Abstract
Background: Activated hepatic stellate cells (HSCs) are the most critical cell responsible for liver fibrosis. In liver fibrogenesis, platelet-derived growth factor (PDGF) is the most prominent mitogen for HSCs. This study aims to explore the potential of gadolinium (Gd)-labeled cyclic peptides (pPB) targeted to PDGF receptor-β (PDGFR-β) as an MRI radiotracer to identify the progress of liver fibrosis by imaging hepatic PDGFR-β expression. Methods: Mouse models of liver fibrosis caused by bile duct ligation (BDL) and CCl 4 treatment were both used to determine the association of hepatic PDGFR-β expression and the progress of hepatic fibrosis. The binding activity of FITC-labeled pPB to PDGFR-β was assessed in culture-activated human HSCs (HSC-LX2). MR imaging was performed to visualize hepatic PDGFR-β expression in mice with different degrees of liver fibrosis after Gd-labeled pPB were injected. Findings: Hepatic PDGFR-β expression level was found to be paralleled with the severity of liver fibrosis, which was increased with the progression of fibrosis and reduced with the regression. Majority of cells expressing PDGFR-β was determined to be activated HSCs in fibrotic livers. Culture-activated HSC-LX2 expressed abundant PDGFR-β, and FITC-labeled pPB could bind to HSC-LX2 in a concentration and time dependent manner. Interpretation: With Gd-labeled pPB as a tracer, the relative hepatic T1-weighed MR signal value was increased progressively along with severity of hepatic fibrosis and reduced with the remission, suggesting that hepatic PDGFR-β expression reflects the progress of hepatic fibrosis. MR imaging using Gd-labeled pPB as a tracer may distinguish different stages of liver fibrosis in mice. Funding Statement: This work was supported by the National Natural Science Foundation of China (Grant NO. 81270007 & 81670513 to Li F), Shanghai Talent Development Funds (Grant NO. 201304 to Li F), Shanghai Rising-Star Program (Grant NO. 13QA1400700 to Li F), And Shanghai Outstanding Young Talent Training Plan in Health System (Grant NO. 13YO56 to Li F). Declaration of Interests: The authors declare no conflict of interests. Ethics Approval Statement: The study was approved by Institutional Ethical Committee of Animal Experimentation, all experiments and postoperative animal care procedures were performed according to the governmental and international guidelines on animal experimentation.
Highlights
Liver fibrosis is a wound-healing response to various liver injuries, such as alcohol, viruses and hepatotoxic materials, and may be protective to a certain extent for fibrosis has been found to be associated with increased resistance of hepatocytes toward these injurious stimuli.[1]
After mice were treated with Bile Duct Ligation (BDL) for 1 weeks (BDL-1W), marked cholestasis and neutrophil infiltration were observed in hepatic lobules, and serum ALT level was significantly increased compared to the control mice (Fig. 1A and 1B)
After mice were treated with BDL for 4 weeks (BDL-4W), the normal architecture of hepatic lobule was damaged, and visible fibrotic septa and extensive bridging fibrosis were observed (Fig. 1A)
Summary
Liver fibrosis is a wound-healing response to various liver injuries, such as alcohol, viruses and hepatotoxic materials, and may be protective to a certain extent for fibrosis has been found to be associated with increased resistance of hepatocytes toward these injurious stimuli.[1]. HSCs contain abundant vitamin A lipid droplets; whereas in the activated state, they lose vitamin A and transdifferentiate into myofibroblast-like cells which express α-smooth muscle actin (α-SMA) and produce extracellular matrix (ECM).[4] When the liver is injured due to various etiological factors, the signals from the damaged hepatocytes and immune cells provoke quiescent HSCs transdifferentiating to an activated state. Activated HSCs are generally considered to be the most critical cell responsible for liver fibrosis.[5, 6]. Activated hepatic stellate cells are the most critical cell responsible for liver fibrosis. Platelet-derived growth factor is the most prominent mitogen for hepatic stellate cells. This study aims to explore the potential of gadolinium (Gd)-labeled cyclic peptides (pPB) targeted to plateletderived growth factor receptor-β (PDGFR-β) as a magnetic resonance imaging (MRI) radiotracer to identify the progress of liver fibrosis by imaging hepatic PDGFR-β expression
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