Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation

Abstract

Hepatic fibrosis is characterized by the pathological accumulation of extracellular matrix (ECM) in the liver resulting from the persistent liver injury and wound-healing reaction induced by various insults. Although hepatic fibrosis is considered reversible after eliminating the cause of injury, chronic injury left unchecked can progress to cirrhosis and liver cancer. A better understanding of the cellular and molecular mechanisms controlling the fibrotic response is needed to develop novel clinical strategies. It is well documented that activated hepatic stellate cells (HSCs) is the most principal cellular players promoting synthesis and deposition of ECM components. In the current review, we discuss pathways of HSC activation, emphasizing emerging extra- and intra-cellular signals that drive this important cellular response to hepatic fibrosis. A number of cell types and external stimuli converge upon HSCs to promote their activation, including hepatocytes, liver sinusoidal endothelial cells, macrophages, cytokines, altered ECM, hepatitis viral infection, enteric dysbiosis, lipid metabolism disorder, exosomes, microRNAs, alcohol, drugs and parasites. We also discuss the emerging signaling pathways and intracellular events that individually or synergistically drive HSC activation, including TGFβ/Smad, Notch, Wnt/β-catenin, Hedgehog and Hippo signaling pathways. These findings will provide novel potential therapeutic targets to arrest or reverse fibrosis and cirrhosis.

Is the Macrophage Phenotype Determinant for Fibrosis Development?

“…Liver fibrosis is the result of the continuous and progressive activation of different liver-resident and infiltrating immune cells, which occurs in response to acute or chronic cell injury, and which perpetuates inflammation [ 94 , 95 ]. Chronic liver injury may arise as a response to the aggression of toxics such as alcohol, infections, or fat accumulation, which characterize alcoholic liver disease, viral hepatitis, or non-alcoholic fatty liver diseases, among others [ 96 ].…”

“…In line with this, hepatic stellate cells (HSCs) are resident non-mesenchymal cells, which upon transdifferentiation become myofibroblast-like cells and are the main collagen producers in the liver. Indeed, the most described action driven by macrophages that contributes to liver fibrosis is the activation of HSCs [ 94 , 95 , 101 ]. Liver macrophages can receive a wide variety of stimuli, which induces the secretion of certain substances that in turn activate the pro-fibrotic role of HSCs in remodeling the immune microenvironment and promoting ECM deposition [ 97 ].…”

“…In this case, as previously described, it has been extensively demonstrated in murine models that macrophages of the Ly6C low phenotype contribute to collagen breakdown and regression of ECM deposition [ 96 , 109 , 127 ]. An example of macrophages that have this phenotype are CD11b high /F4/80 intermediate LY6C low macrophages [ 95 ]. These specific macrophages secrete MMPs such as MMP-9 and MMP-12, which inhibit scar tissue deposition as well as prevent inflammation by inducing HSC apoptosis [ 128 ].…”

Nonalcoholic Fatty Liver Disease (NAFLD): Pathogenesis and Noninvasive Diagnosis

“…Hepatic fibrogenesis is driven by HSC activation and proliferation. Usually, HSCs are quiescent non-proliferative cells, and their activations lead to extracellular matrix (ECM) protein synthesis and production [ 29 ]. Lipotoxic hepatocytes and Kupffer cells could trigger HSC activation via the release of the pro-fibrotic cytokines (TNF, platelet-derived growth factor (PDGF), and transforming growth factor-β (TGFB)).…”

“…Lipotoxic hepatocytes and Kupffer cells could trigger HSC activation via the release of the pro-fibrotic cytokines (TNF, platelet-derived growth factor (PDGF), and transforming growth factor-β (TGFB)). The increase of α-smooth muscle actin (ACTA2) and desmin (DES) productions change the HSC phenotypes into proliferative and contractile shapes [ 29 ]. These activated HSCs also promote the secretion of pro-inflammatory cytokines, including CCL2 and interleukins (IL-6 and IL-8), to maintain the inflammatory environment and promote the fibrogenic environment further [ 30 ].…”