Matrix metalloproteinases (MMPs) are the enzymes responsible for matrix degradation in the liver . These are calcium-dependent enzymes that specifically degrade collagens and noncollagenous substrates. MMPs are divided into 5 categories according to their substrate :
1) interstitial collagenases (MMP-1, -8, -13),
2) gelatinases (MMP-2,-9, and fibroblast activation protein),
3) stromelysins (MMP-3, -7, -10, -11),
4) membrane type (MMP-14, -15, -16, -17, -24, -25), and
5) metalloelastase (MMP-12).
The degradation of normal extracellular matrix (ECM) is a key event in the process of liver fibrosis as it allows its replacement with scar matrix. Activated HSCs secrete large amounts of MMP-2 and MMP-9, which degrade the collagen type IV of normal ECM . They also express large amounts of MMP-1 mRNA, the principal MMP which degrades scar matrix (predominantly collagen type I), however little active enzyme is detectable in fibrotic liver . Tissue inhibitors of matrix metalloproteinases (TIMPs) are the main regulators (inhibitors) of MMP activity. HSCs produce large amounts of TIMP-1 and TIMP-2 and these prevent the degradation of the interstitial collagens of scar matrix by MMP-1. TIMP-1 also promotes HSC survival [42, 43].
Loss of Retinoids
A characteristic feature of stellate cell activation is the loss of retinoid (Vitamin A) droplets from the perinuclear region. The exact role that this plays in the transition from the quiescent to activated phenotype remains unclear.
1.2.2 Alternative Sources of Myofibroblasts
Recently it has been recognized that myofibroblasts are derived from a number of sources other than the quiescent HSC population. These sources include portal fibroblasts, circulating fibrocytes and the bone marrow. Epithelial-mesenchymal transformation (EMT) of both hepatocytes and cholangiocytes was also thought to contribute to the myofibroblast population however lineage tracing studies in experimental models of liver fibrosis have shown that this does not occur [44, 45]. EMT may, however, still play a role in malignant transformation and invasion in advanced injury.
a) Portal Fibroblasts
Myofibroblasts may also derive from portal fibroblasts found in the connective tissue surrounding blood vessels and the biliary tree  and these are thought to play a particularly important role in biliary fibrosis [47-49]. Beaussier et al  have shown that HSCs do not undergo myofibroblastic differentiation in biliary fibrosis and that portal myofibroblasts are the major contributors to the myofibroblast population in this form of injury. The portal myofibroblast population was initially identified as distinct from HSCs by their different growth characteristics in culture. Portal myofibroblasts can be subcultured several times whereas activated HSCs quickly undergo apoptosis [48, 50]. These observations aided in the identification of distinct gene-expression profiles which differentiate the two cell types. Both HSCs...