{"title":"cGAS-STING 通路的激活会导致老年小鼠子宫接受能力异常。","authors":"Si-Ting Chen, Wen-Wen Shi, Feng Ran, Cheng-Kan Liu, Hui-Na Luo, Li-Juan Wu, Ying Wu, Tong-Tong Zhang, Zeng-Ming Yang","doi":"10.1111/acel.14303","DOIUrl":null,"url":null,"abstract":"<p>Maternal age is one of the most important factors affecting the success of maternal pregnancy. Uterine aging is the leading cause of pregnancy failure in older women. However, how uterine aging affects uterine receptivity and decidualization is unclear. In this study, naturally aged one-year-old female mice were used to investigate effects of maternal age on embryo implantation during early pregnancy. In our study, we found abnormal uterine receptivity in aged mice. Aged mouse uterus indicates a decrease in nuclear LAMIN A, and an increase in PRELAMIN A and PROGERIN. In aged mouse uterus, double-stranded DNA (dsDNA) in cytoplasmic fraction is significantly increased. PROGERIN overexpression in mouse uterine epithelial cells and epithelial organoids leads to nuclear DNA leakage and impaired uterine receptivity. DNase I, DNase II, and TREX1 are obviously reduced in aged mouse uterus. Treatments with foreign DNA or STING agonist significantly downregulate uterine receptivity markers and activate cGAS-STING pathway. Uterine estrogen (E<sub>2</sub>) concentration is significantly increased in aged mice. After ovariectomized mice are treated with a high level of E<sub>2</sub>, there are significant increase of PROGERIN and cytoplasmic DNA, and activation of cGAS-STING pathway. CD14 is significantly increased in aged uterus. Intrauterine CD14 injection inhibits embryo implantation. In vitro CD14 treatment of cultured epithelial cells or epithelial organoids decreases uterine receptivity. Uterine abnormality in aged mouse can be partially rescued by STING inhibitor. In conclusion, uterine PROGERIN increase in aged mouse uterus results in cytoplasmic DNA accumulation and cGAS-STING pathway activation. CD14 secretion in aged uterus impairs uterine receptivity.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 11","pages":""},"PeriodicalIF":7.8000,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561655/pdf/","citationCount":"0","resultStr":"{\"title\":\"The activation of cGAS-STING pathway causes abnormal uterine receptivity in aged mice\",\"authors\":\"Si-Ting Chen, Wen-Wen Shi, Feng Ran, Cheng-Kan Liu, Hui-Na Luo, Li-Juan Wu, Ying Wu, Tong-Tong Zhang, Zeng-Ming Yang\",\"doi\":\"10.1111/acel.14303\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Maternal age is one of the most important factors affecting the success of maternal pregnancy. Uterine aging is the leading cause of pregnancy failure in older women. However, how uterine aging affects uterine receptivity and decidualization is unclear. In this study, naturally aged one-year-old female mice were used to investigate effects of maternal age on embryo implantation during early pregnancy. In our study, we found abnormal uterine receptivity in aged mice. Aged mouse uterus indicates a decrease in nuclear LAMIN A, and an increase in PRELAMIN A and PROGERIN. In aged mouse uterus, double-stranded DNA (dsDNA) in cytoplasmic fraction is significantly increased. PROGERIN overexpression in mouse uterine epithelial cells and epithelial organoids leads to nuclear DNA leakage and impaired uterine receptivity. DNase I, DNase II, and TREX1 are obviously reduced in aged mouse uterus. Treatments with foreign DNA or STING agonist significantly downregulate uterine receptivity markers and activate cGAS-STING pathway. Uterine estrogen (E<sub>2</sub>) concentration is significantly increased in aged mice. After ovariectomized mice are treated