The FASEB Journal最新文献

{"title":"The TNFRSF1B Connection: Implications for Androgenetic Alopecia Pathogenesis and Treatment","authors":"Feihong Xu,&nbsp;Ye He,&nbsp;Yang Sun,&nbsp;Shizhao Liu,&nbsp;Hailin Wang,&nbsp;Wenzhen Li,&nbsp;Xin Li,&nbsp;Zhiqi Hu","doi":"10.1096/fj.202402832R","DOIUrl":"https://doi.org/10.1096/fj.202402832R","url":null,"abstract":"<div>\u0000 \u0000 <p>Androgenetic alopecia (AGA) is a prevalent form of hair loss with poorly understood mechanisms. This study investigates the association between the tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) gene and AGA, aiming to validate its potential causal relationship. Transcriptomic data from AGA patients were obtained from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, along with Weighted Gene Co-expression Network Analysis (WGCNA), were employed to determine AGA-related key genes. We then performed Mendelian randomization (MR) analysis with genome-wide association study (GWAS) data to assess the causal relationship between key genes and AGA, employing methods such as weighted median and MR-Egger regression for sensitivity analysis. Meta-analysis of AGA-related datasets from GEO was conducted, followed by in vitro and in vivo experiments on TNFRSF1B to evaluate its impact on hair dermal papilla cells (HDPCs) and AGA models. RNA-seq data revealed significant upregulation of TNFRSF1B, PIK3CD, and THEMIS2 in AGA patient hair follicles. ROC analysis indicated their diagnostic potential, with WGCNA and gene intersection analysis identifying TNFRSF1B as closely associated with AGA. MR confirmed a causal relationship between TNFRSF1B and AGA. Meta-analysis further validated TNFRSF1B upregulation across multiple AGA datasets. In vitro experiments demonstrated that TNFRSF1B knockdown enhanced HDPC proliferation and migration, reduced apoptosis, and upregulated β-catenin and CyclinD1 expression. Additionally, TNFRSF1B knockdown reduced ROS levels and increased Catalase and SOD2 expression under oxidative stress. In vivo, TNFRSF1B knockdown promoted hair regeneration and reduced oxidative stress in an AGA mice model. The findings suggest that TNFRSF1B is a potential pathogenic factor in AGA, providing a novel therapeutic target for intervention.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 9","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beige Adipocytes Promote Triple-Negative Breast Cancer Cell Migration and Malignancy Through BMP4 Signaling","authors":"Ying-Fang Chen,&nbsp;Chung-Lin Jiang,&nbsp;Chi-Ling Tan,&nbsp;Pei-Hsiang Lai,&nbsp;Fu-Jung Lin","doi":"10.1096/fj.202500158R","DOIUrl":"https://doi.org/10.1096/fj.202500158R","url":null,"abstract":"<div>\u0000 \u0000 <p>Breast cancer remains a leading cause of cancer-related mortality among women, with adipocyte–breast cancer interactions playing a critical role in cancer progression. Mammary gland fat contains both white and brown-like adipocytes. While white adipocytes have been associated with aggressive tumor behavior, the impact of brown-like adipocytes on cancer progression remains largely unclear. This study investigated the roles of beige (UCP1^high) and white (UCP1^low) adipocytes derived from human adipose-derived mesenchymal stem cells within the tumor microenvironment. Triple-negative breast cancer (TNBC) MDA-MB-231 cells exhibited increased migration and invasion when exposed to white (hWCM) or beige (hBCM) adipocyte-conditioned medium, with a more pronounced effect observed with hBCM. Mechanistically, beige adipocytes secreted significantly higher levels of bone morphogenetic protein 4 (BMP4) compared to white adipocytes, which enhanced TNBC cell migration. Inhibition of BMP signaling with Noggin effectively reduced the migration and malignancy of MDA-MB-231 cells induced by hBCM, underscoring the pivotal role of BMP4 in breast cancer progression. Furthermore, an ex vivo model using primary mature adipocytes revealed that co-culturing MDA-MB-231 cells with UCP1^high adipocytes from cold-exposed mice increased cell migration and altered epithelial-mesenchymal transition gene expression compared to UCP1^low adipocytes from room temperature-housed mice. These findings highlight the critical role of UCP1^high beige adipocytes and BMP4 signaling in TNBC progression, suggesting that targeting BMP4 signaling may offer a novel therapeutic strategy for managing TNBC.