Friedman (1) defines hepatic stellate cells as non-parenchymal quiescent cells which majorly function to store vitamin A. He notes that the cell also helps in maintaining the normal basement membrane-type matrix. After a long research by; the physiologists, pathologists and herpetologists; it has been revealed that the hepatic stellate cell has a role in hepatic injury. According to Friedman (1), hepatic stellate cell responds to liver injury by undergoing an activation process during which its vitamin A is lost. This makes the cells become highly proliferative triggering the synthesis of fibrotic matrix with type 1 collagen. The findings have helped the relevant medical expertise to come up with new therapies aimed at solving problems related to the fibrotic diseases. This write up will examine the location, physiology and the factors influencing this physiology.

Locations and physiology

This physiological process occurs in the liver. Sato, Suzuki and Senoo (102) noted that, in a normal situation, the sub-endothelial space of Disse contains the basement membrane’s components, which are normally low in density. They further explain that their replacement by the interstitial matrix which, on the other hand, is of high density causes a disturbance of the hepatocyte function. According to Friedman (2), this leads to the activation of the HSCs which further impairs the transport of solutes to the hepatocytes from the sinusoid in both fibrosis and cirrhosis. This causes the scar matrix to accumulate lading to the loss hepatocyte microvilli and the sinusoidal endothelial fenestrae. The result is a failure in the hepatic function which causes both the metabolic and the synthetic dysfunction.

riedman (2) notes that the HSC is the major source of ECM in the liver whether normal or fibrotic. He observes that the HSC are also the primary place where vitamin A is stored in the bodies. According to Friedman (2), the activation of the stellate cells is a key step in the process that results into the injury of the liver. The cells lose vitamin A thereby becoming highly fibrogenic. In cases of serious injuries, the stellate cell normally proliferates. This is normally followed by an influx of inflammatory cells which are associated with the subsequent accumulation of ECM. Presently, among the humans the stellate cells have been characterized in a number of liver diseases. These include; the alcoholic liver disease (Friedman, 2).

The activation of the Stellate Cells and Factors Affecting it

The activation of the stellate cells takes place in two phases; initiation and perpetuation. Initiation phase involves the paracrine-mediated changes in the expression of genes and phenotype which triggers the cells to respond to cytokines and stimuli. On the other hand, perpetuation is triggered by the effect of the actions of the stimuli in maintaining the now active phenotype while also generating fibrosis (Sato, Suzuki and Senoo, 103).

According to Friedman (2), it is the paracrine stimulation by different neighboring cells that triggers the first changes occurring in the stellate cells. The cells include hepatocytes, platelets, and leucocytes. Other key cells whose presence affects this process include the endothelial cells and the Kupffer cells. Friedman (2) notes that the endothelial cell normally participates in this process by producing cellular fibronectin and by activating the transforming growth factor (TGF) to its active form. The activation and infiltration of Kupffer cells stimulates the synthesis of matrix, the proliferation of the cell, and the activation of cytokines which is responsible for the release retinoid by the stellate cells. Kupffer cells also stimulate the lipid peroxides. Normally, the leucocytes transported to the liver during injury together with the Kupffer cells produce certain compound, which determines the behavior of the stellate cells.

According to Friedman (3), perpetuation of stellate cells activation involves a number of changes in the behavior of the cell. First, is proliferation which is the process by which PDGF receptors are induced in the process of the activation of the stellate cells. The second change process is brought about by chemo-taxis. It involves the migration of the stellate cells towards chemo-attractants. It partly explains the tendency of the stellate cells to align themselves within the inflammatory septa in vivo. Third change results from fibrogenesis which involves the increase in the production of matrix which allows the generation of the hepatic fibrosis by the stellate cells. Forth is contractility of the satellite cells which normally determines the increase in portal resistance during the liver fibrosis both in the earlier and the latter stages. The active cells from this process bar the portal blood flow by constricting the individual sinusoids and also by forcing the cirrhotic liver to contract (Friedman, 3).

