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Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinase and Matrix Turnover and the Fate of Hepatic Stellate Cells

and *.

* Corresponding Author: Southampton University School of Medicine, Department of Hepatology, Liver Research Group, IIR, South Block , Southampton General Hospital, Tremona Road, Southampton, SO 16 6YD, U.K. Email: jpi@soton.ac.uk

Liver injury is associated with activation of hepatic stellate cells (HSC) to a myofibroblast-like phenotype. In cirrhotic liver injury, activated HSCs are the major source of fibrillar collagens, an excess of which characterise fibrotic matrix. HSCs also have the capacity to remodel this matrix as they express matrix metalloproteinases (MMPs) and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Recovery from acute and chronic injury is characterized by apoptosis of the TIMP expressing HSCs thereby relieving the inhibition of matrix degradation. HSC apoptosis is regulated in progressive injury and counterbalances cell proliferation. Apoptosis probably also represents a default pathway for the HSCs resulting from the withdrawal of survival signals after cessation of injury. The survival of activated HSCs in liver injury is dependent on soluble growth factors and cytokines, and on compontents of the fibrotic matrix itself. Additionally, stimulation of death domain receptors expressed on HSCs can precipitate their apoptosis.

Introduction

In many respects, liver fibrosis can be considered to be a model for solid organ wound healing. There is increasing evidence in models derived from other organs and the skin that demonstrate common features in the processes of inflammation, repair and resolution. Specifically the response to tissue damage is associated with activation of myofibroblasts, the secretion of fibrillar collagens to effectively mediate repair and, with withdrawal of the injurious stimulus, resolution. Resolution is characterized by degradation and remodelling of the fibrillar collagens with the restitution of normal architecture.1,2 In association with this there is reepithelialisation as well as loss of the myofibroblasts through apoptosis.3 In liver injury, the wound healing myofibroblasts are derived in major part from activated hepatic stellate cells, although there may also be contributions from peri-portal myofibroblasts.4,5

With the advent of effective treatments for chronic liver disease, most importantly the development of interferon and other anti-virals for the treatment of chronic viral hepatitis, there is increasing evidence that liver fibrosis is, at least in part, reversible.6 Models of liver fibrosis in animals have provided key experimental data which identify the events determining resolution. 7 Prominent amongst these is loss of the activated hepatic stellate cells through apoptosis. This has the effect of removing the major source of fibrillar collagen. Increasing evidence indicates that stellate cell apoptosis is determined by an imbalance in the presence of survival factors and pro-apoptotic stimuli. Amongst these, there is evidence for a role for soluble factors providing survival stimuli and critical changes to the matrix providing survival signals.2,8 In addition, soluble pro-apoptotic factors have been demonstrated to impact on stellate cells which express a variety of receptors for ligands of the TNF receptor super family.8-10

A Brief Review of the Role of Activated Stellate Cells/Myofibroblasts in Hepatic Fibrosis

Liver fibrosis can be considered as a paradigm for wound healing elsewhere in the body. In response to injury, virtually regardless of the insult, the hepatic stellate cell, which is normally a noncycling, quiescent vitamin A storing cell lying in the space of Disse, becomes activated to a myofibroblast-like state (the so called ‘activated stellate cell).11-13 When activated these cells express a variety of cytoskeletal markers, including α smooth muscle actin.10,14 In addition, the cells enter the growth cycle with the result that the number of activated stellate cells present within the space of Disse and ultimately, in more extensive areas of bridging fibrosis, increases. Stellate cell activation is mediated via the impact of soluble factors secreted by facets of the inflammatory response in addition to products released by damaged hepatocytes and critical changes to the sub-cellular matrix. Once activated, the stellate cells exhibit a number of autocrine and paracrine functions, several of which perpetuate the activation state.15 These include expression of transforming growth factor β-1.15 Stellate cell expression of type 1 collagen is significantly upregulated whilst concurrently its degradation is inhibited by expression of TIMPs 1 and 2. However stellate cells also express MMPs, including those with collagenase activity demonstrating the latent capability that the liver has for matrix degradation. Therefore changes in phenotype and cell behaviour leading to the laying down of matrix proteins in which a fibrillar matrix critically predominates depend on the balance between these factors.

