Yan Gu, Ling-Han Chen, Long Yang, Yan Shi, Hao-Lan Xu, Ya-Wei Xin, Ning Song, Wen-Wen Gu, Jian Wang
{"title":"Decreased miR-486-5p is involved in lipopolysaccharide-induced HTR-8/SVneo cell dysfunction by promoting SMAD2 expression.","authors":"Yan Gu, Ling-Han Chen, Long Yang, Yan Shi, Hao-Lan Xu, Ya-Wei Xin, Ning Song, Wen-Wen Gu, Jian Wang","doi":"10.1530/REP-23-0502","DOIUrl":null,"url":null,"abstract":"<p><strong>In brief: </strong>Insufficiency of extravillous trophoblast (EVT) cell invasion is implicated in pregnancy complications. This study reveals the roles of the miR-486-5p/Smad2 pathway in lipopolysaccharide (LPS)-induced EVT dysfunctions and in the pathogenesis of early pregnancy loss (EPL).</p><p><strong>Abstract: </strong>Placenta-associated pathologies, including EPL and preeclampsia, are characterized by insufficient EVT invasion. Previously, downregulated miR-486-5p expression was shown to inhibit the invasion of EVTs, and decreased peripheral miR-486-5p expression was associated with EPL. However, the exact roles of miR-486-5p in the pathogenesis of EPL, as well as the molecular pathway underlying the role of miR-486-5p in EVT invasion, remain poorly understood. In this study, decreased miR-486-5p expression in the uterine embryo implantation site on gestational day 8.5 and increased uterine expression of Smad2, a target of miR-486-5p, were observed in an LPS-induced EPL model. The invasion and viability of the immortalized human EVT line, HTR-8/SVneo, were inhibited by LPS, accompanied by reduced miR-486-5p expression. LPS promoted Smad2 expression, which was attenuated by the miR-486-5p mimics. The downregulation of Smad2 effectively restored the impaired invasion and viability of HTR-8/SVneo cells caused by LPS or the miR-486-5p inhibitor. Furthermore, LPS promoted TNFα production in HTR-8/SVneo cells, whereas both siSMAD2 and miR-486-5p mimics reversed this effect. An analysis of human decidua single-cell RNA sequencing and transcriptome datasets derived from Gene Expression Omnibus revealed that, compared with that in control early pregnant women, SMAD2 expression was significantly increased in recurrent miscarriage patients. Collectively, these data suggest that decreased miR-486-5p expression might lead to EPL, at least partially by inhibiting invasion and/or promoting TNFα production in EVTs by targeting SMAD2.</p>","PeriodicalId":21127,"journal":{"name":"Reproduction","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Reproduction","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1530/REP-23-0502","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"Print","JCR":"Q1","JCRName":"DEVELOPMENTAL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
In brief: Insufficiency of extravillous trophoblast (EVT) cell invasion is implicated in pregnancy complications. This study reveals the roles of the miR-486-5p/Smad2 pathway in lipopolysaccharide (LPS)-induced EVT dysfunctions and in the pathogenesis of early pregnancy loss (EPL).
Abstract: Placenta-associated pathologies, including EPL and preeclampsia, are characterized by insufficient EVT invasion. Previously, downregulated miR-486-5p expression was shown to inhibit the invasion of EVTs, and decreased peripheral miR-486-5p expression was associated with EPL. However, the exact roles of miR-486-5p in the pathogenesis of EPL, as well as the molecular pathway underlying the role of miR-486-5p in EVT invasion, remain poorly understood. In this study, decreased miR-486-5p expression in the uterine embryo implantation site on gestational day 8.5 and increased uterine expression of Smad2, a target of miR-486-5p, were observed in an LPS-induced EPL model. The invasion and viability of the immortalized human EVT line, HTR-8/SVneo, were inhibited by LPS, accompanied by reduced miR-486-5p expression. LPS promoted Smad2 expression, which was attenuated by the miR-486-5p mimics. The downregulation of Smad2 effectively restored the impaired invasion and viability of HTR-8/SVneo cells caused by LPS or the miR-486-5p inhibitor. Furthermore, LPS promoted TNFα production in HTR-8/SVneo cells, whereas both siSMAD2 and miR-486-5p mimics reversed this effect. An analysis of human decidua single-cell RNA sequencing and transcriptome datasets derived from Gene Expression Omnibus revealed that, compared with that in control early pregnant women, SMAD2 expression was significantly increased in recurrent miscarriage patients. Collectively, these data suggest that decreased miR-486-5p expression might lead to EPL, at least partially by inhibiting invasion and/or promoting TNFα production in EVTs by targeting SMAD2.
期刊介绍:
Reproduction is the official journal of the Society of Reproduction and Fertility (SRF). It was formed in 2001 when the Society merged its two journals, the Journal of Reproduction and Fertility and Reviews of Reproduction.
Reproduction publishes original research articles and topical reviews on the subject of reproductive and developmental biology, and reproductive medicine. The journal will consider publication of high-quality meta-analyses; these should be submitted to the research papers category. The journal considers studies in humans and all animal species, and will publish clinical studies if they advance our understanding of the underlying causes and/or mechanisms of disease.
Scientific excellence and broad interest to our readership are the most important criteria during the peer review process. The journal publishes articles that make a clear advance in the field, whether of mechanistic, descriptive or technical focus. Articles that substantiate new or controversial reports are welcomed if they are noteworthy and advance the field. Topics include, but are not limited to, reproductive immunology, reproductive toxicology, stem cells, environmental effects on reproductive potential and health (eg obesity), extracellular vesicles, fertility preservation and epigenetic effects on reproductive and developmental processes.