with a high level of E<sub>2</sub>, there are significant increase of PROGERIN and cytoplasmic DNA, and activation of cGAS-STING pathway. CD14 is significantly increased in aged uterus. Intrauterine CD14 injection inhibits embryo implantation. In vitro CD14 treatment of cultured epithelial cells or epithelial organoids decreases uterine receptivity. Uterine abnormality in aged mouse can be partially rescued by STING inhibitor. In conclusion, uterine PROGERIN increase in aged mouse uterus results in cytoplasmic DNA accumulation and cGAS-STING pathway activation. CD14 secretion in aged uterus impairs uterine receptivity.</p>\",\"PeriodicalId\":55543,\"journal\":{\"name\":\"Aging Cell\",\"volume\":\"23 11\",\"pages\":\"\"},\"PeriodicalIF\":7.8000,\"publicationDate\":\"2024-08-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561655/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Aging Cell\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/acel.14303\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Aging Cell","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/acel.14303","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
引用次数: 0
摘要
孕产妇年龄是影响孕产妇妊娠成功的最重要因素之一。子宫老化是高龄妇女妊娠失败的主要原因。然而,子宫衰老如何影响子宫接受能力和蜕膜化还不清楚。本研究利用自然衰老的一岁雌性小鼠来研究母体年龄对早期妊娠胚胎着床的影响。在我们的研究中,我们发现高龄小鼠的子宫接受能力异常。老年小鼠子宫显示核 LAMIN A 减少,PRELAMIN A 和 PROGERIN 增加。在老年小鼠子宫中,细胞质部分的双链 DNA(dsDNA)显著增加。PROGERIN 在小鼠子宫上皮细胞和上皮器官组织中的过表达会导致核 DNA 泄漏和子宫接受能力受损。老化小鼠子宫中的 DNase I、DNase II 和 TREX1 明显减少。外来 DNA 或 STING 激动剂能显著下调子宫接受性标志物并激活 cGAS-STING 通路。老龄小鼠子宫雌激素(E2)浓度明显增加。卵巢切除的小鼠经高浓度 E2 处理后,PROGERIN 和细胞质 DNA 明显增加,cGAS-STING 通路被激活。老化子宫中的 CD14 明显增加。宫内注射 CD14 可抑制胚胎着床。体外 CD14 处理培养的上皮细胞或上皮器官组织会降低子宫的接受能力。STING 抑制剂可部分缓解老龄小鼠的子宫异常。总之,老龄小鼠子宫 PROGERIN 的增加导致细胞质 DNA 积累和 cGAS-STING 通路激活。CD14在老化子宫中的分泌会损害子宫的接受能力。
The activation of cGAS-STING pathway causes abnormal uterine receptivity in aged mice
Maternal age is one of the most important factors affecting the success of maternal pregnancy. Uterine aging is the leading cause of pregnancy failure in older women. However, how uterine aging affects uterine receptivity and decidualization is unclear. In this study, naturally aged one-year-old female mice were used to investigate effects of maternal age on embryo implantation during early pregnancy. In our study, we found abnormal uterine receptivity in aged mice. Aged mouse uterus indicates a decrease in nuclear LAMIN A, and an increase in PRELAMIN A and PROGERIN. In aged mouse uterus, double-stranded DNA (dsDNA) in cytoplasmic fraction is significantly increased. PROGERIN overexpression in mouse uterine epithelial cells and epithelial organoids leads to nuclear DNA leakage and impaired uterine receptivity. DNase I, DNase II, and TREX1 are obviously reduced in aged mouse uterus. Treatments with foreign DNA or STING agonist significantly downregulate uterine receptivity markers and activate cGAS-STING pathway. Uterine estrogen (E2) concentration is significantly increased in aged mice. After ovariectomized mice are treated with a high level of E2, there are significant increase of PROGERIN and cytoplasmic DNA, and activation of cGAS-STING pathway. CD14 is significantly increased in aged uterus. Intrauterine CD14 injection inhibits embryo implantation. In vitro CD14 treatment of cultured epithelial cells or epithelial organoids decreases uterine receptivity. Uterine abnormality in aged mouse can be partially rescued by STING inhibitor. In conclusion, uterine PROGERIN increase in aged mouse uterus results in cytoplasmic DNA accumulation and cGAS-STING pathway activation. CD14 secretion in aged uterus impairs uterine receptivity.
期刊介绍:
Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.