Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury

Abstract

extracellular matrix reactive oxygen intermediates transforming growth factor-β1 Kruppel-like factor receptor tyrosine kinase discoidin domain receptor platelet-derived growth factor extracellular signal-regulated kinase endothelin-1 matrix metalloproteinase tissue inhibitor of metalloproteinase monocyte chemotactic protein-1 retinoic acid interleukin-10 Encapsulation of injury with fibrosis is a highly evolved response of adult tissues. In liver, the components of the process have been greatly clarified, leading to a coherent view of how wound healing occurs in response to injury. Hepatic fibrogenesis provides an important biological and clinical context for emerging concepts in molecular biochemistry that is relevant to many other tissues. Chronic injury leading to fibrosis in liver occurs in response to a variety of insults, including viral hepatitis (especially hepatitis B and C), alcohol abuse, drugs, metabolic diseases due to overload of iron or copper, autoimmune attack of hepatocytes or bile duct epithelium, or congenital abnormalities (1.Friedman S.L. Schiff E. Sorrell M. Maddrey W. Diseases of the Liver. 8th Ed. Lippincott-Raven, Philadelphia1998: 371-386Google Scholar). Typically, injury is present for months to years before significant scar accumulates, although the time course may be accelerated in congenital liver disease. Liver fibrosis is reversible, whereas cirrhosis, the end-stage consequence of fibrosis, is generally irreversible. Thus, efforts to understand fibrosis focus primarily on events that lead to the early accumulation of scar in hopes of identifying therapeutic targets to slow its progression. Like other parenchyma, the normal liver contains an epithelial component (hepatocytes), an endothelial lining (which in liver is distinguished by fenestrae or pores), tissue macrophages (Kupffer cells), and a perivascular mesenchymal cell called the stellate cell (previously called Ito cell, lipocyte, perisinusoidal cell, or fat-storing cell) (Fig. 1); stellate cells are the key fibrogenic cell (see next section). The cellular elements of liver are organized within the sinusoid, or microvascular unit, with the subendothelial space of Disse separating the epithelium (hepatocytes) from the sinusoidal endothelium. In normal liver this space contains a basement membrane-like matrix, although it is not electron-dense like a typical basement membrane. The normal subendothelial extracellular matrix (ECM)1 is essential for maintaining the differentiated function of all resident liver cells. Establishing the importance of the normal ECM in liver has illuminated recent attempts to develop artificial liver support by recognizing that all cellular elements and supporting structures (not just the hepatocyte compartment) must be reconstituted to preserve differentiated function of liver ex vivo (2.Mitaka T. Sato F. Mizuguchi T. Yokono T. Mochizuki Y. Hepatology. 1999; 29: 111-125Crossref PubMed Scopus (206) Google Scholar). As the liver becomes fibrotic, there are both quantitative and qualitative changes in composition of the hepatic ECM. The total content of collagens and noncollagenous components increases 3–5-fold, accompanied by the shift in the type of ECM in subendothelial space from the normal low density basement membrane-like matrix to interstitial type matrix containing fibril-forming collagens. Hepatic stellate cells comprise 15% of the total number of resident liver cells. In normal liver they are the principal storage site for retinoids (3.Wang X.D. Nutr. Rev. 1999; 57: 51-59Crossref PubMed Scopus (57) Google Scholar). Stellate cells constitute a heterogeneous group of cells that are functionally and anatomically similar but different in their expression of cytoskeletal filaments, their retinoid content, and their potential for ECM production (4.Knittel T. Kobold D. Saile B. Grundmann A. Neubauer K. Piscaglia F. Ramadori G. Gastroenterology. 1999; 117: 1205-1221Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar). Stellate cells have an intriguing embryologic origin, with recent evidence suggesting that they are neural crest-derived because they express glial fibrillary acidic protein and nestin (Ref. 5.Niki T. Pekny M. Hellemans K. Bleser P.D. Berg K.V. Vaeyens F. Quartier E. Schuit F. Geerts A. Hepatology. 1999; 29: 520-527Crossref PubMed Scopus (242) Google Scholar and references therein). A neural crest origin is further supported by studies in rat neural crest stem cells, which differentiate into myofibroblasts that express smooth muscle α-actin (6.Morrison S.J. White P.M. Zock C. Anderson D.J. Cell. 1999; 96: 737-749Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar), a marker of activated stellate cells. These observations raise the possibility of using neural crest-specific promoters to drive transgene expression selectively in stellate cells in vivo and the prospect of reconstituting stellate cells from a neural crest precursor as part of efforts t