Hepatic stellate cells (HSCs) have been identified as the central collagen-producing cells in the injured liver. Upon chronic inflammation, HSCs transdifferentiate from a quiescent to an activated state, showing proliferative myofibroblast phenotype and representing the primary source of ECM deposition in the fibrotic liver.
Hypertrophied HSCs have been observed in many toxic, nutritional, or mixed harmful/healthy models of hepatic fibrosis. This occurrence may be related to specific features of HSCs, such as their function as liver-specific pericytes.
The normal liver is protected by a first barrier consisting of sinusoidal endothelial cells and Kupffer cells (liver macrophages). When the liver is exposed to chronic injury caused by viruses, alcohol, hepatitis B or C infection, toxins, schistosomes, nonalcoholic steatohepatitis, or other factors, hepatic stellate cells become activated. They adopt a proliferative myofibroblast phenotype, secrete a battery of extracellular matrix proteins that facilitate fibrosis progression, and are the primary contributor to the expansion of collagen expression and deposition in the injured liver.
Stellate cell activation is a complex process with two major phases, initiation and perpetuation. Paracrine-mediated changes in stellate cell gene expression and morphology trigger initiation. It is followed by the autocrine production of various cytokines that enhance stellate cell activation, matrix synthesis, and contractility.
Hepatic stellate cells also promote the recruitment of mono- and polymorphonuclear leukocytes into the injured liver and amplify the infiltration through chemoattractant and cytokine production. In addition, they can modulate inflammatory responses through immunoregulatory mechanisms. Therefore, they integrate cytokine-mediated inflammatory reactions in the sinusoids and relay them to the parenchyma, amplifying or suppressing inflammation through different pathways depending on the context.
Stellate cells are specialized contractile cells essential in forming scar tissue (fibrosis) in response to chronic liver injury. This scarring process ultimately leads to loss of hepatic function and cirrhosis. It is, therefore, essential to find therapeutic strategies that prevent or delay fibrosis progression.
Hepatic stellate cells (HSC) localize to the perisinusoidal space known as the Space of Disse between sinusoidal endothelial cells and hepatocytes. Quiescent HSCs mainly serve as vitamin A reserves in the liver. However, inflammatory mediators promote HSC activation and differentiation into myofibroblasts upon hepatic injury, leading to ECM synthesis and hepatic fibrogenesis.
Activated HSCs secrete ECM proteins, including collagens, glycoproteins, and angiogenesis-promoting factors. They also promote hepatocyte proliferation through mitogens, such as hepatocyte growth factors.
Hepatic stellate cell activation and proliferation are associated with increased portal pressure due to vascular distortion and enhanced hepatic fibrosis. Consequently, antagonism of the endothelin system (with either ETA or mixed ETA/B receptor antagonists) reduces portal pressure and has been shown to inhibit hepatic fibrosis.
Activated hepatic stellate cells (HSC) increase at an increased rate and produce large amounts of ECM, thus contributing to fibrosis progression. Hepatocellular carcinoma (HCC) often develops in the context of hepatic cirrhosis, and the role of HSC-generated fibrosis in advancing hepatocellular tumors has been suggested.
Other hepatic cell types surround stellate cells, including sinusoidal endothelial, Kupffer, and hepatocytes. Paracrine stimulation by all these cells promotes the phenotypic changes in hepatic stellate cells that characterize liver fibrosis. These changes include loss of cytosolic lipid droplets, up-regulation of proteins involved in migration, and reduced levels of proteins associated with hepatic lipid biosynthesis.
Several mesenchymal-specific genes regulate hepatic stellate cells, including the Wnt1 homolog Wnt1 and the LIM homeobox gene Lhx2. Inhibition of these signals, such as through expression of a dominant-negative CREB-Ala-133 mutant that competes with CREB/Ser133 for cognate DNA binding sites or protein interactions, inhibited hepatic stellate cell activation in vitro and reduced the deposition of ECM proteins in vivo in a model of chronic liver injury. These results suggest that targeting specific signaling pathways is a promising approach for treating liver fibrosis and hepatocellular carcinoma.
As fibrosis progresses, stellate cells undergo many phenotypic changes. These include apoptosis, senescence, and reversion to a quiescent phenotype. Apoptosis and senescence have received considerable attention as mechanisms underlying the regression of liver fibrosis. Recent studies have also highlighted the role of autophagy. This catabolic mechanism involves cellular degradation of unnecessary or dysfunctional components through the lysosomal pathway in stellate cell reprogramming and activation.
Stellate cells also regulate hepatic sinusoidal endothelial cells and Kupffer cells (liver macrophages). Liver sinusoids, which are connected directly to the portal circulation, serve as the first barrier against systemic inflammatory challenges by producing a variety of chemokines and cytokines, which attract innate immune cells from the blood and lymphoid organs.
Recently, it has emerged as an excellent vertebrate model system for hepatic development and disease, particularly for studying stellate cell behavior in vivo. The rapid external development and translucence of embryos and larvae allow for easy tracking of cell behaviors in the live animal. Moreover, the availability of lines expressing fluorescent proteins in hepatic cells enables unbiased chemical screening to identify compounds that modulate hepatic stellate cell activation or reversion from the activated to a quiescent state.
Stellate cells have a significant role in liver regeneration and HCC development. In addition, they secrete ECM proteins that infiltrate the hepatic tumor microenvironment (TME) and facilitate primary tumor growth. Activated hepatic stellate cells may promote hepatocarcinogenesis by regulating paracrine signaling between the TME and primary liver cancer cells.
Several animal models have been used to study the interaction between hepatic stellate cells and primary liver tumor cells. The model is particularly suitable for studies of hepatic stellate cell interactions with primary liver tumors, as it is morphologically and genetically similar to the human liver.