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 9","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pro-Atherosclerotic Effects of Osteopontin Is Contributed to Promoting Foam Cell Formation Derived From VSMCs by Inhibiting Cholesterol Efflux","authors":"Wentao Liu,&nbsp;Yuan Wang,&nbsp;Chen Liu,&nbsp;Bowei Shi,&nbsp;Xiaowei Xiong,&nbsp;Sheng Chen,&nbsp;Qianqian Huang,&nbsp;Li Wang,&nbsp;Guohua Zeng,&nbsp;Qiren Huang","doi":"10.1096/fj.202403104RR","DOIUrl":"https://doi.org/10.1096/fj.202403104RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Atherosclerosis (AS) is the primary pathological basis of many cardiovascular diseases, and the formation of foam cells plays a critical role in the progression of AS. Increasing evidence shows that a considerable proportion of foam cells derive from vascular smooth muscle cells (VSMCs) in atherosclerotic plaques. Osteopontin (OPN), a glycosylated protein secreted by cells, is supposed to promote the development of AS. However, the underlying mechanisms of OPN contributing to the AS progression remain unclear. Therefore, the purpose of the study is to investigate the effects and mechanisms of OPN on VSMC-foaming and AS. Mouse AS model was established by feeding ApoE^−/− mice with high fat diet (HFD), and the foam cell model of murine aortic vascular smooth muscle cells (MOVAS) was induced with Ox-LDL. During modeling, both ApoE^−/− mice and MOVAS were infected with mouse recombinant adenoviruses expressing OPN (Ad-OPN). Our results show that OPN aggravates vascular smooth muscle dysfunction and AS in the ApoE^−/− mice fed with HFD. Besides, OPN reduces cholesterol efflux and further promotes the formation of VSMC-derived foam cells by decreasing the expressions of ABCA1 and ABCG1. Furthermore, OPN inhibits the phosphorylation of p38MAPK through binding to its membrane receptor CD44, thereby reducing the expressions of LXRα, ABCA1, and ABCG1. Our results demonstrate that OPN reduces the expression of cholesterol transporters ABCA1 and ABCG1 and promotes the formation of VSMC-derived foam cells, exacerbating the development of AS. The findings would provide a more powerful theoretical support for preventing and treating AS with OPN as the target.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 9","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic FABP7 Alleviates Depression-Like Behaviors of Chronic Unpredictable Mild Stress Mice by Regulating Neuroinflammation and Hippocampal Spinogenesis","authors":"Zihui Geng,&nbsp;Fanzhen Peng,&nbsp;Ziqian Cheng,&nbsp;Jingyun Su,&nbsp;Jinfang Song,&nbsp;Xu Han,&nbsp;Runxin Li,&nbsp;Xin Li,&nbsp;Ranji Cui,&nbsp;Bingjin Li","doi":"10.1096/fj.202403417RR","DOIUrl":"https://doi.org/10.1096/fj.202403417RR","url":null,"abstract":"<p>Fatty acid binding protein 7 (FABP7) is prominently expressed in astrocytes and is a critical regulator of inflammatory responses. Accumulating evidence suggests that FABP7 is crucial in neuropsychological disease through the modulation of spinogenesis. Nonetheless, the impact of FABP7 on depressive disorders and the underlying mechanisms is not fully understood. Here, we investigated the antidepressant properties of FABP7 using the chronic unpredictable mild stress (CUMS)-induced model of depression and possible mechanisms. Our results revealed that depressive-like behavior induced by CUMS was associated with decreased levels of FABP7 protein in the hippocampus (HP). Furthermore, the overexpression of FABP7 in the HP mitigated the depressive-like behavior and increased the expression of its downstream target caveolin-1 (Cav-1). FABP7 overexpression in the HP specifically regulates the expression of the astrocyte marker protein GFAP, as well as the blood–brain barrier (BBB)-associated proteins AQP4, CLDN-5, occludin, and LRP1. Notably, the CUMS-induced upregulation of the pro-inflammatory factors IL-1β and IL-6 was also significantly reversed by FABP7 overexpression in the HP. This intervention also led to increased levels of postsynaptic proteins, including PSD95 and GluA1, as well as an increase in brain-derived neurotrophic factor (BDNF) and enhanced neuronal dendritic spine density. The findings indicate that FABP7 exerts antidepressant-like properties by inhibiting inflammation, regulating spinogenesis, and modulating BBB-related proteins.