Previously considered irreversible, there are extensive (albeit anecdotal or numerically small clinical trials) which have documented an improvement in overall liver fibrosis as a result of the effective treatment of underlying liver disorders. These examples include venesection in haemochromatosis and effective immunosuppression in autoimmune chronic active hepatitis.16 With the advent of effective anti-viral treatments, however, the first evidence based on large scale studies is available and is providing compelling evidence for at least partial reversibility of fibrotic change in successfully treated patients in whom viral eradication occurs.6,16 It is important to note, however, that evidence for a reversal of cirrhotic change is as yet incomplete. Indeed compelling histological evidence for reversal of cirrhosis has yet to be demonstrated. Moreover, animal models of advanced cirrhosis do not demonstate the complete resolution observed in models of fibrosis.17,18 In each of these examples, resolution may take months or years but the improvement in overall histology and the net loss of fibrotic tissue must, by definition, be associated with a net loss of activated hepatic stellate cells. An alternative view is that there may be a change in activation status of the hepatic stellate cells. However, in none of these examples is there evidence of increased numbers of quiescent hepatic stellate cells present in the recovered liver. Furthermore, there is good evidence for resolution of injury being associated with the loss of hepatic stellate cells in the acute setting. Following paracetamol (acetaminophen) injury, in areas of necrosis and inflammation, stellate cells become activated and α smooth muscle actin positive. Successful resolution following conservative treatment was associated with a return to normal histological appearance with a loss of these actin expressing cells. Therefore, this study provides direct evidence that resolution of injury is associated with a reduction in the number of α smooth muscle positive myofibroblast cells.1

Animal models complement these human models of resolution of liver disease. Exposure of rodents to chronic CCl4 intoxication results in the development of fibrosis and ultimately cirrhosis over a period of four to twelve weeks. The resulting scars link vascular structures and are populated by large numbers of activated stellate cells which have proliferated in response to the injurious and inflammatory stimuli. Following induction of an advanced fibrosis or early cirrhosis (4 to 8 weeks of CCl4 intoxication) spontaneous resolution occurs with a restitution of normal liver architecture and loss of the activated stellate cells over a period of 28 to 168 days. This process of resolution is accompanied by a decrease in the hepatic expression of TIMP-1 and an increase in overall hepatic collagenase activity.7

A similar change can be demonstrated following the induction of bile duct ligation induced fibrosis if the ligated bile duct is successfully reanastomosed to the jejunum with resulting biliary decompression.2,19 In each of these models, the loss of α smooth muscle actin positive activated stellate cells is mediated by apoptosis. Thus, resolution is characterised not only by changes in the pattern of matrix degradation but by apoptosis of myofibroblast-like activated hepatic stellate cells. This process serves the dual function of removing the major matrix-producing cell whilst at the same time removing the cells that are expressing TIMPs and thus inhibiting matrix degradation. We have subsequently gone on to demonstrate the beneficial effects of removing activated hepatic stellate cells by inducing apoptosis using the fungal metabolite gliotoxin. When this toxin is given to rats during chronic CCl4 induced injury, apoptosis of stellate cells rapidly ensues with significant decrease in the overall number of activated hepatic stellate cells and a reduction in the width of fibrotic septa.2,20 This work has recently been corroborated in several other laboratories.2,21-23 In addition, in data as yet unpublished, we have gone on to demonstrate that induction of activated stellate cell apoptosis via NGF stimulation (see below) also results in amelioration of the fibrotic response.

