Abstract
BackgroundPlatelet-derived growth factor receptor α (PDGFRα) expression is increased in activated hepatic stellate cells (HSCs) in cirrhotic liver, while normal hepatocytes express PDGFRα at a negligible level. However, cancerous hepatocytes may show upregulation of PDGFRα, and hepatocellular carcinoma is preceded by chronic liver injury. The role of PDGFRα in non-cancerous hepatocytes and liver fibrosis is unclear. We hypothesized that upon liver injury, PDGFRα in insulted hepatocytes contributes to liver fibrosis by facilitating intercellular crosstalk between hepatocytes and HSCs.MethodsHepatocytes were isolated from normal and thioacetamide (TAA)-induced cirrhotic livers for assessment of PDGFRα expression. Conditional knock-out (KO) C57BL/6 mice, in which PDGFRα was selectively deleted in hepatocytes, were generated. Liver fibrosis was induced by injecting TAA for 8 weeks. Hep3B cells were transfected with a small interfering RNA (siRNA) (PDGFRα or control) and co-cultured with LX2 cells.ResultsPDGFRα expression was increased in hepatocytes from fibrotic livers compared to normal livers. Conditional PDGFRα KO mice had attenuated TAA-induced liver fibrosis with decreased HSC activation and proliferation. Immunoblot analyses revealed decreased expression of phospho-p44/42 MAPK in TAA-treated KO mice; these mice also showed almost complete suppression of the upregulation of mouse double minute 2. Although KO mice exhibited increased expression of transforming growth factor (TGF)-β and Smad2/3, this was compensated for by increased expression of inhibitory Smad7. LX2 cells co-cultured with PDGFRα siRNA-infected Hep3B cells showed decreased PDGFRα, α smooth muscle actin, collagen α1(I), TGFβ, and Smad2/3 expression. LX2/PDGFRα-deleted hepatocyte co-culture medium showed decreased PDGF-BB and PDGF-CC levels.ConclusionsDeletion of PDGFRα in hepatocytes attenuated the upregulation of PDGFRα in HSCs after TAA treatment, resulting in decreased liver fibrosis and HSC activation. This suggests that in the event of chronic liver injury, PDGFRα in hepatocytes plays an important role in liver fibrosis by affecting PDGFRα expression in HSCs.
Highlights
Platelet-derived growth factor receptor α (PDGFRα) expression is increased in activated hepatic stellate cells (HSCs) in cirrhotic liver, while normal hepatocytes express PDGFRα at a negligible level
We report for the first time that conditional abolition of PDGFRα expression in hepatocytes attenuates chemically induced liver fibrosis by suppressing the upregulation of PDGFRα and Transforming growth factor beta (TGFβ) in HSCs, reducing their activation and proliferation
PDGFRα deletion in hepatocytes attenuated the TAAinduced increase in PDGFRα expression in the whole liver The level of PDGFRα expression is increased in fibrotic liver due to its overexpression in HSCs [19, 34]
Summary
Platelet-derived growth factor receptor α (PDGFRα) expression is increased in activated hepatic stellate cells (HSCs) in cirrhotic liver, while normal hepatocytes express PDGFRα at a negligible level. Cancerous hepatocytes may show upregulation of PDGFRα, and hepatocellular carcinoma is preceded by chronic liver injury. Repetitive chronic liver insults result in liver fibrosis, which may progress to cirrhosis [3, 6, 7], the major contributing factor to development of hepatocellular carcinoma (HCC) [8]. HSCs are activated by cytokines, including platelet-derived growth factors (PDGFs), which are potent mitogens [9, 10]. The cellular effects of PDGFs require the function of cell surface receptor tyrosine kinases comprising platelet-derived growth factor receptor (PDGFR)α and PDGFRβ subunits [11, 12]. Elevated PDGFR expression is observed in human cardiac fibrosis after myocardial infarct, pulmonary fibrosis, kidney fibrosis, and liver fibrosis [13,14,15,16]
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