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Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options.

Gressner OA, Weiskirchen R, Gressner AM - Comp Hepatol (2007)

Bottom Line: They offer innovative diagnostic and therapeutic options.As an example, modulation of TGF-beta/BMP-7 ratio changes the rate of EMT, and so the simultaneous determination of these parameters and of connective tissue growth factor (CTGF) in serum might provide information on fibrogenic activity.The extension of pathogenetic concepts of fibrosis will provide new therapeutic possibilities of interference with the fibrogenic mechanism in liver and other organs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany. gressner@rwth-aachen.de

ABSTRACT
Despite intensive studies, the clinical opportunities for patients with fibrosing liver diseases have not improved. This will be changed by increasing knowledge of new pathogenetic mechanisms, which complement the "canonical principle" of fibrogenesis. The latter is based on the activation of hepatic stellate cells and their transdifferentiation to myofibroblasts induced by hepatocellular injury and consecutive inflammatory mediators such as TGF-beta. Stellate cells express a broad spectrum of matrix components. New mechanisms indicate that the heterogeneous pool of (myo-)fibroblasts can be supplemented by epithelial-mesenchymal transition (EMT) from cholangiocytes and potentially also from hepatocytes to fibroblasts, by influx of bone marrow-derived fibrocytes in the damaged liver tissue and by differentiation of a subgroup of monocytes to fibroblasts after homing in the damaged tissue. These processes are regulated by the cytokines TGF-beta and BMP-7, chemokines, colony-stimulating factors, metalloproteinases and numerous trapping proteins. They offer innovative diagnostic and therapeutic options. As an example, modulation of TGF-beta/BMP-7 ratio changes the rate of EMT, and so the simultaneous determination of these parameters and of connective tissue growth factor (CTGF) in serum might provide information on fibrogenic activity. The extension of pathogenetic concepts of fibrosis will provide new therapeutic possibilities of interference with the fibrogenic mechanism in liver and other organs.

No MeSH data available.


Related in: MedlinePlus

Up-to-date mechanisms of fibrogenesis. HSC activation, EMT, influx of fibrocytes, and differentiation of peripheral monocytes to fibroblasts at sites of injury. (Explanation is in the text).
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Figure 7: Up-to-date mechanisms of fibrogenesis. HSC activation, EMT, influx of fibrocytes, and differentiation of peripheral monocytes to fibroblasts at sites of injury. (Explanation is in the text).

Mentions: Beside activation and transdifferentiation of HSC, a cell type, which is developmentally most likely derived from the septum transversum mesenchyme, from endoderm or from the mesothelial liver capsule [104], an increasing number of experimental studies points to an additional mechanism for the enlargement of the resident (local) pool of fibroblasts during the fibrotic reaction of the damaged organs, e.g., in kidney and lung [105]. This process, termed epithelial-mesenchymal transition (EMT), is well known in the context of embryonic development, but is now discussed as an important mechanism in the generation of fibroblasts during fibrogenesis in adult tissues [106] (Fig. 7). It was proven that in fibrotic kidney disease tubulus epithelial cells can transdifferentiate to fibroblasts expressing the fibroblast-specific protein 1 (FSP-1), also known as S100A4 calcium-binding protein, and are able to express collagens [106]. Similarly, alveolar epithelial cells of the lung are subject to EMT and also cardial endothelial cells can switch to fibroblasts under conditions of damage (mesenchymal-mesenchymal transition). It is estimated that in the kidney about 66% of fibroblasts are the result of EMT, in the heart the number climbs to about 20% (R. Kalluri, personal communication). In vitro and in vivo observations made in blood vessels following sustained inflammation support a hypothesis that endothelial cell transformation to myofibroblast-like cells may explain the increase of matrix proteins and of MFB pathognomonic of fibrotic diseases [107]. Very recent studies have also discussed EMT in liver fibrogenesis, after a transition of albumin-positive hepatocytes to FSP-1 positive and albumin-negative fibroblasts was shown. Preliminary studies claim that about 40% of hepatic fibroblasts derive from hepatocytes, but these data need further confirmation (R. Kalluri, personal communication). A very recent report provides evidence for EMT of mature mouse hepatocytes in vitro and of the mouse hepatocyte cell line AML12 [108]. The EMT-state was indicated by strong up-regulation of α1(I) collagen mRNA expression and type I collagen deposition. Thus, hepatocytes are capable of EMT changes and type I collagen synthesis. A further source of EMT are cholangiocytes (bile duct epithelial cells). In primary biliary cirrhosis (PBC) it was proven that bile duct epithelial cells express FSP-1 (S100A4) and vimentin as early markers of fibroblasts [109]. The bidirectional consequence of EMT of cholangiocytes are ductopenia (reduction of bile ducts) and enlargement of the pool of portal fibroblasts, which significantly contributes to portal fibrosis. In vitro studies with cultured human cholangiocytes have confirmed the clinical observations described. Thus, EMT proves to be a general pathogenetic principle of chronic cholestatic liver diseases [110]. In addition, activation and proliferation of portal/periportal mesenchymal cells to peribiliary MFB, which are stimulated in a paracrine manner by bile duct epithelial cells via TGF-β, PDGF-BB and endothelin-1 [111] turned out to be an important pathogenetic mechanism of portal fibrosis and septa formation in cholestatic liver diseases. Indeed, only a minority of ECM-producing MFB in obstructive cholestatic injuries are derived from HSC [112,113]. This also underlines the heterogeneous origin of MFB in fibrogenesis and emphasizes the importance of the underlying fibrogenic liver disease [82].


Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options.

