Hedgehog signaling in biliary fibrosis

Abstract

Congenital and acquired diseases of the biliary tree, or cholangiopathies, represent a significant source of morbidity and mortality in both children and adults. In late stages of the disease, cholangiocytes can no longer proliferate, resulting in loss of bile ducts, increased fibrosis, and ultimately cirrhosis and liver failure. Epithelial-mesenchymal transition has been proposed as a potential mechanism underlying both cholangiocyte proliferation and fibrogenesis in biliary diseases. In this issue of the JCI, using a myofibroblast-cholangiocyte coculture system and genetically modified mice, Omenetti and colleagues present evidence supporting the importance of paracrine hedgehog signaling between the two cell types and increased expression of mesenchymal markers in cholangiocytes (see the related article beginning on page 3331). These findings set the stage for future studies to further investigate the contribution of hedgehog signaling in both cholangiocyte repair and fibrogenesis in biliary diseases.

Figure 1. Model of paracrine signaling in a ductular reaction in the cholestatic liver.

(A) Schematic of the portal triad of the portal vein, hepatic artery, and bile duct in the normal liver. Hepatic stellate cells, the site of vitamin A storage, are located in the Disse space near hepatocytes. Portal myofibroblasts are also in close proximity to the bile ducts. (B) After bile duct ligation and cholestatic liver injury, the liver responds with a ductular reaction and the expansion of the biliary tree. In their study in this issue of the JCI, Omenetti and colleagues (12) propose that hepatic stellate cells produce and release sonic hedgehog (Hh) in response to the injury, which acts on a subpopulation of bile duct epithelial cells known as cholangiocytes to activate several markers of mesenchymal cells. The authors suggest that cholangiocytes then undergo EMT and migrate into the parenchyma. The latter hypothesis remains to be proven in vivo. Also, additional signals from the portal myofibroblasts likely contribute to the activation of bile duct epithelial cells.