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 9","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403417RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Host Regulatory T Cell Differentiation by emu-let-7-5p in Echinococcus multilocularis Infection Through Targeting NFκB2","authors":"Liqun Wang,&nbsp;Keke Wu,&nbsp;Li Li,&nbsp;Tharheer Oluwashola Amuda,&nbsp;Yixuan Wu,&nbsp;Guiting Pu,&nbsp;TingLi Liu,&nbsp;Shanling Cao,&nbsp;Hong Yin,&nbsp;Baoquan Fu,&nbsp;Hongbin Yan,&nbsp;Xuenong Luo","doi":"10.1096/fj.202403437R","DOIUrl":"https://doi.org/10.1096/fj.202403437R","url":null,"abstract":"<div>\u0000 \u0000 <p>Regulatory T cells (Treg) play a crucial role in creating an immunosuppressive microenvironment surrounding the metacestode during chronic alveolar echinococcosis (AE). However, the mechanisms by which <i>E. multilocularis</i> induces Treg differentiation, particularly the role of parasite-derived microRNAs (miRNAs), remain largely unexplored. Here, we demonstrate that <i>E. multilocularis</i> can significantly induce the differentiation of Treg in mice. Emu-let-7-5p is upregulated in peripheral blood lymphocyte cells (PBLC) and splenic lymphocytes of <i>E. multilocularis-</i>infected mice. Exosomes enriched with emu-let-7-5p were found to upregulate the expressions of Treg markers. Conversely, exosomes collected following the knockdown of worm-derived emu-let-7-5p via RNA interference resulted in a reversal of Treg marker expression in PBLC. Mechanistically, emu-let-7-5p regulates Treg differentiation by targeting NFκB2. Knockdown of emu-let-7-5p in <i>E. multilocularis</i>-infected mice resulted in diminished Treg differentiation, leading to a significant reduction in worm load. These findings reveal that emu-let-7-5p drives Treg differentiation by suppressing NFκB2, representing a novel immune evasion strategy of <i>E. multilocularis</i>. Sustained inhibition of parasite-derived emu-let-7-5p may provide a therapeutic avenue for controlling AE progression.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 9","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering Chromosome Bridges Through CRISPR/Cas9 to Decipher the Impact of Intercentromeric Distance on Resolution Dynamics","authors":"Teresa Anglada,&nbsp;Marina Rodriguez-Muñoz,&nbsp;Núria Pulido-Artola,&nbsp;Anna Genescà","doi":"10.1096/fj.202402258RR","DOIUrl":"https://doi.org/10.1096/fj.202402258RR","url":null,"abstract":"<p>Resolution of chromosome bridges during mitosis is a critical yet incompletely understood process with implications for genomic stability and cancer development. In this study, we investigated the impact of the bridging chromatin length on the timing and mechanism of chromosome bridge resolution. Using CRISPR/Cas9 technology, we engineered chromosome bridges with precisely defined intercentromeric distances in human RPE-1 cells. Our study revealed a decline in the frequency of chromosome bridges as cells progressed from early anaphase to late telophase, indicating resolution during mitosis. Moreover, the longer the bridging chromatin length, the higher the frequency of chromosome bridges observed at the mitotic exit, demonstrating that the size of the bridge influences its resolution during mitosis. Additionally, the separation between the bridge kinetochores needed for bridge breakage was strongly dependent on the megabase length of the bridging chromatin, with longer chromosome bridges requiring greater separation for their resolution. Given that chromosome bridge resolution occurs in a concerted manner with spindle elongation and is influenced by the length of the bridging chromatin, we posit that the traction forces generated by microtubules attaching to dicentric chromosomes play a significant role in resolving chromosome bridges during mitosis. Our study underscores the intricate interplay between chromosome bridge geometry and mechanical forces in mitotic chromosome bridge resolution. Our model offers a valuable framework for future investigations into the molecular mechanisms underlying chromosome bridge resolution, with potential implications for cancer biology and genomic stability maintenance.