Molecular characterization of lysyl oxidase‐mediated extracellular matrix remodeling during mouse decidualization

Li, Shuyun; Yan, Jiaqi; Song, Zhuo; Liu, Yue-Fang; Song, Min-Jie; Qin, Jia-Wen; Yang, Zeng‐Ming; Liang, Xiao-Huan

doi:10.1002/1873-3468.12645

Cited by 20 publications

(22 citation statements)

References 30 publications

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“…These findings indicate that direct contact between the embryo and uterine stroma is required for activation of the PI3K-AKT-FOXO1 pathway as an embryonic survival signal to avoid programmed embryonic death. VEGF, adrenomedullin (ADM), and LOX, which can activate the PI3K-AKT pathway and are regulated by HIF (48)(49)(50), are expressed in the uterine stroma and involved in the process of embryo implantation (15,(51)(52)(53)(54). We found that mRNA expression of VEGF and ADM as well as LOX at the stroma of implantation sites collected by LCM technique was significantly decreased in Hif2a-uKO mice ( implantation.…”

Section: Mice With Uterine Deletion Of Hif2a Show Infertility and Thomentioning

confidence: 93%

HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment

Matsumoto¹,

Hirota²,

Saito‐Fujita³

et al. 2018

Journal of Clinical Investigation

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Although it has been reported that hypoxia inducible factor 2 α (Hif2a), a major transcriptional factor inducible by low oxygen tension, is expressed in the mouse uterus during embryo implantation, its role in pregnancy outcomes remains unclear. This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2a in the whole uterus (Hif2a-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone (P4) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2a-uKO mice, respectively, but did not rescue pregnancy failure. Histological analyses in Hif2a-uKO mice revealed persistence of the intact luminal epithelium, which blocked direct contact between stroma and embryo, inactivation of PI3K-AKT pathway (embryonic survival signal), and failed embryo invasion. Mice with stromal deletion of Hif2a (Hif2a-sKO mice) showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2a (Hif2a-eKO mice) showed normal fertility, suggesting the importance of stromal HIF2α in embryo invasion. This was reflected in reduced expression of membrane type 2 metalloproteinase (MT2-MMP), lysyl oxidase (LOX), VEGF, and adrenomedullin (ADM) in Hif2a-uKO stroma at the attachment site, suggesting that stromal HIF2α regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2α allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.

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Section: Mice With Uterine Deletion Of Hif2a Show Infertility and Thomentioning

confidence: 93%

HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment

Matsumoto¹,

Hirota²,

Saito‐Fujita³

et al. 2018

Journal of Clinical Investigation

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“…GSK has been shown to modulate many transcription factors, such as AP-1, CREB, and b-catenin (29)(30)(31)(32)(33)(34). AP-1 acts as a transcription factor that regulates cell proliferation, survival, and apoptosis (35).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of GSK‐3β induces AP‐1‐mediated osteopontin expression to promote cholestatic liver fibrosis

Zhuang

Hua

et al. 2018

FASEB j.

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The contribution of glycogen synthase kinase-3β (GSK-3β) to cholestatic liver disease (CLD) remains unknown. We investigated the role and mechanism of GSK-3β in vivo in liver tissues of patients with CLD and the bile duct ligation (BDL) mouse model and in vitro using a hepatic progenitor cell (HPC) and hepatic stellate cell (HSC) coculture system. In liver tissues of patients with CLD, expression of the inactive form of GSK-3β, phospho-GSK-3β(Ser9), was increased in HPCs. GSK-3β inhibition by SB216763 treatment aggravated liver fibrosis and elevated the expression of osteopontin (OPN) in the BDL mouse model. OPN was significantly overexpressed in liver tissues and serum from patients with CLD. In an HPC and HSC coculture system, inhibition of GSK-3β induced OPN production, which activated HSCs in a cholestatic environment. The expression of activator protein 1 (AP-1), an important downstream transcription factor of GSK-3β, was significantly increased in liver tissues of patients with CLD and SB216763-treated BDL mice. Finally, OPN expression was directly modulated by AP-1. These observations indicate that GSK-3β inhibition up-regulates OPN expression via AP-1 activation, which accelerates the progression of cholestatic liver fibrosis in patients with CLD and in BDL mice.-Zhuang, S., Hua, X., He, K., Zhou, T., Zhang, J., Wu, H., Ma, X., Xia, Q., Zhang, J. Inhibition of GSK-3β induces AP-1-mediated osteopontin expression to promote cholestatic liver fibrosis.

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“…Lox, also known as protein-lysine 6-oxidase, is rarely detected in normal or non-proliferative senescent HSCs, but is expressed in culture-activated HSCs and intra-hepatic HSCs following CCl 4 injury [30, 31]. Recent studies attributed ECM remodeling, spontaneous reversion of fibrogenesis, and induced phenotypic reversion of HSCs to Lox overexpression [7, 32]. These findings suggested that the dysregulated lncRNA-mRNA network might be closely associated with ECM remodeling and HSC activation.…”

Section: Discussionmentioning

confidence: 99%

RNA Sequencing and Bioinformatics Analysis Implicate the Regulatory Role of a Long Noncoding RNA-mRNA Network in Hepatic Stellate Cell Activation

Guo

Xiao

Sheng

et al. 2017

Cell Physiol Biochem

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Background/Aims: To analyze the long noncoding (lncRNA)-mRNA expression network and potential roles in rat hepatic stellate cells (HSCs) during activation. Methods: LncRNA expression was analyzed in quiescent and culture-activated HSCs by RNA sequencing, and differentially expressed lncRNAs verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) were subjected to bioinformatics analysis. In vivo analyses of differential lncRNA-mRNA expression were performed on a rat model of liver fibrosis. Results: We identified upregulation of 12 lncRNAs and 155 mRNAs and downregulation of 12 lncRNAs and 374 mRNAs in activated HSCs. Additionally, we identified the differential expression of upregulated lncRNAs (NONRATT012636.2, NONRATT016788.2, and NONRATT021402.2) and downregulated lncRNAs (NONRATT007863.2, NONRATT019720.2, and NONRATT024061.2) in activated HSCs relative to levels observed in quiescent HSCs, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that changes in lncRNAs associated with HSC activation revealed 11 significantly enriched pathways according to their predicted targets. Moreover, based on the predicted co-expression network, the relative dynamic levels of NONRATT013819.2 and lysyl oxidase (Lox) were compared during HSC activation both in vitro and in vivo. Our results confirmed the upregulation of lncRNA NONRATT013819.2 and Lox mRNA associated with the extracellular matrix (ECM)-related signaling pathway in HSCs and fibrotic livers. Conclusion: Our results detailing a dysregulated lncRNA-mRNA network might provide new treatment strategies for hepatic fibrosis based on findings indicating potentially critical roles for NONRATT013819.2 and Lox in ECM remodeling during HSC activation.

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Molecular characterization of lysyl oxidase‐mediated extracellular matrix remodeling during mouse decidualization

Cited by 20 publications

References 30 publications

HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment

HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment

Inhibition of GSK‐3β induces AP‐1‐mediated osteopontin expression to promote cholestatic liver fibrosis

RNA Sequencing and Bioinformatics Analysis Implicate the Regulatory Role of a Long Noncoding RNA-mRNA Network in Hepatic Stellate Cell Activation

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