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Bennaser and Bird: Hepatic stellate cell – vitamin A-rich cells

Hepatic stellate cell

Hepatic stellate cells (HSCs) were described first by Kupffer in the nineteenth century.1 He reported the finding of stellate cells in 1876 by using a gold chloride method that identified vitamin A droplets.2 Recently, HSCs have been considered to be mesenchymal cells with differing functions that are critical to the state of the liver and the response to liver injury.1 Confusion arose during research and reporting on HSCs owing to the different names in use to refer to these cells; in 1996, investigators in the field agreed to the standard name hepatic stellate cell to refer to the quiescent phase of the cell type found in a normal liver.1 This term is now widely accepted2 as an alternative to the former litany of names including perisinusoidal cell, Ito cell, lipocyte, parasinusoidal cell and fat-storing cell (FSC).

Hepatic stellate cells are located in the subendothelial space (space of Disse) between the basolateral surface of the hepatocytes and the endothelial cells that line the sinusoidal space. These cells represent approximately one-third of the non-parenchymal cell population and approximately 15% of the total number of cells in a normal liver.3 Some researchers have found a difference in the distribution of normal liver HSCs between species. In humans, there is a slight predominance of HSCs in the pericentral zone,4 whereas in porcine liver there is a higher concentration of HSCs in the periportal zone.5 The significance of these different patterns of cell distribution between species is not understood.1

In a normal human liver, stellate cells have spindle-shaped cell bodies with oval, or elongated, nuclei, the cytoplasm of which extends into the recesses between the neighbouring parenchymal cells. Additionally, each cell has a moderately developed rough endoplasmic reticulum, a juxtanuclear small Golgi complex6 and dendritic cytoplasmic processes.7 These dendritic cytoplasmic processes have numerous microprojections (spines) which wrap around the sinusoids between the endothelial cells and parenchymal cells.8 The significance of these spines was unclear until a recent study showed that they play a critical role as the leading edge of the cell by sensing chemotactic signals and mechanically transmitting the cell under a contractile force.9

A single HSC usually surrounds more than two sinusoids. On the anti-luminal surface of the cells, multiple processes extend from the HSC through the space of Disse to make contact with the hepatocytes.8 This close contact with the hepatocytes may facilitate the intercellular transport of soluble mediators and cytokines.1 HSCs also make direct contact with nerve endings,10,11 a finding which has emerged from papers identifying neurotrophin receptors.12 In addition, functional studies have also confirmed that HSCs display a neurohumoral response.1315

Hepatic stellate cells identification

Many antibodies have been developed for the different cytoskeletal and cell surface markers that have facilitated the extensive features of the stellate cell's phenotype. These markers revealed heterogeneity and plasticity in the adult liver, depending on their lobular location, the type of liver investigated (human or non-human) and whether the tissue was normal or injured. Desmin is an intermediate filament present in stellate cells16 and a marker of contractile cells. It has been widely used as a stellate cell marker in human and rodent liver; however, in human liver, the expression of desmin is inconsistent.17,18 This may be related to the distribution of desmin, i.e. desmin-negative cells may be concentrated in the pericentral zone whereas desmin-positive cells may be typically concentrated in the periportal zone.19 In the quiescent phase, the HSCs can also be detected by vitamin A contained within lipid droplets using vitamin A autofluorescence, which creates a rapidly fading blue-green fluorescence at 328 nm (Figure 1A).20 Lipid droplets also represent a characteristic morphological feature of these cells that can be detected in a normal liver (Figure1B).21 Von Kupffer originally described HSCs using a gold chloride method, which is a technique that was later modified.2 Using gold chloride staining on the human liver, a higher number of cells were detected in the centrolobular zone.22 Glial fibrillary acidic protein (GFAP) (Abcam, Cambridge, UK) is an intermediate filament marker for astrocytes which can be detected in normal stellate cells only, and for a period of up to 2 days after their isolation (Figure 2).23 Another stellate cell marker is actin, which comprises six isoforms including gamma (γ) and beta (β) non-muscle actin, known as cytoplasmic actin. In contrast, alpha-smooth muscle actin (α-SMA), α-cardiac, α-skeletal and γ-smooth muscle actin (γ-SMA) are considered tissue-specific actin isoforms.24 The enhanced expression of α-SMA is the most consistent marker of stellate cell activation as it is absent from other resident hepatocytes in normal or injured liver, with the exception of the smooth muscle cells surrounding large vessels, where it is present (Figure 3).1

FIGURE 1

(a) Vitamin A autofluorescence excited at 330 nm (the light blue regions). (b) Visualization of lipid droplets within the HSCs obtained from a Wistar rat liver incubated with Oil red O to stain lipid vesicles red. ×40 magnification. (These photos are the unpublished results of a research project by Sirag Bennaser in 2010.)

