{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:13:04Z","timestamp":1753891984075,"version":"3.41.2"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Hrvatska Zaklada za Znanost","doi-asserted-by":"publisher","award":["UIP-2017-05-1965"],"award-info":[{"award-number":["UIP-2017-05-1965"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Recent research suggests a possible role of Notch signaling pathway in development of liver fibrosis, but exact cellular and molecular mechanisms are still not well defined. Methods: We modulated Notch signaling in activated hepatic stellate cells\/myofibroblasts using the model of inducible activation or inhibition of Notch signaling selective for \u03b1SMA positive cells in murine models of toxic fibrosis induced by CCl4 and cholestatic fibrosis induced by DDC supplemented feeding.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results confirm that Notch signaling pathway is activated in both CCL4 and DDC model of liver fibrosis and that \u03b1SMA positive myofibroblasts are of activated hepatic stellate cells origin. However, neither the inhibition of canonical Notch signaling (in tamoxifen treated \u03b1SMACreER\/RBP-J<jats:sup>fl\/fl<\/jats:sup> mice) nor its overactivation (in tamoxifen treated \u03b1SMACreER\/NICD1 mice) changed the degree of liver fibrosis in comparison to the control groups in either of the investigated models. Furthermore, after the withdrawal of the fibrogenic treatment the degree of resolution of fibrosis was similar between the animals with Notch overactivation and controls. In addition to genetic manipulation, we investigated the effect of antibodies against NOTCH1 and NOTCH2 on the development of liver fibrosis. Treatment with antibodies had effects on thymus and spleen respectively, but failed to ameliorate liver fibrosis. In conclusion, our data demonstrate that modulation of Notch activity in activated HSC is not sufficient to change the outcome of liver fibrosis. The results obtained with inhibitory antibodies further demonstrate limitations of targeting Notch 1 and 2 receptors as antifibrotic therapy. Notch pathway remains a potential target for the treatment of liver fibrosis, but future studies should be directed to Notch 3 signaling and\/or targeting different populations of cells.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1440236","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T04:46:59Z","timestamp":1730090819000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Modulation of Notch signaling pathway in activated hepatic stellate cells does not ameliorate the outcome of liver fibrosis in carbon tetrachloride and DDC-feeding models"],"prefix":"10.3389","volume":"15","author":[{"given":"Dino","family":"\u0160isl","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavao","family":"Planini\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanja","family":"Novak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma\u0161a","family":"Filipovi\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darja","family":"Flegar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"\u0160u\u0107ur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Tur\u010di\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nata\u0161a","family":"Kova\u010di\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivo","family":"Kalajzi\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danka","family":"Gr\u010devi\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomislav","family":"Kelava","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"608","DOI":"10.3390\/biom9100608","article-title":"The roles of notch signaling in liver development and disease","volume":"9","author":"Adams","year":"2019","journal-title":"Biomolecules"},{"key":"B2","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1016\/j.lfs.2011.10.012","article-title":"Activation of Notch1 signaling by marrow-derived mesenchymal stem cells through cell-cell contact inhibits proliferation of hepatic stellate cells","volume":"89","author":"Chen","year":"2011","journal-title":"Life Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e46512","DOI":"10.1371\/journal.pone.0046512","article-title":"Inhibition of Notch signaling by a \u03b3-secretase inhibitor attenuates hepatic fibrosis in rats","volume":"7","author":"Chen","year":"2012","journal-title":"PloS one"},{"key":"B4","first-page":"243","article-title":"Thymus quantitative morphological changes during CCl4-induced liver cirrhosis","volume":"24","author":"Chirculescu","year":"1978","journal-title":"Morphol. embryologie"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.1038\/s41467-019-09276-w","article-title":"Rbpj expression in regulatory T cells is critical for restraining TH2 responses","volume":"10","author":"Delacher","year":"2019","journal-title":"Nat. Commun."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.7150\/ijbs.80122","article-title":"Myeloid-specific blockade of Notch signaling ameliorates nonalcoholic fatty liver disease in mice","volume":"19","author":"Ding","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"15244","DOI":"10.1038\/s41598-020-72179-0","article-title":"Optimization of tamoxifen-induced Cre activity and its effect on immune cell populations","volume":"10","author":"Donocoff","year":"2020","journal-title":"Sci. Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1002\/hep.29834","article-title":"Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice","volume":"68","author":"Duan","year":"2018","journal-title":"Hepatol. Baltim. Md"},{"key":"B9","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1002\/stem.780","article-title":"In vivo fate mapping identifies mesenchymal progenitor cells","volume":"30","author":"Grcevic","year":"2012","journal-title":"Stem cells Dayt. Ohio"},{"key":"B10","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1007\/s00535-016-1190-4","article-title":"Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights","volume":"51","author":"Greuter","year":"2016","journal-title":"J. gastroenterology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2549","DOI":"10.1007\/s00204-018-2254-4","article-title":"Confounding influence of tamoxifen in mouse models of Cre recombinase-induced gene activity or modulation","volume":"92","author":"Hammad","year":"2018","journal-title":"Archives Toxicol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.phrs.2016.04.010","article-title":"Notch in fibrosis and as a target of anti-fibrotic therapy","volume":"108","author":"Hu","year":"2016","journal-title":"Pharmacol. Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e2005233","DOI":"10.1371\/journal.pbio.2005233","article-title":"Jagged1\/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming","volume":"16","author":"Huang","year":"2018","journal-title":"PLoS Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/377355a0","article-title":"Signalling downstream of activated mammalian Notch","volume":"377","author":"Jarriault","year":"1995","journal-title":"Nature"},{"key":"B15","first-page":"16","article-title":"Immunotoxic effects of carbon tetrachloride--the effect on morphology and function of the immune system in mice","volume":"4","author":"Jirova","year":"1996","journal-title":"Central Eur. J. public health"},{"key":"B16","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.jcmgh.2023.09.008","article-title":"The origin and fate of liver myofibroblasts","volume":"17","author":"Kim","year":"2024","journal-title":"Cell. Mol. gastroenterology hepatology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1053\/j.gastro.2004.09.004","article-title":"The role of notch signaling in the development of intrahepatic bile ducts","volume":"127","author":"Kodama","year":"2004","journal-title":"Gastroenterology"},{"key":"B18","first-page":"12688","article-title":"Notch signaling affects biliary fibrosis via transcriptional regulation of RBP-j\u03ba in an animal model of chronic liver disease","volume":"8","author":"Lee","year":"2015","journal-title":"Int. J. Clin. Exp. pathology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2981","DOI":"10.1111\/jcmm.14930","article-title":"LPS-induced inflammation desensitizes hepatocytes to Fas-induced apoptosis through Stat3 activation-The effect can be reversed by ruxolitinib","volume":"24","author":"Markotic","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1038\/nprot.2015.017","article-title":"High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers","volume":"10","author":"Mederacke","year":"2015","journal-title":"Nat. Protoc."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2823","DOI":"10.1038\/ncomms3823","article-title":"Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology","volume":"4","author":"Mederacke","year":"2013","journal-title":"Nat. Commun."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1002\/jor.24650","article-title":"Modulation of Notch1 signaling regulates bone fracture healing","volume":"38","author":"Novak","year":"2020","journal-title":"J. Orthop. Res. official Publ. Orthop. Res. Soc."},{"key":"B23","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1158\/1078-0432.CCR-14-0809","article-title":"Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer","volume":"21","author":"Previs","year":"2015","journal-title":"Clin. cancer Res. official J. Am. Assoc. Cancer Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.3390\/biomedicines10051209","article-title":"Tamoxifen ameliorates cholestatic liver fibrosis in mice: upregulation of TGF\u03b2 and IL6 is a potential protective mechanism","volume":"10","author":"\u0160isl","year":"2022","journal-title":"Biomedicines"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e346","DOI":"10.1002\/mco2.346","article-title":"Cellular senescence primes liver fibrosis regression through Notch-EZH2","volume":"4","author":"Song","year":"2023","journal-title":"MedComm"},{"key":"B26","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.imlet.2020.04.010","article-title":"Notch receptors and ligands in inflammatory arthritis - a systematic review","volume":"223","author":"Sucur","year":"2020","journal-title":"Immunol. Lett."},{"key":"B27","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1006\/jaut.2001.0522","article-title":"Genomic analysis of differentially expressed genes in liver and biliary epithelial cells of patients with primary biliary cirrhosis","volume":"17","author":"Tanaka","year":"2001","journal-title":"J. Autoimmun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"60778","DOI":"10.18632\/oncotarget.18484","article-title":"Reversal effect of Jagged1 signaling inhibition on CCl4-induced hepatic fibrosis in rats","volume":"8","author":"Tang","year":"2017","journal-title":"Oncotarget"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1053\/j.gastro.2012.06.036","article-title":"Deactivation of hepatic stellate cells during liver fibrosis resolution in mice","volume":"143","author":"Troeger","year":"2012","journal-title":"Gastroenterology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"8608","DOI":"10.2174\/0929867328666210419123200","article-title":"Regulatory roles of the notch signaling pathway in liver repair and regeneration: a novel therapeutic target","volume":"28","author":"Valizadeh","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1038\/nature08878","article-title":"Therapeutic antibody targeting of individual Notch receptors","volume":"464","author":"Wu","year":"2010","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1002\/hep.26511","article-title":"Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice","volume":"58","author":"Xie","year":"2013","journal-title":"Hepatol. Baltim. Md"},{"key":"B33","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1002\/biof.1771","article-title":"Notch1 signaling enhances collagen expression and fibrosis in mouse uterus","volume":"47","author":"Xu","year":"2021","journal-title":"BioFactors Oxf. Engl."},{"key":"B34","doi-asserted-by":"publisher","first-page":"53","DOI":"10.3389\/fphys.2012.00053","article-title":"Differential regulation of TGF-\u03b2\/smad signaling in hepatic stellate cells between acute and chronic liver injuries","volume":"3","author":"Yoshida","year":"2012","journal-title":"Front. physiology"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.7150\/ijbs.60056","article-title":"Disruption of myofibroblastic Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression","volume":"17","author":"Yue","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"eaat0344","DOI":"10.1126\/scitranslmed.aat0344","article-title":"Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis","volume":"10","author":"Zhu","year":"2018","journal-title":"Sci. Transl. Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1440236\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T04:47:01Z","timestamp":1730090821000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1440236\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,28]]},"references-count":36,"alternative-id":["10.3389\/fphar.2024.1440236"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1440236","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2024,10,28]]},"article-number":"1440236"}}