Human chronic liver diseases (CLDs) are characterised by reiteration of liver injury due to chronic infection by viral agents (mainly hepatitis B and C viruses) or to metabolic, toxin/drug-induced (alcohol being predominant) and autoimmune causes. This results in the chronic activation of the wound-healing response that represents the driving force for progressive accumulation of extracellular matrix (ECM) components, eventually leading to liver cirrhosis and hepatic failure. Accordingly, cirrhosis can be defined as an advanced stage of fibrosis involving the formation of regenerative nodules of parenchyma surrounded and separated by fibrotic septa, a scenario also characterised by significant changes in hepatic angioarchitecture [1–4].
Fibrosis progression is strictly related to the underlying cause of CLD and four distinct patterns of fibrosis progression (shown below) have been identified that are related to the 'topographic site' of tissue injury (as previously reported in detail [2]), the involvement of different populations of hepatic myofibroblast-like (MF) cells and the predominant profibrogenic mechanism [2, 4, 5].
Bridging fibrosis
This is typically found in chronic viral hepatitis, considered as result of portal-central (vein) bridging necrosis, resulting primarily in the formation of portal-central fibrotic septa. Interface hepatitis, development of portal-portal septa and early changes in vascular connections with portal system complete this scenario.
Perisinusoidal/pericellular fibrosis
This is typically found in non-alcoholic steatohepatitis (NASH) or associated with alcoholic aetiology (ALD); excess deposition of ECM is primarily in the spaces of Disse around sinusoids or groups of hepatocytes, leading to the two scenarios of 'capillarisation of sinusoids' or 'chicken-wire pattern', respectively.
Biliary fibrosis
This is a pattern sustained by concomitant proliferation of reactive bile ductules and periductular MFs at the interface between portal areas and parenchyma, leading to the characteristic development of portal-portal fibrotic septa.
Centrolobular fibrosis
This is secondary to conditions altering venous outflow, as in chronic heart failure, characterised by the development of central-central (vein) fibrotic septa.
Clinical problems
Fibrogenesis progression has a major clinical impact because [2, 4]: (1) millions of patients worldwide are affected by a form of CLD, and among these 25% to 30% are expected to develop significant fibrosis and cirrhosis; (2) liver cirrhosis is the most common non-neoplastic cause of death in Europe and USA among diseases interesting the gastrointestinal (GI) tract, and represents the seventh most common cause of death in western countries; (3) liver cirrhosis predisposes patients to hepatocellular carcinoma (HCC) that further increases mortality rate; (4) epidemiological analysis predict a peak for advanced CLD in the next decade, with an increased number of patients reaching end-stage disease and requiring liver transplantation.
Relevant basic science context
Liver fibrogenesis is sustained by a heterogeneous population of profibrogenic hepatic MFs expressing a peculiar repertoire of antigens [5], including α smooth muscle actin (αSMA), which is expressed by the majority, but not all, of these cells. On the basis of tissue localisation and/or antigen profile different populations of MFs may be recognised: (a) activated, MF-like, hepatic stellate cells (HSC-MFs) found primarily in or around capillarised sinusoids of fibrotic/cirrhotic livers; (b) portal/septal MFs (PS/MFs) found in the connective tissue around expanded portal tracts or in the inner part of fibrotic septa; and (c) interface MFs (IF/MFs), found at the edge between fibrotic septa and the surrounding parenchyma.
Hepatic MFs can originate from different cellular sources: (1) activation of hepatic stellate cells [1–6] where HSC/MFs are likely to predominate in a pattern of 'perisinusoidal/pericellular fibrosis' and contribute to 'bridging fibrosis'; (2) activation of portal fibroblasts (that can give origin also to septal MFs), relevant in ischemic conditions and in obstructive cholestatic diseases and giving origin also to septal MFs; (3) MFs (IF/MFs and some portal MFs) may originate from recruitment of bone marrow derived cells [7] such as mesenchymal stem cells (MSCs) [8, 9] and circulating fibrocytes [10]; and (4) MFs, with a significant number of cells reported to be αSMA negative, may also originate by means of epithelial to mesenchymal transition (EMT) of hepatocytes and/or cholangiocytes [11, 12], although this possibility remains controversial.
Present knowledge on profibrogenic MFs is derived mainly from studies performed on human or rodent HSC/MFs [1–6, 13, 14]. Activation of HSCs in CLD progresses in sequential stages of initiation and perpetuation. Initiation is an early response stimulated by paracrine signals and leading to a transient and potentially reversible contractile and profibrogenic phenotype, characterised by rapid induction of platelet-derived growth factor (PDGF)β receptor and primed to respond to several growth factors and mediators that will be crucial in eliciting phenotypic responses operated by fully activated MF-like phenotype (perpetuation), including proliferation, migration/chemotaxis, contractility, excess deposition and altered remodelling of ECM (Figure 1).
Experimental models or material: advantages and limitations
Major advances in our understanding of fibrogenic mechanisms come directly from experimental studies. Studies on primary cultures of rat and human HSCs have dissected mechanisms and signalling pathways controlling the process of activation and related major phenotypic responses, in a scenario [1–6] that identifies these cells as crucial cellular crossroads in a complex sinusoidal environment requiring tightly regulated autocrine and paracrine crosstalk, rapid responses to evolving ECM content, and selective responsiveness to the metabolic needs imposed by liver growth and repair. This also includes evidence suggesting that HSCs may be essential for hepatic progenitor cell amplification and differentiation and be involved in antigen presentation and induction of tolerance. Emerging evidence suggesting that hepatic MFs may also originate from portal fibroblasts, the EMT process and bone marrow-derived cells represent the major limitation to these studies that theoretically may not represent an absolute paradigm for all the fibrosis patterns.
Similarly, rodent models of CLD [1–6, 13–22] including those taking advantage of knock-out or transgenic mice, have been instrumental in the mechanistic comprehension of major tissue, cellular and molecular mechanisms relevant to liver fibrogenesis as well as in identifying potential therapeutic targets. Although most of these pathogenic features have been confirmed in clinical conditions, major general limitations of animal models in relation to human CLDs [15, 23] are represented by the fact that the most reliable rodent models of CLD usually do not completely match either the histopathology or selected pathophysiological features of the corresponding human condition. For example [23], most common rodent models of NASH lack the development of obesity and insulin resistance (methionine and choline deficient (MCD) diet) or significant progression towards fibrosis (high fat diet). Moreover, when these models (chronic CCl4 administration, bile duct ligation) are discontinued, an almost complete reversion even from cirrhosis is detected; a scenario that can hardly apply to human cirrhosis.