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Hepatic Stellate Cells and Liver Fibrosis

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Hepatic stellate cells are resident perisinusoidal cells distributed throughout the liver, with a remarkable range of functions in normal and injured liver. Derived embryologically from septum transversum mesenchyme, their precursors include submesothelial cells that invade the liver parenchyma from the hepatic capsule. In normal adult liver, their most characteristic feature is the presence of cytoplasmic perinuclear droplets that are laden with retinyl (vitamin A) esters. Normal stellate cells display several patterns of intermediate filaments expression (e.g., desmin, vimentin, and/or glial fibrillary acidic protein) suggesting that there are subpopulations within this parental cell type. In the normal liver, stellate cells participate in retinoid storage, vasoregulation through endothelial cell interactions, extracellular matrix homeostasis, drug detoxification, immunotolerance, and possibly the preservation of hepatocyte mass through secretion of mitogens including hepatocyte growth factor. During liver injury, stellate cells activate into alpha smooth muscle actin‐expressing contractile myofibroblasts, which contribute to vascular distortion and increased vascular resistance, thereby promoting portal hypertension. Other features of stellate cell activation include mitogen‐mediated proliferation, increased fibrogenesis driven by connective tissue growth factor, and transforming growth factor beta 1, amplified inflammation and immunoregulation, and altered matrix degradation. Evolving areas of interest in stellate cell biology seek to understand mechanisms of their clearance during fibrosis resolution by either apoptosis, senescence, or reversion, and their contribution to hepatic stem cell amplification, regeneration, and hepatocellular cancer. © 2013 American Physiological Society. Compr Physiol 3:1473‐1492, 2013.

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Figure 1. Figure 1. Appearance of hepatic stellate cells and the sinusoidal microenvironment in normal and injured liver. In normal liver, stellate cells (shown in blue) are laden with perinuclear retinoid droplets and preserve the differentiated function of surrounding cells, including hepatocytes and sinusoidal endothelial cells. In liver injury, the cells multiply, lose vitamin A and become embedded within dense extracellular matrix. This leads to deterioration of hepatocyte function manifested as loss of microvilli, and decreased size and number of endothelial fenestrations. Reprinted, with permission, from (68).
Figure 2. Figure 2. Roles of hepatic stellate cells in normal liver.
Figure 3. Figure 3. Matrix and cellular alteration in hepatic fibrosis. Normal liver parenchyma contains epithelial cells (hepatocytes) and nonparenchymal cells: fenestrated sinusoidal endothelium, hepatic stellate cells (HSCs), and Kupffer cells (KCs). (A) Sinusoids are separated from hepatocytes by a low‐density basement membrane‐like matrix confined to the space of Disse, which ensures metabolic exchange. Upon injury, the stellate cells become activated and secrete large amounts of extracellular matrix (ECM), resulting in progressive thickening of the septa. (B) Deposition of ECM in the space of Disse leads to the loss of both endothelial fenestrations and hepatocyte microvilli, which results in both the impairment of normal bidirectional metabolic exchange between portal venous flow and hepatocytes and the development of portal hypertension.
Figure 4. Figure 4. Pathways of hepatic stellate cell activation and loss during liver injury and resolution. Features of stellate cell activation can be distinguished between those that stimulate initiation and those that contribute to perpetuation. Initiation is provoked by soluble stimuli that include oxidant stress signals (reactive oxygen intermediates), apoptotic bodies, lipopolysaccharide (LPS), and paracrine stimuli from neighboring cell types including hepatic macrophages (Kupffer cells), sinusoidal endothelium, and hepatocytes. Perpetuation follows, characterized by a number of specific phenotypic changes including proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and inflammatory signaling. During resolution of hepatic fibrosis, there is both programmed cell death (apoptosis) to clear fibrogenic cells, as well as reversion to a more quiescient phenotype. FGF, fibroblast growth factor; ET‐1, endothelin‐1; NK, natural killer; NO, nitric oxide; MT, membrane type. Reprinted, with permission, from (66).

Figure 1. Appearance of hepatic stellate cells and the sinusoidal microenvironment in normal and injured liver. In normal liver, stellate cells (shown in blue) are laden with perinuclear retinoid droplets and preserve the differentiated function of surrounding cells, including hepatocytes and sinusoidal endothelial cells. In liver injury, the cells multiply, lose vitamin A and become embedded within dense extracellular matrix. This leads to deterioration of hepatocyte function manifested as loss of microvilli, and decreased size and number of endothelial fenestrations. Reprinted, with permission, from (68).

Figure 2. Roles of hepatic stellate cells in normal liver.

Figure 3. Matrix and cellular alteration in hepatic fibrosis. Normal liver parenchyma contains epithelial cells (hepatocytes) and nonparenchymal cells: fenestrated sinusoidal endothelium, hepatic stellate cells (HSCs), and Kupffer cells (KCs). (A) Sinusoids are separated from hepatocytes by a low‐density basement membrane‐like matrix confined to the space of Disse, which ensures metabolic exchange. Upon injury, the stellate cells become activated and secrete large amounts of extracellular matrix (ECM), resulting in progressive thickening of the septa. (B) Deposition of ECM in the space of Disse leads to the loss of both endothelial fenestrations and hepatocyte microvilli, which results in both the impairment of normal bidirectional metabolic exchange between portal venous flow and hepatocytes and the development of portal hypertension.

Figure 4. Pathways of hepatic stellate cell activation and loss during liver injury and resolution. Features of stellate cell activation can be distinguished between those that stimulate initiation and those that contribute to perpetuation. Initiation is provoked by soluble stimuli that include oxidant stress signals (reactive oxygen intermediates), apoptotic bodies, lipopolysaccharide (LPS), and paracrine stimuli from neighboring cell types including hepatic macrophages (Kupffer cells), sinusoidal endothelium, and hepatocytes. Perpetuation follows, characterized by a number of specific phenotypic changes including proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and inflammatory signaling. During resolution of hepatic fibrosis, there is both programmed cell death (apoptosis) to clear fibrogenic cells, as well as reversion to a more quiescient phenotype. FGF, fibroblast growth factor; ET‐1, endothelin‐1; NK, natural killer; NO, nitric oxide; MT, membrane type. Reprinted, with permission, from (66).
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Further Reading
 1. Friedman SL, Sheppard D, Duffield J and Violette S. Therapy for fibrotic diseases: Nearing the starting line. Sci Transl Med, 5:167sr1, 2013.
 2.Friedman SL, guest editor. Special issue on fibrosis. Biochim Biophys Acta. 2013 Mar 16. pii: S0925‐4439(13)00077‐X. doi: 10.1016/j.bbadis.

Further Reading

Friedman SL, Sheppard D, Duffield J and Violette S.  Therapy for fibrotic diseases: nearing the starting line.  Science Translational Medicine, 5:167sr1, 2013.

Friedman SL, guest editor.   Special issue on fibrosis.  Biochimica Biophysica Acta, in press, 2013.

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Juan E. Puche, Yedidya Saiman, Scott L. Friedman. Hepatic Stellate Cells and Liver Fibrosis. Compr Physiol 2013, 3: 1473-1492. doi: 10.1002/cphy.c120035