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

Significance Statement

Hepatic fibrosis is the outcome of many chronic liver diseases, including cholestatic liver disease (primary sclerosing cholangitis (PSC), primary and secondary biliary cirrhosis (PBC and SBC)) and hepatotoxic liver diseases (hepatitis B and C virus (HBV and HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD))[1]. It is caused by deregulation of physiological wound healing, and results in excessive production of extracellular matrix (ECM), mostly collagen Type I, and scar formation. Release of TGFb1 and activation of collagen producing myofibroblasts (which are not present in the normal liver) are critical for the pathogenesis of liver fibrosis [1; 4]. For that reason, myofibroblasts are the primary targets for anti-fibrotic therapy. The composition of hepatic myofibroblasts varies dependent on etiology of liver injury, and therefore, identification of the myofibroblast origin is crucial for liver fibrosis treatment. Recent studies on the hepatic myofibroblasts in fibrotic liver are summarized in the review article by Xu et al. Although myofibroblasts may originate from distinct cellular sources, they share common characteristics (such as expression of Col1a1, a-SMA, TGFbRI, TIMP1, PAI-1, activin, vimentin, fibronectin). Xu et al. discuss that three cellular populations are major contributors to hepatic myofibroblasts in patients and in experimental models of liver fibrosis: liver resident Hepatic Stellate Cells (HSCs) [2; 11] and Portal Fibroblasts (PFs)[12], and bone marrow (BM)-derived collagen Type I+ fibrocytes[13; 14; 15; 16]. Activated HSCs (aHSCs) are the primary source of myofibroblasts in response to toxic liver injury (carbon tetrachloride (CCl4) and Tsukamoto-French model of alcoholic liver fibrosis), and can be identified by expression of Vitamin A, desmin, glial fibrillar acidic protein (GFAP), synaptophisin, synemin, and nerve growth factor receptor p75[1; 29]. aHSCs also upregulate Crlf1, Spp1, Lox, LoxL2, IL-17Ra, Fosl1 and Folr1 genes that are uniquely associated with myofibroblast-like phenotype, and therefore, can serve as potential targets for anti-fibrotic therapy[7]. Activated Portal fibroblasts (aPFs) are implicated in the pathogenesis of cholestatic liver fibrosis (caused by bile duct ligation, BDL)[1], and can be we identified by expression of fibulin 2, elastin, Thy1, interleukin 6, and the ectonucleotidase NTPDase 2[89]. A recent study from Iwaisako et al. identified novel markers of aPFs (calcitonin a, asporin, mesothelin, mucin 16, basonuclin 1, uroplakin 1b and others), and demonstrated that aPFs are a major source of myofibroblasts in cholestatic liver injury, contributing >70% of myofibroblasts at the onset of BDL, and secreting factors (such as IL-13) that facilitate activation of HSCs. Interestingly, BDL-activated HSCs exhibit more similarities to aPFs, than to CCl4-activated HSCs. Finally, recruitment of bone marrow (BM)-derived fibrocytes into the injured liver is observed in animal models of both toxic and cholestatic liver fibrosis. However, the contribution of fibrocytes to collagen producing myofibroblasts is probably quantitatively small, since only 5-6% of hepatic myofibroblasts originate from fibrocytes in experimental liver fibrosis, although earlier studies reported higher numbers. Hepatic fibrosis can regress upon cessation of liver injury. Regression of liver fibrosis is accompanied by disappearance of fibrogenic myofibroblasts and by resorption of the fibrous scar. Only recently the fate of hepatic myofibroblasts has been revealed by Kisseleva et al. using a cell fate mapping technology. Myofibroblasts either apoptose or inactivate into a quiescent-like state (e.g. stop collagen production and partially restore expression of lypogenic genes). Inactivation of myofibroblasts is a recently described phenomenon, which provides new directions for anti-fibrotic therapy.

The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

Journal Reference

Xu J, Liu X, Koyama Y, Wang P, Lan T, Kim IG, Kim IH, Ma HY, Kisseleva T. Front Pharmacol. 2014 Jul 22;5:167.

School of Medicine, University of California at San Diego La Jolla, CA, USA.

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 thathepatic 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.

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