6-2-6-fig1.jpg
FIGURE 2

Immunocytochemistry reveals GFAP in quiescent HSCs at day 0. The regions that fluoresce green due to fluorescein isothiocyanate (FITC) represent the GFAP protein whereas the regions that are stained blue by 4′, 6-diamidino-2-phenylindole (DAPI) are the nuclei of the quiescent cells. ×20 magnification. Scale bar = 100 μm. (These photos are the unpublished results of a research project by Sirag Bennaser in 2010.)

6-2-6-fig2.jpg
FIGURE 3

Immunocytochemistry technique expressed actin filaments (Abcam, Cambridge, UK) in activated HSCs at day 10. The regions that fluoresce green due to FITC represent actin filaments whereas the regions that are stained blue by DAPI are the nuclei of the activated cells. ×20 magnification. Scale bar = 100 μm. (These photos are the unpublished results of a research project by Sirag Bennaser in 2010.)

6-2-6-fig3.jpg

There are continuous changes in gene expression during the fluctuating phenotype stages of a stellate cell. For instance, the quiescent cell has a pattern of gene expression that changes during the activated phase and that continuously changes during the myofibroblast-like phase. The pattern of gene expression changes in an ageing stellate cell to become more inflammatory and less fibrogenic.25 A study26 has reported the change from E-cadherin to N-cadherin in activated stellate cells during liver fibrosis, which suggests that HSC activation represents transdifferentiation from an epithelial to a mesenchymal phenotype (Table 1).26

TABLE 1

A summary of the HSC markers in the quiescent and activated phases

Marker Quiescent HSCs Activated HSCs
Desmin + in the periportal area of the liver lobule. However, outside this area, the positivity of desmin is approximately 50%
Vitamin A autofuorescence +
Lipid droplets +
GFAP +
α-SMA +
E-cadherin +
N-cadherin +

+, positive; −, negative.

Hepatic stellate cells function in normal and injured liver

In a normal human liver under standard physiological conditions, stellate cells store and transport vitamin A compounds and 50–80% of the total retinoid produced by the body is stored in these cells.27,28 Stellate cells also exert immunoregulatory activity by producing chemokines which promote monomorphonuclear and polymorphonuclear leucocyte infiltration, activate neutrophils and regulate lymphocyte populations.2,29 They express Toll-like receptors which cause HSC activation when interacting with bacteria.30,31 HSCs also act as antigen-presenting cells that activate T-lymphocytes.30,32 Stellate cells secrete, and respond to, a variety of cytokines (Table 2) and they modify the activity of various growth factors. Stellate cells also express adhesion molecules such as intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1 and neural cell adhesion molecule, and they mediate detoxification of ethanol and xenobiotics.2,33

TABLE 2

Cytokines associated with HCS activity. The expression and interaction of HSCs with a large variety of biological molecules allow them to mediate multiple activities and functions (adapted from reference 2)

Cytokines Cytokine actin
Transforming growth factors: TGFβl, TGFα Proliferative or fibrogenic
Platelet-derived growth factors: PDGF-B
Hepatocyte growth factor
Stem cell factor
Fibroblast growth factors: aFGF, bFGF
Vascular endothelial growth factor
Insulin-like growth factors: IGF-I, II
Endothelin-1: ET-1, endothelin-converting enzyme
Leptin
Plasminogen: urokinase plasminogen activator, plasminogen activator inhibitor-1
Fibrillar collagens: collagens I, II
Renin, angiotensin II
Macrophage colony-stimulating factor Chemotactic or inflammatory
Platelet-activating factor
CD40
Tumour necrosis factor α
Opioids
Toll-like receptor ligands: TLR4, CD14
Interleukin 6 Regenerative
Neurotrophins: NT-4, nerve growth factor, brain-derived neurotrophic factor
Interleukin 10 Antifibrogenic
Adiponectin
Follistatin
Fas signalling Apoptotic

