Decreased miR-486-5p is involved in lipopolysaccharide-induced HTR-8/SVneo cell dysfunction by promoting SMAD2 expression.

IF 3.7 3区 生物学 Q1 DEVELOPMENTAL BIOLOGY
Reproduction Pub Date : 2025-01-02 Print Date: 2025-01-01 DOI:10.1530/REP-23-0502
Yan Gu, Ling-Han Chen, Long Yang, Yan Shi, Hao-Lan Xu, Ya-Wei Xin, Ning Song, Wen-Wen Gu, Jian Wang
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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.

通过促进 Smad2 的表达,miR-486-5p 的减少参与了 LPS 诱导的 HTR-8/SVneo 细胞功能障碍。
胎盘相关病症,包括早期妊娠丢失(EPL)和子痫前期(PE),都有一个共同的现象,即胚胎滋养层外滋养细胞(EVTs)侵袭不足。以前曾观察到,miR-486-5p表达下调会抑制EVTs的侵袭,而外周miR-486-5p的减少与EPL有关。然而,miR-486-5p在EPL发病机制中的确切作用,以及miR-486-5p在EVTs侵袭中发挥作用的分子途径仍不甚明了。本研究发现,在脂多糖(LPS)诱导的EPL小鼠模型中,妊娠8.5天时子宫胚胎植入部位的miR-486-5p表达减少,miR-486-5p的靶点Smad2表达增加。LPS抑制了永生化人EVTs株HTR-8/SVneo的侵袭和活力,同时降低了miR-486-5p的表达。LPS对Smad2的表达有促进作用,而miR-486-5p模拟物可降低Smad2的表达。而下调的Smad2能有效恢复LPS或miR-486-5p抑制剂对HTR-8/SVneo细胞侵袭和活力的损害。此外,LPS能促进HTR-8/SVneo细胞中TNFα的产生,而siSmad和miR-486-5p模拟物都能逆转这种效应。通过分析基因表达总库(Gene Expression Omnibus)中的人类蜕膜单细胞 RNA 测序和转录组数据集,发现与对照组早孕妇女相比,复发性流产(RM)患者的 Smad2 表达显著增加。总之,这些数据表明,miR-486-5p表达的减少可能至少部分地通过靶向Smad2抑制EVT的侵袭和/或促进TNFα的产生,从而导致EPL。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Reproduction
Reproduction 生物-发育生物学
CiteScore
7.40
自引率
2.60%
发文量
199
审稿时长
4-8 weeks
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.
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