The Regulation of Hepatic Stellate Cell Apoptosis

Apoptosis is a major regulatory mechanism active in mammalian tissues which removes unwanted cells when they become too numerous, redundant or potentially damaging, e.g., oncogenesis. There is evidence for a constant background of apoptosis in activated hepatic stellate cells during liver injury and it is likely that this is a major mechanism regulating overall stellate cell numbers. In common with other cells, stellate cells demonstrate susceptibility to apoptosis induced via two basic intracellular pathways. These include stimulation of specific cell surface receptors which carry a so-called death domain, e.g., Fas (CD-95, AP0-1). Exposure of the cell to the relevant ligand results in activation of the death receptor and activation of the intracellular cascade which may result in apoptosis. Although activation of the caspase cascade leading to the activation of caspase-3 is frequently an effective means of inducing apoptosis, this pathway is, nevertheless susceptible to modification and inhibition.24 The second major pathway involves the stability and integrity of the mitochondrial membrane. Pro and anti-apoptotic proteins, present in the mitochondrial membrane, (e.g., BCL-2 family members) are imbalanced. When pro-apoptotic proteins predominate and are allowed to homo-dimerise, cytochrome C is released from the mitochondrion which complexes with APAF-1 resulting in activation of specific caspases and apoptotic death of the cells. The balance of mitochondrial membrane proteins is regulated in major part via specific signals received by the cell, including those derived from soluble factors and cell-cell and cell-matrix interactions.25

The stellate cell fits very nicely the model proposed by Raff26,27 in which a cell is imminently prone to undergo apoptosis as the default position but this process is forestalled by the presence of survival signals. These signals may be derived from the cellular environment in the form of soluble growth factors and cytokines, or in the example of hepatic stellate cell from the matrix (see below). During the resolution of injury, apoptosis will ensue when these survival factors fall below a critical level and the balance of pro and anti-apoptotic factors in the cells shift.

Soluble Cytokines and Survival Factors in the Regulation of Stellate Cell Apoptosis

Several cytokines and growth factors released during liver cell injury may impact on stellate cells apoptosis. These include IGF-1 released in an autocrine manner by damaged hepatocytes and by stellate cells.28,29 IGF-1 is a powerful survival factor for stellate cells and may act in concert with other soluble factors.30-33 There is published evidence to suggest that tumour necrosis factor (TGF)-β1 may also regulate stellate cell survival, as may TNFα, although the latter may mediate its effect via fas/fas ligand (see below).34

The Role of TNF Receptor Super Family Members in Mediating Stellate Cell Apoptosis and Survival

Several members of the TNF receptor super family bear a so-called death domain and are caspase activating, when stimulated with the appropriate ligands. Stellate cells have been described to express fas (CD-95 APO-1) and to respond to fas ligand by undergoing apoptosis.8,35 Stellate cells have also been reported to express fas ligand itself, a product which is cleaved by metalloproteinases to yield a soluble cell signal. Thus, it is possible that stellate regulate their own survival via this autocrine loop.9,34,36 We, and others, have also described the expression of a further member of the TNF receptor super family, low affinity nerve growth factor receptor (LANGFR) or p75. LANGFR/p75 is expressed by activated stellate cells which undergo apoptosis in response to nerve growth factor.8-10,37-41 Subsequent studies using a model of self-limiting fibrotic injury have indicated that during resolution and particularly whilst undergoing proliferation, hepatocytes are a potent source of NGF. Thus we have demonstrated a potential paracrine loop in which the injured liver by regenerating hepatic epithelium affects apoptosis of hepatic stellate cells via NGF.42

Matrix Stability and the Role of Tissue Inhibitor of Metalloproteinases in Mediating Stellate Cell Survival

