Liver Injury and the Activation of the Hepatic Myofibroblasts

Abstract

Liver fibrosis is a wound healing process, the end result of chronic liver injury elicited by different noxious stimuli. Activated hepatic stellate cells or myofibroblasts and portal myofibroblasts are considered as the main producers of the extracellular matrix in the liver. Upon liver injury the quiescent stellate cells transdifferentiate into myofibroblasts a process highlighted by the loss of vitamin A stores, upregulation of interstitial type collagens, smooth muscle α actin, matrix metalloproteinases, proteoglycans, and the induction of cell survival pathways. Activation of hepatic stellate cells is a result of a complex interplay between the parenchymal cells, immune cells, extracellular matrix mechanics and extrahepatic milieu such as the gut microbiome. In this review we will focus on the pathomechanism of stellate cell activation following chronic liver injury; with the aim of identifying possible treatment targets for anti-fibrogenic agents.

Keywords: Epigenetic signaling; Gut microbiota; Hepatocyte apoptosis; Inflammasome; Liver fibrosis; Myofibroblast; Pathobiology; Reactive oxidative species; Stellate cell activation; Sterile inflammation.

Figure 1. Mechanism of liver injury-mediated stellate cell activation

Under pathologic conditions, hepatocytes first initiate adaptive responses such as induction of ER stress and the unfolded protein response (UPR), and the induction of autophagy. After prolonged insult however, hepatocytes undergo apoptosis or necrosis and during the latter, release DAMPs reacting with PRRs on the target cells, to launch the sterile inflammation responses. This leads to inflammasome formation and the production of proinflammatory and profibrogenic cytokines, and the recruitment of inflammatory cells. DAMPs from injured hepatocytes may directly activate HSC by the engagement of TLRs on HSC. Compounding the above events, dysbiosis and increased permeability of the gut also contributes to fibrosis by releasing high levels of LPS, a PAMP molecule inducing macrophage and HSC activation via TLR4 signaling.