The Myofibroblastic Conversion of Peribiliary Fibrogenic Cells Distinct from Hepatic Stellate Cells Is Stimulated by Platelet-Derived Growth Factor During Liver Fibrogenesis

Abstract

SUMMARY:The origin of myofibroblasts and the factors promoting their differentiation during liver fibrogenesis remain uncertain. During biliary-type fibrogenesis, the proliferation and chemoattraction of hepatic stellate cells (HSC) toward bile ducts is mediated by platelet-derived growth factor (PDGF), while myofibroblastic conversion of peribiliary cells distinct from HSC also occurs. We herein examined the phenotype of these peribiliary myofibroblasts as compared with myofibroblastic HSC and tested whether their differentiation was affected by PDGF. Biliary-type liver fibrogenesis was induced by common bile duct ligation in rats. After 48 hours, periductular fibrosis in portal tracts colocalized with smooth muscle ␣-actin-immunoreactive myofibroblasts, the majority of which were desmin negative. Simultaneously, in sinusoids, desmin immunoreactivity was induced in a large number of HSC, which were smooth muscle ␣-actin negative. Cultures of peribiliary myofibroblasts were expanded from isolated bile duct segments and compared with myofibroblastic HSC. Peribiliary myofibroblasts outgrowing from bile duct segments expressed smooth muscle ␣-actin, ␣1 (I) collagen mRNA, and PDGF receptor-␤ subunit. Desmin immunoreactivity gradually decreased in cultured peribiliary myofibroblasts, contrasting with constant labeling of all myofibroblastic HSC. In addition, IL-6 expression in peribiliary myofibroblasts was up to 100-fold lower than in myofibroblastic HSC, whereas the expression of the complement-activating protease P100 in both cell types showed little difference and that of the extracellular matrix component fibulin 2 was similar. The expression of smooth muscle ␣-actin protein in cultured peribiliary myofibroblasts was stimulated by PDGF-BB and inhibited by STI571, a PDGF receptor tyrosine kinase inhibitor, whereas in bile duct-ligated rats, the administration of STI571 caused a significant decrease in peribiliary smooth muscle ␣-actin immunoreactivity, and to a lesser extent, a decrease in peribiliary fibrosis. These results indicate that peribiliary cells distinct from HSC undergo a PDGF-mediated conversion into myofibroblasts expressing IL-6 at lower levels than myofibroblastic HSC and contribute to the initial formation of biliary-type liver fibrosis. (Lab Invest 2003, 83:163-173).

Targeting Liver Fibrosis

“…Although activated HSC are undoubtedly the major producers of the excessive and abnormal ECM in liver fibrosis, these cells are heterogeneous in vivo, and may derive from different precursors, including portal or perivenular fibroblasts, 20 circulating fibrocytes, 7,21 or from epithelial-mesenchymal transition (EMT) 9,10 (Fig. 1).…”

Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation

“…Data were collected, analyzed with Sequence Detector v1.7 software (Applied Biosystems) and expressed as a copy number reported to the amount of 18S RNA or as a relative amount (2 Ϫ⌬⌬CT ), as reported. 22 Immunohistochemistry. BSEP immunolabeling was performed on liver tissue cryosections using an anti-BSEP polyclonal antibody, and a three-step immunoperoxidase method, as reported.…”

Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats

“…PDGF is the most potent proliferating stimulus for HSCs (4,8). It has been reported that the PDGF receptor (PDGFR) is up-regulated along with HSC activation in carbon tetrachloride (CCl4)-and bile duct ligation-induced liver injuries (9)(10)(11). Dominant-negative soluble PDGFR or anti-sense PDGF gene transfer significantly attenuated experimental liver fibrosis development (12,13).…”