Chapter 6 - Stellate Cells, Portal Myofibroblasts, and Epithelial-to-Mesenchymal Transition

Abstract

There is strong evidence using a variety of methodologies that myofibroblasts are the major source of fibrillar collagen and other extracellular matrix proteins that constitute the fibrous scar in clinical and experimental liver fibrosis. Myofibroblasts are easily identified by immunohistochemistry for α-smooth muscle actin. There are no detectable myofibroblasts in the normal liver, but chronic liver injury induces thick bands of myofibroblasts embedded in the fibrous scar. Despite extensive studies, the origin of myofibroblasts in different types of fibrotic liver diseases is still controversial. Genetic cell fate mapping is the most robust, reliable method to trace the origin of myofibroblasts. On the basis of many studies, activated hepatic stellate cells (HSCs) are the major source of myofibroblasts in a variety of cholestatic and hepatotoxic models of liver injury in mice. However, activated portal fibroblasts (aPFs) are a major initial source of myofibroblasts in cholestatic liver injury, contributing>70% of myofibroblasts at the onset of injury 5 days after bile duct ligation (BDL). The relative contribution of aPFs decreases with progressive injury, as HSCs become activated and eventually become the largest contributor to the myofibroblast population (14 and 20 days BDL). Epithelial-to-mesenchymal transition has also been evaluated as a source of myofibroblasts in liver fibrosis. On the basis of cell fate mapping, hepatocytes, changiocytes, and bipotential progenitor cells do not contribute to the myofibroblast population in multiple models of liver fibrosis.