Because of the close correlation between TIMP expression within the liver and survival of hepatic stellate cells, we have directly addressed whether TIMP-1 may act as survival factor for hepatic stellate cells. Previously, evidence from oncological studies indicated that TIMP-1 may mediate survival of specific tumours, although intriguingly these effects appeared independent of MMP inhibitory activity.43 In tissue culture models of activated hepatic stellate cells, TIMP-1 acts as a potent pro survival factor for stellate cells.44 By using TIMP-1 bearing a critical mutation (resulting in a failure to bind and then inhibit MMPs) we have demonstrated that MMP inhibitory activity is necessary for the anti-apoptotic effect of TIMP-1 for hepatic stellate cells.45 This work has highlighted a potential link between MMP activity and stellate cell apoptosis. Specifically it poses the question, what are the critical MMPs and what are the MMP substrates that these MMPs are acting upon that impact on activated stellate cell survival?

We have gone on to examine two potential substrates which may act as survival factors for stellate cells. N-cadherin has been shown to mediate cell-cell contacts in fibroblasts and promote survival in 3T3 cells.46 In addition, MMP inhibitors have been shown to upregulate N-cadherin function and promote survival in fibroblasts. In unpublished studies we have demonstrated that activated hepatic stellate cells express N-cadherin and antibody-mediated blockade of N-cadherin promotes stellate cell apoptosis. Analysis of N-cadherin structure by Western blotting, during stellate cell apoptosis, indicates that N-cadherin cleavage is an early apoptotic event. Moreover, immunostaining demonstrates loss of intact N-cadherin from the cell surface early in stellate cell apoptosis. Addition of wild-type active TIMP-1 results in a reduction of stellate cell apoptosis, both in response to a stress such as serum deprivation and in response to a specific apoptogen such as gliotoxin or cyclohexamide. This is accompanied by a decrease in the cleavage of N-cadherin detected by Western analysis. In contrast, parallel experiments undertaken with the mutated TIMP-1 demonstrate persistent cleavage and enhanced level of apoptosis. We have identified that a synthetic MMP-2 inhibitor will also prevent a cleavage of N-cadherin suggesting that this enzyme, which is released and activated by apoptotic hepatic stellate cells may be responsible for cleavage of N-cadherin. Further experiments in which recombinant MMP-2 have been added to stellate cells demonstrate both cleavage of N-cadherin and enhanced apoptosis.43,44,47

A further substrate, likely to impact on stellate cell apoptosis is collagen-1. There is an extensive literature suggesting that matrix may dramatically regulate stellate cell function.21-23,48 Indeed we and others have recently demonstrated that stellate cells can be reverted to quiescence by culture on a model basement membrane like matrix Engelbreth-Holm-Swarm (EHS). In contrast stellate cells plated on to type 1 collagen maintain α smooth muscle actin positivity and demonstrate a propensity to apoptosis on withdrawal of growth factors. Intriguingly, expression of the anti-apoptotic protein, Bcl-2 appears throughout regulated by sub-cellular matrix. Indeed, plating hepatic stellate cells onto EHS matrix results in enhanced expression of Bcl-2 in contrast to cells plated on to Type 1 collagen.49-51 Because of the tight correlation between Type 1 collagen degradation and stellate cell apoptosis in vivo, we have studied the role of collagen-1 as a survival factor using a transgenic in vivo model. The rr collagen mouse contains a targeted mutation of the collagen-1 gene which results in the secretion of a gene product resistant to cleavage mediated by MMP-2, MMP-8 or MMP-13. Using these mice in comparison to wild type counterparts, we have induced reversible fibrosis by giving 8 weeks of CCl4. Animals were then allowed to recover for periods of up to 28 days. Wild type animals demonstrated a significant resolution of the fibrotic change in association with which stellate cell apoptosis resulted in clearance of the α smooth muscle positive activated hepatic stellate cells. In contrast, there was persistence of fibrotic change in the mutant animals, indicating a failure of degradation of the collagenase resistant collagen-1, in association with which activated stellate cells persisted within the liver and there was a failure of hepatocellular regeneration.51

