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, 134 (6), 1655-69

Mechanisms of Hepatic Fibrogenesis


Mechanisms of Hepatic Fibrogenesis

Scott L Friedman. Gastroenterology.


Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, post-transcriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.


Figure 1
Figure 1
Contributions of activated stellate cells and other fibrogenic cell types to hepatic fibrosis. Quiescent stellate cell activation is initiated by a range of soluble mediators (Figure 2). The activated cell is stimulated further by key cytokines (detailed further in Figure 2) into myofibroblasts (which contain contractile filaments). Over time, however, other sources also contribute to fibrogenic populations in liver, including bone marrow (which likely gives rise to circulating fibrocytes), portal fibroblasts, and epithelial mesenchymal transition (emt) from hepatocytes and cholangiocytes. Relative contributions and the stages at which these cell types add to the myofibroblast population is likely to differ among various etiologies of liver injury (see text).
Figure 2
Figure 2
Pathways of hepatic stellate cell activation. 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. fgf, fibroblast growth factor; et-1, endothelin-1; nk, natural killer; no, nitric oxide; mt, membrane type. Modified with permission from Friedman.
Figure 3
Figure 3
Pathways of matrix degradation in fibrosis progression and regression. Macrophages have assumed an important role in matrix degradation, which is profibrogenic during progression of fibrosis but antifibrotic during fibrosis resolution. Although key sources of matrix degrading activity are uncertain, it seems increasingly likely that both scar-associated macrophages and stellate cells are sources of interstitial collagenases. At the same time, decreased TIMP-1 fosters apoptosis of fibrogenic myofibroblasts. Figure adapted from studies of Duffield and Iredale (and accompanying editorial, pp 29–32).
Figure 4
Figure 4
Possible links between stellate cells, fibrosis, regeneration, and cancer. Upon liver injury, activated stellate cells release paracrine factors that may promote progenitor cell expansion, the outcome of which could be either hepatic regeneration and/or promotion of hepatocellular cancer. The possibility also exists that stellate cells may harbor the potential to transdifferentiate into progenitor cells directly, which remains speculative. Moreover, fibrosis promotes hepatocarcinogenesis through unknown mechanisms that may include release of survival signals.
Figure 5
Figure 5
Cirrhosis is a series of progressive stages, not a single stage. Within the spectrum of cirrhosis, the disease is characterized by progressive increases in hepatic venous pressure gradient (hvpg), decompensation, and matrix cross-linking, associated with shrinking nodule size, thickening septae, and enhanced risk of decompensation. For each 1-mm increase in HVPG the risk of decompensation increases by 11%. Concepts presented here are not rigorously supported by primary data for all features, but rather are intended to convey the progressive changes that underlie deterioration in patients with chronic hepatic injury and fibrosis. Stages are based on data from D’Amico et al. he, hepatic encephalopathy; vh, variceal hemorrhage.

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