Hepatic Fibrosis -- Role of Hepatic Stellate Cell Activation

Scott L. Friedman, MD

Disclosures
In This Article

Extracellular Matrix

The Composition in Normal Liver and Hepatic Scar

The components of hepatic extracellular matrix (ECM) include several families of structural and supporting molecules: collagens, noncollagen glycoproteins, matrix-boundgrowth factors, glycosaminoglycans, proteoglycans, and matricellular proteins.[2] In the normal liver, collagens (types I, III, V, and XI) are largely confined to the capsule, the area around large vessels, and the portal triad, with only scattered fibrils containing types I and III in the subendothelial space. In advanced fibrosis, collagen content increases 3- to 10-fold.[3]

Biologic Activity in Liver

ECM is a dynamic regulator of cell function. Early, subendothelial matrix accumulation leading to "capillarization" of the subendothelial space of Disse is a key event, and may be more important than overall increases in matrix content (Figure 1). Normally, this space contains the components of a basement membrane. Replacement of the normally low-density matrix of basement membrane by high-density interstitial matrix directly perturbs hepatocyte function and activates HSCs. The latter may explain the synthetic and metabolic dysfunction[4] and the impaired transport of solutes from the sinusoid to hepatocytes[5] in advanced fibrosis and cirrhosis.

Figure 1.

Matrix and cellular alterations in hepatic fibrosis. Changes in the subendothelial space of Disse and sinusoid as fibrosis develops in response to liver injury include alterations in both cellular responses and extracellular matrix composition. Stellate cell activation leads to accumulation of scar (fibril-forming) matrix. This in turn contributes to the loss of hepatocyte microvilli and sinusoidal endothelial fenestrae, which result in deterioration of hepatic function. Kupffer cell (macrophage) activation accompanies liver injury and contributes to paracrine activation of stellate cells. (Reprinted with permission from Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000;275:2247-2250).

ECM can directly influence the function of surrounding cells through interaction with cell surface receptors, including integrins and nonintegrin matrix receptors (such as discoidin domain receptor 2). ECM can also indirectly affect cell function via release of soluble cytokines, which in turn are controlled by local metalloproteinases.

Cellular Sources of ECM in Normal and Fibrotic Liver

The HSC (previously called lipocyte, Ito, fat-storing, or perisinusoidal cell) is the primary source of ECM in normal and fibrotic liver; minor contributions by portal fibroblasts are likely, but their relationship to stellate cells is uncertain. HSCs are resident perisinusoidal cells in the subendothelial space between hepatocytes and sinusoidal endothelial cells[6,7]; they are the primary site for storing retinoids (vitamin A) within the body.

Stellate cell "activation" is a key event in liver injury, and refers to the transition from a quiescent vitamin A-rich cell to a highly fibrogenic cell. Cells with features of both quiescent and activated states are often called "transitional cells." Proliferation of stellate cells occurs in regions of greatest injury, and is typically preceded by an influx of inflammatory cells and associated with subsequent ECM accumulation.

Stellate cells have now been characterized in many human liver diseases. Alcoholic liver disease is the best-studied example of this characterization, with numerous reports documenting features of activation in situ.[8]

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