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.
Highlights
(C) Notch pathway components: Notch receptors (Notch-1, -2 and -3), Notch ligands (Dll[1], Dll[4] and Jag1) and downstream Notch signaling molecule (Hes1) in the livers of olive oil-treated and CCl4treated mice. (D) Representative fluorescent photomicrographs (200 μ m) showing α -SMA, Notch-1 and Notch-3 stained liver sections from fibrotic human livers (n = 4)
Since hepatic stellate cells (HSCs) and macrophages are the key cells in the fibrous areas[22], we investigated the activation of Notch pathway activation in these cells in vitro
We unveil the dual role of Notch signaling in HSC activation and in determining M1 versus M2 polarization in vitro and in vivo in liver fibrosis
Summary
During fetal development and liver regeneration, several highly conserved signaling pathways (Wnt, Hedgehog and Notch) are utilized that orchestrate organogenesis[14] One of these pathways is the Notch pathway, which has been shown to be aberrantly upregulated during several malignancies and fibrotic diseases[15,16,17,18,19]. We demonstrate that Notch signaling pathway plays a dual role by regulating HSC activation/ differentiation and in determining M1 versus M2 polarization in vitro and in vivo in liver fibrosis. Notch signaling pathway was upregulated in activated hepatic stellate cells and inflammatory M1 macrophages suggesting Notch-mediated regulation during fibrosis progression. We hypothesized that inhibition of this pathway at the fibrogenic stage might alleviate the fibrosis progression by inhibiting HSC activation and macrophage polarization
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