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 9","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402258RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transamniotic Fetal Delivery of Human Alpha-1 Antitrypsin mRNA in a Healthy Rodent Model","authors":"Abbie E. Naus,&nbsp;Kamila Moskowitzova,&nbsp;Shuqi B. Lin,&nbsp;Tanya T. Dang,&nbsp;David Zurakowski,&nbsp;Dario O. Fauza","doi":"10.1096/fj.202500540","DOIUrl":"https://doi.org/10.1096/fj.202500540","url":null,"abstract":"<div>\u0000 \u0000 <p>Alpha-1 antitrypsin deficiency (AATD) can manifest at any age, including the perinatal period. Its manifestations include obstructive lung disease, which can be severe and for which current therapies are of limited benefit. We sought to determine whether the transamniotic route could be a viable alternative for administering AAT mRNA to the fetus. Twelve pregnant dams underwent volume-matched intra-amniotic injections in all their fetuses (<i>n</i> = 139) of either a suspension of human AAT (hAAT) mRNA encapsulated by a synthetic cationic polymer-based composite, lipopolyplex (mRNA group; <i>n</i> = 99) or of lipopolyplex free of mRNA (controls; <i>n</i> = 40), on gestational day 17 (E17; term = E21). Fetal lung and liver samples were procured daily thereafter until term to screen for hAAT by ELISA. Liver function panels were performed at term. Statistical analysis included median regression (<i>p</i> &lt; 0.05). Fetal survival was 79% (110/139), significantly higher in the mRNA group (<i>p</i> = 0.012). Controlled by mRNA-free injections, hAAT was found in the fetal lungs at all time points (<i>p</i> = 0.005 to &lt; 0.001) but in the liver only at E20, suggesting interspecies homology manifesting at that site. The term liver function panels were comparable between groups. Encapsulated exogenous mRNA encoding for human alpha-1 antitrypsin protein can be incorporated and translated by fetal lung cells following simple intra-amniotic injection in a healthy rat model. Fetal hepatic incorporation and translation remain to be determined in a model with minimal to no human homology. Transamniotic mRNA delivery could become a novel strategy for the perinatal management of alpha-1 antitrypsin deficiency.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 9","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrandrine Improves Severe Acute Pancreatitis by Inhibiting NCOA4 Glycosylation-Mediated Binding to FTH1 and Inducing Autophagy-Dependent Ferroptosis","authors":"Sen Lu,&nbsp;Pin Wang,&nbsp;Junting Hu,&nbsp;Zhao Zhang","doi":"10.1096/fj.202500404R","DOIUrl":"https://doi.org/10.1096/fj.202500404R","url":null,"abstract":"<div>\u0000 \u0000 <p>Severe acute pancreatitis (SAP) is an acute abdominal disease with extremely high mortality; autophagy-dependent ferroptosis plays a crucial role in acute pancreatitis. However, the specific underlying mechanism remains unclear. To investigate the role of nuclear receptor coactivator 4 (NCOA4) in SAP and the mechanism by which tetrandrine influences it. Experimental SAP models were established using L-arginine (L-Arg) induction to observe changes in NCOA4 expression. Knockout and overexpression experiments of NCOA4 were conducted to assess the impact on SAP. Additionally, in vitro cell experiments were performed to verify these findings. Furthermore, the impact of N-glycosylation of NCOA4 on its function, particularly its binding ability with ferritin heavy chain 1 (FTH1), was studied. Finally, the effects of tetrandrine on N-glycosylation of NCOA4, the binding between NCOA4 and FTH1, and the progression of SAP were analyzed. NCOA4 expression was significantly upregulated in SAP. Knockout of NCOA4 improved the phenotype of SAP, whereas its overexpression exacerbated SAP. This was also confirmed in vitro. N-glycosylation of NCOA4 is crucial for its binding with FTH1, which in turn affects ferroptosis. Tetrandrine targets the N-glycosylation of NCOA4, weakening the interaction between NCOA4 and FTH1, thereby inhibiting the progression of SAP. This study demonstrates that tetrandrine targets the N-glycosylation of NCOA4, inhibiting autophagy-dependent ferroptosis mediated by its binding to FTH1 and thus ameliorates SAP. This finding provides us with a novel therapeutic approach for SAP and offers a new perspective on understanding the mechanism of action of tetrandrine in SAP.