title: The interplay of the Notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis.
abstract: Hepatic stellate cells (HSCs) known as "master producers" and macrophages as "master regulators", are the key cell types that strongly contribute to the progression of liver fibrosis. Since Notch signaling regulates multiple cellular processes, we aimed to study the role of Notch signaling in HSCs differentiation and macrophages polarization and to evaluate its implication in liver fibrogenesis. Notch pathway components were found to be significantly upregulated in TGFβ-activated HSCs, inflammatory M1 macrophages, and in mouse and human fibrotic livers. Interestingly, inhibition of Notch using a selective γ-secretase inhibitor, Avagacestat, significantly inhibited TGFβ-induced HSC activation and contractility, and suppressed M1 macrophages. Additionally, Avagacestat inhibited M1 driven-fibroblasts activation and fibroblasts-driven M1 polarization (nitric oxide release) in fibroblasts and macrophages co-culture, and conditioned medium studies. In vivo, post-disease treatment with Avagacestat significantly attenuated fibrogenesis in CCl4-induced liver fibrosis mouse model. These effects were attributed to the reduction in HSCs activation, and inhibition of inflammatory M1 macrophages and upregulation of suppressive M2 macrophages. These findings suggest that Notch signaling plays a crucial role in HSC activation and M1/M2 polarization of macrophages in liver fibrosis. These results provide new insights for the development of novel therapies against liver fibrosis through modulation of Notch signaling.
authors.affiliation: Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, 7522NB, The Netherlands.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Bansal
authors.affiliation: Laboratorium Pathologie Oost-Nederland, Hengelo, 7555 BB, The Netherlands.
authors.forename: Joop
authors.initials: J
authors.lastname: van Baarlen
authors.affiliation: Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, 7522NB, The Netherlands.|Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, 3584 CG, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, 7522NB, The Netherlands.
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010069:Oxadiazoles / Q000494:pharmacology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C554092:BMS 708163; D010069:Oxadiazoles; D051880:Receptors, Notch; D013449:Sulfonamides; D016212:Transforming Growth Factor beta