PDGF-Mediated Chemoattraction of Hepatic Stellate Cells by Bile Duct Segments in Cholestatic Liver Injury

Abstract

SUMMARY:The accumulation of myofibroblasts and fibrosis around proliferating bile ducts in cholestatic liver disease has been attributed to the proliferation and phenotypic modulation of portal fibroblasts, whereas the contribution of hepatic stellate cells remains uncertain. There is increasing evidence to indicate that bile ducts may stimulate chemoattraction of hepatic stellate cells (HSC). In the present study, we undertook dynamic tests to examine such a possibility and to investigate the role of two potential mediators: platelet-derived growth factor-BB (PDGF-BB) and endothelin-1. Cholestasis was induced by bile duct ligation in rats. HSC were isolated from normal rats and culture activated into myofibroblasts expressing PDGF-␤ receptors. Migration of myofibroblastic HSC was investigated in a Transwell chemotaxis filter assay. As compared with basal conditions, PDGF-BB (100 g/l) and endothelin-1 (10 Ϫ8 M) induced a 3-fold and 1.7-fold increase in HSC migration, respectively. Bile duct segments isolated from cholestatic rats triggered a 3-fold increase in migration. This stimulation was significantly more potent than that observed in the presence of normal bile ducts. It was inhibited by neutralizing anti-PDGF antibodies and by STI571 PDGF receptor tyrosine kinase inhibitor, by 60% and 85%, respectively, whereas Bosentan, an endothelin receptor antagonist, had no significant inhibiting effect. In bile duct segments from cholestatic rats PDGF-B chain mRNA was detected at higher levels than in controls, whereas PDGF-BB was immunolocalized in bile duct epithelial cells. The results indicate that chemotaxis of HSC towards bile duct structures may contribute to the development of periductular fibrosis in cholestatic disorders, and that PDGF-BB is the major mediator in this process. In addition, anti-liver fibrogenic properties of STI571 are suggested by potent inhibition of myofibroblastic HSC function. (Lab Invest 2000, 80:697-707).

Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment

“…These data may also explain, in part, the recruitment of portal (myo)fibroblasts to the periductular region in cholestasis. Previous studies using whole bile duct segments isolated from BDL rats also demonstrated induction in HSC chemotaxis, 34 and neutralizing antibody to platelet-derived growth factor caused a 60% inhibition of chemotaxis, while anti-endothelin-1 had no effect. Kruglov and colleagues showed that MCP-1 derived from BDL rat cholangiocytes induced the transformation of portal fibroblasts to myofibroblasts, although they did not specifically evaluate the role of cholangiocyte-derived MCP-1 in HSC or portal fibroblast chemotaxis.…”

Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9

“…Naïve HSCs do not express the PDGF receptor, and responsiveness to PDGF is an indicator of at least a minimum level of HSC activation. 32 We therefore propose that DNA from apoptotic cells acts as a late differentiation signal inducing a change from very mobile, partially activated HSCs to immobile effector HSCs.…”

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

“…[25][26][27] Hyperactive signaling along the PDGF/PDGFR axis also has been demonstrated in several nonmalignant disorders, such as atherosclerosis, 28,29 pulmonary fibrosis (both PDGFRa and PDGFRb), 30,31 hepatic cirrhosis (PDGFRb only), 32,33 and glomerular diseases characterized by mesangial proliferation. [34][35][36][37][38][39][40] PDGFRb-associated functions in cancer biology include pericyte recruitment and the regulation of interstitial fluid pressure in tumors, and the latter may affect the uptake of anticancer therapeutics into malignant tumors. [41][42][43] The Role of PDGFRa in Malignancy PDGF/PDGFRa signaling plays a relevant role in cancer biology not only because of direct effects on tumor cells but also because of paracrine effects mediated by PDGFRa expressed on tumor stroma and effects mediated through the regulation of malignant angiogenesis (Fig.…”