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 9","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced Palmitoylation of SQSTM1/p62 in Huntington Disease Is Associated With Impaired Autophagy","authors":"F. Abrar,&nbsp;M. C. Davies,&nbsp;Y. Alshehabi,&nbsp;A. Kumar,&nbsp;A. Dang,&nbsp;Y. T. N. Nguyen,&nbsp;J. Collins,&nbsp;N. S. Caron,&nbsp;J. S. Choudhary,&nbsp;S. S. Sanders,&nbsp;M. O. Collins,&nbsp;M. R. Hayden,&nbsp;D. D. O. Martin","doi":"10.1096/fj.202401781R","DOIUrl":"https://doi.org/10.1096/fj.202401781R","url":null,"abstract":"<p>Disruption of autophagy has emerged as a common feature in many neurodegenerative diseases. Autophagy is a membrane-dependent pathway that requires many key regulators to quickly localize on and off membranes during induction, promoting membrane fusion. Previously, our bioinformatic approaches have shown that autophagy and Huntington disease (HD) are enriched in palmitoylated proteins. Palmitoylation involves the reversible addition of long-chain fatty acids to promote membrane binding. Herein, we show that inhibition of palmitoylation regulates the abundance of several key regulators of autophagy and leads to a partial block of autophagic flux. We confirm that the autophagy receptor SQSTM1/p62 (sequestosome 1) is palmitoylated and directed to the lysosome. Importantly, we report that SQSTM1 palmitoylation is significantly reduced in HD patient and mouse model brains. This finding reveals a novel mechanism contributing to the generation of empty autophagosomes previously seen in HD models and patient-derived cells.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 9","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401781R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-1β Stimulates Matrix Metalloproteinase 10 Secretion: A Possible Mechanism in Trophoblast-Dependent Spiral Artery Remodeling","authors":"Holly Tinsley,&nbsp;Zoe Tryfonos,&nbsp;Miriam Aziz,&nbsp;Nora Lagzouli,&nbsp;Charlotte Longhurst,&nbsp;Alexander Frick,&nbsp;Sandra Ashton,&nbsp;Judith E. Cartwright,&nbsp;Guy S. Whitley","doi":"10.1096/fj.202402329RR","DOIUrl":"https://doi.org/10.1096/fj.202402329RR","url":null,"abstract":"<p>Maternal uterine spiral arteries (SpA) undergo significant structural changes in early pregnancy, resulting in increased blood flow to the developing fetus. Endothelial cells (EC) and vascular smooth muscle cells (VSMC) are lost from the SpA wall and are replaced by trophoblasts. We have previously shown that matrix metalloproteinase 10 (MMP-10) and Heparin binding-EGF like growth factor (HB-EGF) gene expression is increased in a 3D EC/VSMC co-culture system in response to trophoblast secreted factors. This study investigated trophoblast mediated MMP-10 and HB-EGF expression and determined if there was a relationship between the secretion of MMP-10 and the release of soluble HB-EGF (sHB-EGF) from EC. MMP-10 was widely expressed in first trimester decidual tissue including trophoblast, and EC, but not VSMC. MMP-10 expression was significantly lower in decidual tissue from pregnancies at increased risk of developing pre-eclampsia compared to low-risk pregnancies. In vitro, SGHEC-7 cells, a human EC line, but not SGHVMC-9, a human VSMC cell line, secreted MMP-10 in response to trophoblast conditioned medium (TCM). TCM contains several growth factors and cytokines, but only interleukin-1β (IL1β) significantly stimulated MMP-10 secretion by SGHEC-7 cells. Interleukin-1 receptor antagonist (IL-1Ra) significantly inhibited TCM-induced MMP-10 secretion. Interrogation of intracellular pathways established the involvement of MEK and JNK in TCM and IL-1β stimulated MMP-10 secretion. Although IL-1β also significantly increased sHB-EGF, inhibition of MMP-10 activity using a broad spectrum MMP inhibitor had no effect on sHB-EGF. Western blot analysis indicated that MMP-10 secreted by EC in response to IL-1β stimulation was the enzymatically inactive pro form.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 9","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402329RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}