Abstract
Chronic liver injury leads to fibrosis, cirrhosis, and loss of liver function. Liver cirrhosis is the 12th leading cause of death in the United States, and it is the primary risk factor for developing liver cancer. Fibrosis and cirrhosis result from activation of hepatic stellate cells (HSCs), which are the primary collagen producing cell type in the liver. Here, we show that platelet-derived growth factor receptor α (PDGFRα) is expressed by human HSCs, and PDGFRα expression is elevated in human liver disease. Using a green fluorescent protein (GFP) reporter mouse strain, we evaluated the role of PDGFRα in liver disease in mice and found that mouse HSCs express PDGFRα and expression is upregulated during carbon tetrachloride (CCl4) induced liver injury and fibrosis injection. This fibrotic response is reduced in Pdgfrα heterozygous mice, consistent with the hypothesis that liver fibrosis requires upregulation and activation of PDGFRα. These results indicate that Pdgfrα expression is important in the fibrotic response to liver injury in humans and mice, and suggest that blocking PDGFRα–specific signaling pathways in HSCs may provide therapeutic benefit for patients with chronic liver disease.
Highlights
Chronic liver injury is a major cause of morbidity and mortality in the US and worldwide, due to complications of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [1]
As platelet derived growth factors (PDGFs) ligands can activate both plateletderived growth factor receptor a (PDGFRa) and PDGFRb, we sought to investigate the role of PDGFRa in chronic liver injury. 80–90% of human HCC arise in the setting of a cirrhotic liver, in which hepatic stellate cells (HSCs) have been activated [35], so we first performed IHC analysis to determine whether PDGFRa and PDGFRb levels are elevated in human cirrhosis and HCC
IHC analysis of this specimen demonstrated PDGFRa immunoreactive cells within the tumor (Figure 1 E, F), but these cells did not have the histological appearance of hepatocytes, suggesting that non-parenchymal cells (NPCs) had invaded the parenchymal tumor and account for the PDGFRa immunoreactivity observed in this tumor by immunoblot analysis
Summary
Chronic liver injury is a major cause of morbidity and mortality in the US and worldwide, due to complications of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [1]. There are no effective treatments for patients with liver fibrosis, so a better understanding of pathways that regulate fibrosis has great clinical potential [2]. The PDGF family of ligands and receptors plays a central role in repair after injury, and are key regulators of the formation of connective tissue [4,5]. Elevated platelet-derived growth factor receptor (PDGFR) expression is detected in human heart disease, pulmonary fibrosis, and kidney fibrosis [6,7,8], and blocking PDGFR signaling decreases collagen deposition after myocardial infarct, in pulmonary fibrosis, and in kidney fibrosis [9,10,11]. Targeting the PDGF pathway may modulate liver fibrosis
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