Changing the pathogenetic roadmap of liver fibrosis? Where did it start; where will it go?
The pathophysiology of liver injury has attracted the interest of experimentalists and clinicians over many centuries. With the discovery of liver-specific pericytes - formerly called fat-storing cells, Ito-cells, lipocytes, and currently designated as hepatic stellate cells (HSC) - the insight into the cellular and molecular pathobiology of liver fibrosis has evolved and the pivotal role of HSC as a precursor cell-type for extracellular matrix-producing myofibroblasts has been established. Although activation and transdifferentiation of HSC to myofibroblasts is still regarded as the pathogenetic key mechanism of fibrogenesis, recent studies point to a prominent heterogeneity of the origin of myofibroblasts. Currently, the generation of matrix-synthesizing fibroblasts by epithelial-mesenchymal transition, by influx of bone marrow-derived fibrocytes into damaged liver tissue, and by differentiation of circulating monocytes to fibroblasts after homing in the injured liver are discussed as important complementary mechanisms to enlarge the pool of (myo-)fibroblasts in the fibrosing liver. Among the molecular mediators, transforming growth factor-beta (TGF-beta) plays a central role, which is controlled by the bone-morphogenetic protein (BMP)-7, an important antagonist of TGF-beta action. The newly discovered pathways supplement the linear concept of HSC activation to myofibroblasts, point to fibrosis as a systemic response involving extrahepatic organs and reactions, add further evidence to a more or less uniform concept of organ fibrosis in general (e.g. liver, lung, kidney), and offer innovative approaches for the development of non-invasive biomarkers and antifibrotic trials.
Gressner
Olav A
OA
Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany. agressner@ukaachen.de
Rizk
Mohamed S
MS
Kovalenko
Evgeniya
E
Weiskirchen
Ralf
R
Gressner
Axel M
AM
D001854:Bone Marrow Cells / Q000473:pathology; D002465:Cell Movement; D054338:Cell Transdifferentiation; D004847:Epithelial Cells / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology; D049672:History, 19th Century; D049673:History, 20th Century; D049690:History, Ancient; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000266:history / Q000378:metabolism / Q000473:pathology*; D009000:Monocytes / Q000473:pathology; D020286:Pericytes / Q000473:pathology; D015398:Signal Transduction
D016326:Extracellular Matrix Proteins