Gressner OA, Weiskirchen R, Gressner AM - Comp Hepatol (2007)

Up-to-date mechanisms of fibrogenesis. HSC activation, EMT, influx of fibrocytes, and differentiation of peripheral monocytes to fibroblasts at sites of injury. (Explanation is in the text).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1994681&req=5

Figure 7: Up-to-date mechanisms of fibrogenesis. HSC activation, EMT, influx of fibrocytes, and differentiation of peripheral monocytes to fibroblasts at sites of injury. (Explanation is in the text).
Mentions: Beside activation and transdifferentiation of HSC, a cell type, which is developmentally most likely derived from the septum transversum mesenchyme, from endoderm or from the mesothelial liver capsule [104], an increasing number of experimental studies points to an additional mechanism for the enlargement of the resident (local) pool of fibroblasts during the fibrotic reaction of the damaged organs, e.g., in kidney and lung [105]. This process, termed epithelial-mesenchymal transition (EMT), is well known in the context of embryonic development, but is now discussed as an important mechanism in the generation of fibroblasts during fibrogenesis in adult tissues [106] (Fig. 7). It was proven that in fibrotic kidney disease tubulus epithelial cells can transdifferentiate to fibroblasts expressing the fibroblast-specific protein 1 (FSP-1), also known as S100A4 calcium-binding protein, and are able to express collagens [106]. Similarly, alveolar epithelial cells of the lung are subject to EMT and also cardial endothelial cells can switch to fibroblasts under conditions of damage (mesenchymal-mesenchymal transition). It is estimated that in the kidney about 66% of fibroblasts are the result of EMT, in the heart the number climbs to about 20% (R. Kalluri, personal communication). In vitro and in vivo observations made in blood vessels following sustained inflammation support a hypothesis that endothelial cell transformation to myofibroblast-like cells may explain the increase of matrix proteins and of MFB pathognomonic of fibrotic diseases [107]. Very recent studies have also discussed EMT in liver fibrogenesis, after a transition of albumin-positive hepatocytes to FSP-1 positive and albumin-negative fibroblasts was shown. Preliminary studies claim that about 40% of hepatic fibroblasts derive from hepatocytes, but these data need further confirmation (R. Kalluri, personal communication). A very recent report provides evidence for EMT of mature mouse hepatocytes in vitro and of the mouse hepatocyte cell line AML12 [108]. The EMT-state was indicated by strong up-regulation of α1(I) collagen mRNA expression and type I collagen deposition. Thus, hepatocytes are capable of EMT changes and type I collagen synthesis. A further source of EMT are cholangiocytes (bile duct epithelial cells). In primary biliary cirrhosis (PBC) it was proven that bile duct epithelial cells express FSP-1 (S100A4) and vimentin as early markers of fibroblasts [109]. The bidirectional consequence of EMT of cholangiocytes are ductopenia (reduction of bile ducts) and enlargement of the pool of portal fibroblasts, which significantly contributes to portal fibrosis. In vitro studies with cultured human cholangiocytes have confirmed the clinical observations described. Thus, EMT proves to be a general pathogenetic principle of chronic cholestatic liver diseases [110]. In addition, activation and proliferation of portal/periportal mesenchymal cells to peribiliary MFB, which are stimulated in a paracrine manner by bile duct epithelial cells via TGF-β, PDGF-BB and endothelin-1 [111] turned out to be an important pathogenetic mechanism of portal fibrosis and septa formation in cholestatic liver diseases. Indeed, only a minority of ECM-producing MFB in obstructive cholestatic injuries are derived from HSC [112,113]. This also underlines the heterogeneous origin of MFB in fibrogenesis and emphasizes the importance of the underlying fibrogenic liver disease [82].

Bottom Line: They offer innovative diagnostic and therapeutic options.As an example, modulation of TGF-beta/BMP-7 ratio changes the rate of EMT, and so the simultaneous determination of these parameters and of connective tissue growth factor (CTGF) in serum might provide information on fibrogenic activity.The extension of pathogenetic concepts of fibrosis will provide new therapeutic possibilities of interference with the fibrogenic mechanism in liver and other organs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany. gressner@rwth-aachen.de

ABSTRACT
Despite intensive studies, the clinical opportunities for patients with fibrosing liver diseases have not improved. This will be changed by increasing knowledge of new pathogenetic mechanisms, which complement the "canonical principle" of fibrogenesis. The latter is based on the activation of hepatic stellate cells and their transdifferentiation to myofibroblasts induced by hepatocellular injury and consecutive inflammatory mediators such as TGF-beta. Stellate cells express a broad spectrum of matrix components. New mechanisms indicate that the heterogeneous pool of (myo-)fibroblasts can be supplemented by epithelial-mesenchymal transition (EMT) from cholangiocytes and potentially also from hepatocytes to fibroblasts, by influx of bone marrow-derived fibrocytes in the damaged liver tissue and by differentiation of a subgroup of monocytes to fibroblasts after homing in the damaged tissue. These processes are regulated by the cytokines TGF-beta and BMP-7, chemokines, colony-stimulating factors, metalloproteinases and numerous trapping proteins. They offer innovative diagnostic and therapeutic options. As an example, modulation of TGF-beta/BMP-7 ratio changes the rate of EMT, and so the simultaneous determination of these parameters and of connective tissue growth factor (CTGF) in serum might provide information on fibrogenic activity. The extension of pathogenetic concepts of fibrosis will provide new therapeutic possibilities of interference with the fibrogenic mechanism in liver and other organs.

No MeSH data available.


Related in: MedlinePlus