Abstract
Liver diseases are the growing health problem with no clinically approved therapy available. Activated hepatic stellate cells (HSCs) are the key driver cells responsible for extracellular matrix deposition, the hallmark of liver fibrosis. Fibroblast growth factor 2 (FGF2) has shown to possess anti-fibrotic effects in fibrotic diseases including liver fibosis, and promote tissue regeneration. Among the fibroblast growth factor receptors (FGFRs), FGF2 interact primarily with FGFR1, highly overexpressed on activated HSCs, and inhibit HSCs activation. However, FGF2 poses several limitations including poor systemic half-life and stability owing to enzymatic degradation. The aim of this study is to improve the stability and half-life of FGF2 thereby improving the therapuetic efficacy of FGF2 for the treatment of liver fibrosis. We found that FGFR1-3 mRNA levels were overexpressed in cirrhotic human livers, while FGFR1c, 2c, 3c, 4 and FGF2 mRNA levels were overexpressed in TGFβ-activated HSCs (LX2 cells) and FGFR1 protein expression was highly increased in TGFβ-activated HSCs. Treatment with FGF2 inhibited TGFβ-induced HSCs activation, migration and contraction in vitro. FGF2 was conjugated to superparamagnetic iron-oxide nanoparticles (SPIONs) using carbodiimide chemistry, and the resulting FGF2-SPIONs were confirmed by dynamic light scattering (DLS), zeta potential, dot-blot analysis and Prussian Blue iron-staining. In vitro, treatment with FGF2-SPIONs evidenced increased therapeutic effects (attenuated TGFβ-induced HSCs activation, migration and contraction) of FGF2 in TGFβ-activated HSCs and ameliorated early liver fibrogenesis in vivo in acute carbon tetrachloride (CCl4)-induced liver injury mouse model. In contrast, free FGF2 showed no significant effects in vivo. Altogether, this study presents a promising therapeutic approach using FGF2-SPIONs for the treatment of liver fibrosis.
Highlights
Liver diseases caused by viral infections, metabolic disorders, alcohol or drug abuse and autoimmune disorders affecting millions of people, represents a major health pro blem associated with high morbidity and mortality [1]
Transcriptomic data analysis revealed a significant increase in the mRNA expression levels of FGFR1 (p < 0.05), FGFR2 (p < 0.001) and FGFR3 (p < 0.05) in the cirrhotic livers compared to the normal livers (p < 0.05) (Fig. 1A)
We demonstrated an improved therapeutic efficacy of Fibroblast growth factor 2 (FGF2) after conjugation to super paramagnetic iron-oxide nanoparticles (SPIONs), as a promising approach for the treatment of liver fibrosis
Summary
Liver diseases caused by viral infections (mainly hepatitis B and C viruses), metabolic disorders, alcohol or drug abuse and autoimmune disorders affecting millions of people, represents a major health pro blem associated with high morbidity and mortality [1]. Hepatic stellate cells (HSCs) play a key role in the progression of liver fibrosis, regardless of the underlying cause [3,6,7]. Hepatocytes undergo apoptosis or necrosis and release pro-in flammatory and pro-fibrogenic mediators that stimulate recruitment and activation of inflammatory cells in the liver resulting in chronic liver inflammation. The resident and infiltrated immune cells, in turn, secrete pro-inflammatory and pro-fibrogenic factors that activate quiescent HSCs [2,3]. Quiescent HSCs transdifferentiate into myofi broblast-like cells and become highly proliferative, migratory and
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