This study provides very cogent evidence that collagen-1 may be a specific survival factor for stellate cells. We have gone on to analyze the integrin which bind to stellate cells and have demonstrated that wild type collagen-1 promotes the activated phenotype and proliferation of stellate cells via interaction with β-1 integrins and αVβ3. However, as noted above, this phenotype is associated with a propensity to apoptosis and blockade, particularly of αVβ3 is associated, not only with a decrease in proliferation, but a significant increase in apoptosis.51,52

Taken together, this provides cogent evidence for a link between the persistence of collagen- 1 rich matrix and stellate cell survival. In contrast, with effective degradation of collagen-1, stellate cells are rendered susceptible to apoptotic stimuli or undergo a critical change in the balance of survival and pro-apoptotic factors resulting in their entering the apoptotic pathway.

These latter observations have led us to postulate that critical changes, involving modification of the matrix, may, therefore, result in persistent fibrosis and potentially persistence of hepatic stellate cells, even after withdrawal of injurious stimuli. Advanced cirrhosis is characterised by the presence of fibrotic bands linking vascular structures and regenerative nodules of hepatic parenchyma. Whilst there is good evidence for a reduction in the overall level of fibrosis following successful anti-viral eradication, there is, as yet, no absolute evidence that cirrhosis will undergo complete resolution. Moreover, studies of human liver disease suggest that in the presence of a micronodular cirrhosis, withdrawal of the injurious stimulus may result in degradation of the least mature matrix and a retreat of the pathological pattern to an attenuated macronodular cirrhosis. To complement these observations and to determine whether matrix modifications impact on reversibility, we have recently developed a further novel of advanced micronodular cirrhosis.17,18,53,54 In rats, given CCl4 for 12 weeks, a micronodular cirrhosis results. Although there is a significant improvement over a year of spontaneous recovery, significant fibrosis persists in the form of an attenuated macronodular cirrhosis. Analysis of the persistent fibrosis suggests that these are areas of the most mature fibrosis and are characterised by the presence of elastin and tissue transglutaminase mediated crosslinks. Stellate cells persist in these fibrotic bands although, after protracted recovery, the numbers of α smooth muscle actin positive stellate cells within the bands are limited and the persistent cells express predominantly Glial Fibrillary Acidic Protein and desmin alone.18

Summary

A wealth of evidence indicates the activated hepatic stellate cell is central to the pathogenesis of liver fibrosis, being both the major source of matrix, particularly fibrillar collagens, and the major source of the metalloproteinase inhibitors which prevent degradation of that matrix. Other myofibroblast lineages likely to contribute to the hepatic scar and may be derived from stem cells and other endogenous liver myofibroblasts. Current evidence suggests that functionally this population contribute in a broadly similar way to the hepatic scar. Spontaneous recovery from liver fibrosis and the associated resolution of fibrotic change is accompanied by apoptosis of hepatic stellate cells. Our current model shows that activated hepatic stellate cells are prone to apoptosis but that this is forestalled by the presence of survival factors. During recovery, the balance of survival factors versus pro-apoptotic stimuli shifts with the result that the cells initially become prone to apoptosis and ultimately enter the apoptotic pathway as a result of loss of survival factors. There is evidence that these survival factors may be derived from inflammatory cells and injured hepatocytes in addition to critical changes in the matrix and the stabilisation of cell-cell receptors such as N-cadherin. With resolution, there is evidence for expression of pro-apoptotic stimuli including Nerve Growth Factor and with withdrawal of stimuli from injured cells and the inflammatory infiltrate, stellate cell apoptosis ensues. Critical changes in the matrix resulting in the loss of fibrillar collagen, particularly collagen-1, may also then result in stellate cell apoptosis. Stabilisation of the matrix via crosslinking may limit the propensity for histological resolution and functional restitution.

By understanding the processes that regulate hepatic stellate cell apoptosis, we will define the attributes of an effective anti-fibrotic agent and inform the development of future anti-fibrotic strategies.

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