential responses to CTX. Targeting this signaling pathway may prove beneficial in mitigating CTX-induced granulosa cell apoptosis and protecting against ovarian injury.

在小鼠和人颗粒细胞中,mTOR活性的内在差异介导了对环磷酰胺的谱系特异性反应。
背景:环磷酰胺(CTX)经常诱导卵母细胞和颗粒细胞损伤,导致年轻女性癌症幸存者的生育能力丧失。破译卵泡细胞损伤的机制可以为保存生育能力提供新的见解。颗粒细胞是卵泡内最丰富的细胞类型,可分为积云颗粒细胞(cumulus Granulosa cells, CGCs)和壁粒细胞(壁粒细胞,MGCs)。尽管颗粒细胞在生理条件下支持卵巢功能的重要作用,但它们对CTX的独特谱系特异性反应仍然难以捉摸。结果:在这里,我们对CTX给药前后的小鼠壁细胞和积云颗粒细胞进行了全基因组转录组分析。与MGCs相比,CGCs表现出更高的基础哺乳动物雷帕霉素靶蛋白(mTOR)活性,损伤后DNA损伤反应增强。药理抑制mTOR或RNA干扰介导的Raptor基因沉默(mTORC1复合物的关键成分)可显著降低4-HC (CTX的一种活化形式)诱导的颗粒细胞DNA损伤。值得注意的是,通过检测人颗粒细胞对4-HC的反应,我们的结果揭示了mTOR抑制在卵巢保护中的保守作用。综上所述,我们的研究结果揭示了CGC和MGC谱系中mTOR活性的内在变化决定了它们对CTX的不同反应。靶向这一信号通路可能有助于减轻ctx诱导的颗粒细胞凋亡和保护卵巢免受损伤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Ovarian Research
Journal of Ovarian Research REPRODUCTIVE BIOLOGY-
CiteScore
6.20
自引率
2.50%
发文量
125
审稿时长
>12 weeks
期刊介绍: Journal of Ovarian Research is an open access, peer reviewed, online journal that aims to provide a forum for high-quality basic and clinical research on ovarian function, abnormalities, and cancer. The journal focuses on research that provides new insights into ovarian functions as well as prevention and treatment of diseases afflicting the organ. Topical areas include, but are not restricted to: Ovary development, hormone secretion and regulation Follicle growth and ovulation Infertility and Polycystic ovarian syndrome Regulation of pituitary and other biological functions by ovarian hormones Ovarian cancer, its prevention, diagnosis and treatment Drug development and screening Role of stem cells in ovary development and function.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信