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The next step is the degradation of the matrix which involves changes in matrix protease activity both qualitatively and qualitatively. Friedman (3) notes that this process plays a major role in the remodeling of ECM which accompanies liver injury. He also argued that because stellate cells express nearly every key component necessary in the process of the degradation of pathologic matrix, it plays a significant role both in the production of matrix and in its degradation. The next step involves the loss of retinoid/vitamin A droplets which is due to activation of the stellate cells. The loss of these droplets enables the stellate cells to attain a more fibroblastic appearance.

Friedman (3) identifies the last process as that of the release of the WBC chemoattractant and the cytokine. He argues that this process is critical for the perpetuation of the activation of the stellate cells by the autocrine and the paracrine. The stellate cells have the potential of inducing the infiltration of the leucocytes by amplifying the inflammatory response.

Stellate Cells in Anti-fibrotic Therapies in Humans and in Animals

Friedman (3) notes that the understanding of the process of the activation of the stellate cells has provided a significant framework which has made it possible for the definition of the sites or targets of anti-fibrotic therapy. Some of the identified strategies include prevention of injury by curing the primary disease, avoidance of the stimulation of the stellate cell activation by reducing inflammation or the response of the host, down regulating the activation of satellite cells directly, and the neutralization of proliferative, fibrogenic, contractile and any proinflammatory response by the stellate cells. Other strategies include; stellate cells apoptosis and those aiming at increasing the degradation of scar matrix.

Sato, Suzuki and Senoo (102), however, note that curing the primary disease has been identified as the most effective way of eliminating hepatic fibrosis. In this process, the major focus is on how to clear the primary cause of the liver disease. This calls for those who have liver disease to stop taking alcohol.

The second approach employed in the anti-fibrotic therapies is the use of various agents to reduce both the inflammation and immune response. Melton (3) gives an example of such agents as the corticosteroids which have for a long time been used in the treatment of various kinds of liver diseases. The third approach involves the inhibiting the activation of the stellate cells. This is normally done by reducing the oxidant stress which stimulates the activation process.

Stellate Cells in Anti-fibrotic Therapies in Animals

Friedman (4) notes that, in the animals’ model of fibrosis, it is the cytokines gamma interferon and the hepatocyte growth factor (HGF) that is being used. This is because they have the inhibitory effects on the stellate cell activation in the animals. Recent examinations are indicating that even though there is uncertainty surrounding the mechanism behind the anti-fibrotic activity of the HGF, there is an indication that it may be involving the inhibition of the activities of TGF-beta 1. Studies have also proved that deleting a variant of HGF is effective even if it is administered after the animal has contacted fibrosis. Guines, (14), however, notes that it is yet to be tried with large animals.

According to Friedman (6), the PPAR-gamma nuclear receptors are normally expressed in the stellate cells making it possible for the synthetic PPAR-gamma ligands to be used in the down-regulation of the activation of the stellate cell. He added that the activation of the stellate cells also results into the production of leptin. This means that animals which have reduced leptin will also experience reduced hepatic injury and fibrosis. Attempts aimed at elucidating and manipulating the actions of leptin in stellate cells to be used in therapies is ongoing.

Additionally, those who are against the use of TGF-beta are researching another possible way of carrying out the neutralization of the potent cytokine to allow the inhibition of the production of matrix and the acceleration of its degradation. In particular, the study of animal and culture through neutralization of cytokine are presently proving to be effective. Another treatment approach that has also been effective even in the case of animals is the use of various mechanisms in increasing the degradation of scar matrix (Strain, 441).


In conclusion, there is an indication that it will be possible for both the treatment and regulation of the fibrosis. However, this will demand more research in therapy and the cytokine inhibitors. Presently, little success has been realized as indicated by the existence of various methods for stellate cell-specific targeting animal models. Moreover, additional study on the role of hepatic stellate cell in fibrosis is necessary for better intervention measures.

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