Abstract
Concomitant expressions of glycan-binding proteins and their bound glycans regulate many pathophysiologic processes, but this issue has not been addressed in liver fibrosis. Activation of hepatic stellate cells (HSCs) is a rate-limiting step in liver fibrosis and is an important target for liver fibrosis therapy. We previously reported that galectin (Gal)-1, a β-galactoside-binding protein, regulates myofibroblast homeostasis in oral carcinoma and wound healing, but the role of Gal-1 in HSC migration and activation is unclear. Herein, we report that Gal-1 and its bound glycans were highly expressed in fibrotic livers and activated HSCs. The cell-surface glycome of activated HSCs facilitated Gal-1 binding, which upon recognition of the N-glycans on neuropilin (NRP)-1, activated platelet-derived growth factor (PDGF)- and transforming growth factor (TGF)-β-like signals to promote HSC migration and activation. In addition, blocking endogenous Gal-1 expression suppressed PDGF- and TGF-β1-induced signaling, migration, and gene expression in HSCs. Methionine and choline-deficient diet (MCD)-induced collagen deposition and HSC activation were attenuated in Gal-1-null mice compared to wild-type mice. In summary, we concluded that glycosylation-dependent Gal-1/NRP-1 interactions activate TGF-β and PDGF-like signaling to promote the migration and activation of HSCs. Therefore, targeting Gal-1/NRP-1 interactions could be developed into liver fibrosis therapy.
Highlights
Liver fibrosis is an abnormal wound-healing response to liver injury, characterized by the excessive accumulation of extracellular matrix (ECM) proteins in the liver
Because galectin-1 binding is masked by the terminal sialic acid modification of poly-LacNac, we examined the amount of α2-6-linked sialic acid using Sambucus nigra agglutinin (SNA)
The fibrotic livers showed higher L-PHA binding compared to normal livers and the L-PHA binding was co-localized with α-smooth muscle actin (Supplemental Fig. S3), indicating the activated hepatic stellate cells (HSCs) had high amount Gal-1 binding glycans in vivo
Summary
Liver fibrosis is an abnormal wound-healing response to liver injury, characterized by the excessive accumulation of extracellular matrix (ECM) proteins in the liver. The etiology of liver fibrosis is diverse, the convergent pathway is hepatic stellate cell (HSC) activation, a process of quiescent stellate cells trans-differentiating into activated myofibroblasts. Aberrant expressions of glycosyltransferase or glycosidases result in the remodeling of cell-surface glycans which generates favorable glycoconjugates for lectin (a carbohydrate-binding protein) binding. Whether the remodeling of cell-surface glycans cooperates with Gal-1 to regulate HSC migration and activation is poorly understood. We previously reported that neuropilin (NRP)-1 is a critical receptor for Gal-1 to induce angiogenesis, vascular permeability, and wound-healing[13, 17, 18], but the role of NRP-1 glycosylation in Gal-1 binding is not fully understood in HSCs. this study investigated whether the glycome of activated HSCs facilitates Gal-1 binding to NRP-1 to induce HSC activation and migration, and liver fibrosis
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