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Review
. 2014 Jul 22:5:167.
doi: 10.3389/fphar.2014.00167. eCollection 2014.

The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies

Jun Xu  1 , Xiao Liu  1 , Yukinori Koyama  1 , Ping Wang  1 , Tian Lan  1 , In-Gyu Kim  1 , In H Kim  1 , Hsiao-Yen Ma  1 , Tatiana Kisseleva  1
Affiliations
Review

The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies

Jun Xu et al. Front Pharmacol. .

Abstract

Liver fibrosis results from dysregulation of normal wound healing, inflammation, activation of myofibroblasts, and deposition of extracellular matrix (ECM). Chronic liver injury causes death of hepatocytes and formation of apoptotic bodies, which in turn, release factors that recruit inflammatory cells (neutrophils, monocytes, macrophages, and lymphocytes) to the injured liver. Hepatic macrophages (Kupffer cells) produce TGFβ1 and other inflammatory cytokines that activate Collagen Type I producing myofibroblasts, which are not present in the normal liver. Secretion of TGFβ1 and activation of myofibroblasts play a critical role in the pathogenesis of liver fibrosis of different etiologies. Although the composition of fibrogenic myofibroblasts varies dependent on etiology of liver injury, liver resident hepatic stellate cells and portal fibroblasts are the major source of myofibroblasts in fibrotic liver in both experimental models of liver fibrosis and in patients with liver disease. Several studies have demonstrated that hepatic fibrosis can reverse upon cessation of liver injury. Regression of liver fibrosis is accompanied by the disappearance of fibrogenic myofibroblasts followed by resorption of the fibrous scar. Myofibroblasts either apoptose or inactivate into a quiescent-like state (e.g., stop collagen production and partially restore expression of lipogenic genes). Resolution of liver fibrosis is associated with recruitment of macrophages that secrete matrix-degrading enzymes (matrix metalloproteinase, collagenases) and are responsible for fibrosis resolution. However, prolonged/repeated liver injury may cause irreversible crosslinking of ECM and formation of uncleavable collagen fibers. Advanced fibrosis progresses to cirrhosis and hepatocellular carcinoma. The current review will summarize the role and contribution of different cell types to populations of fibrogenic myofibroblasts in fibrotic liver.

Keywords: carbon tetrachloride; fibrocyte; hepatic stellate cells; liver fibrosis; myofibroblasts; portal fibroblast.

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Figures

FIGURE 1
FIGURE 1
Pathogenesis of liver fibrosis. (A) Hepatic lobular structure under physiological conditions. Hepatic sinusoid, cholangiocytes and hepatocytes, endothelial cells, hepatic stellate cells (HSCs) and portal fibroblasts (PFs), and Kupffer cells (KCs) are the components of hepatic lobule. The bile duct, portal vein and hepatic artery form the portal triad. HSCs are located in the space between hepatocytes and sinusoidal endothelium, designated as the space of Disse. HSCs are considered as liver pericytes, they contain lipid droplets and serve as the major storage of vitamin A. KCs represent a population of hepatic macrophages. Only few fibrocytes are present in the healthy liver. (B) Changes in the hepatic lobule caused by chronic liver injury. In response to chronic liver injury, hepatocytes undergo apoptosis and release factors that recruit Kupffer cells, BM macrophages, and fibrocytes into the damaged liver. KCs, BM macrophages, and fibrocytes release TGFβ1, the most potent profibrogenic cytokine, which activates HSCs into collagen Type I expressing myofibroblasts. HSCs, PFs and, to a lesser extent fibrocytes, deposit extracellular matrix (ECM).
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