Overall, stellate cells exhibit proliferation, chemotaxis, fibrogenesis, contractility, matrix degradation activity and retinoid loss when activated.1 They have roles in inflammation,34 cell survival and apoptosis,35 fibrinogenesis, matrix metalloproteinase expression, liver regeneration and monitoring of cellular pH.1

Stellate cells and liver fibrosis

Fibrosis is an overgrowth, hardening and scarring of connective tissue caused by excessive deposits of extracellular matrix components, including collagen. Myofibroblasts are a cellular source of fibrosis, which, when activated, become the primary collagen-producing cell. Myofibroblasts develop from different kinds of cells, for instance resident mesenchymal cells, developing epithelial and endothelial cells (termed epithelial–mesenchymal and endothelial–mesenchymal transition respectively) and circulating fibroblast-like cells called fibrocytes that are derived from bone marrow stem cells.36

Stellate cell activation refers to the alteration of a resting vitamin A-rich cell to one that is proliferating, fibrogenic and contractile, which is the main pathway of hepatic fibrosis.1 The activation of stellate cells consists of two major phases – initiation and perpetuation – which is then followed by the resolution of the fibrosis once the underlying cause subsides. The initiation phase, known as the preinflammatory stage, is associated with early changes in gene and phenotype expression that induce the cells to respond to cytokine stimulation. It begins primarily from paracrine stimulation, which is a result of changes in the surrounding extracellular matrix and the exposure to lipid peroxides and the products of damaged hepatocytes.1 In contrast, perpetuation involves maintaining the activated phenotype and fibrosis under the effects of these stimuli. Nonetheless, the resolution of fibrosis is related to pathways that lead the stellate cell to apoptosis or reversion to the quiescent phase.37

Hepatic stellate cells and clinical liver dysfunction

Extracellular matrix accumulation in the space of Disse produces a disruption of the normal, fenestrated microanatomy of the hepatic sinusoids. This mechanism is identified as the capillarization of the sinusoids38 that vitiate the normal bidirectional exchange between the portal venous blood and parenchymal cells. This causes toxic or nutrient substances to be degraded, or metabolized, by the hepatocytes and therefore to enter the bloodstream. In addition, this mechanism leads to problems that are mainly due to portal hypertension and declining hepatocellular synthetic function, for instance hyperbilirubinaemia, hepatic encephalopathy, hypoalbuminaemia and a deficiency of coagulation factors.39 An accumulation of data40 suggests that stellate cells also play a role in the regulation of portal venous blood and affect portal blood resistance. Strong evidence supports the view that portal hypertension may be partially created by the modulation of the contractile activity of stellate cells in the space of Disse under the effect of the vasoactive components.38 In the experimental field, portal hypertension can be reduced by 20–30% by using pharmacological agents. Currently, stellate cells are regarded as therapeutic targets to prevent and treat the complications of chronic liver disease.40

Hepatic stellate cells and tumour metastases

Hepatic stellate cells have a role in tumour growth and metastatic processes. Experimental studies on rats have reported that a conditioned medium from cultures of hepatocellular carcinoma hepatocytes could induce HSC activation.41 Injection of colon carcinoma cells in nude mice provoked the formation of hepatic metastatic foci and the activation of HSCs.42 The latter produced hepatocyte growth factor and transforming growth factor β1 (TGF-β1), which induced tumour cell migration and proliferation. Similarly, tumour cells secreted platelet-derived growth factors (PDGF)-A and PDGF-B and enhanced stellate cell locomotion and proliferation.42 In vitro experiments on melanoma cells that cause liver metastases concluded that tumour cells activate HSCs, which in turn promote angiogenesis through vascular endothelial growth factor expression.43 Experiments on rats44 showed that co-cultures of sinusoidal endothelial cells (SECs) and HSCs presented spontaneous differentiation, with HSCs forming the core of the cell population and SECs forming the surface. In vitro-activated stellate cells, cultured with SECs, expressed a functional smooth muscle cell phenotype and formed capillary-like structures in angiogenesis assays. Tumours may activate HSCs and therefore these studies44 implicated their mediation in neoangiogenesis through interactions with SECs. In hepatocellular carcinoma and colorectal liver metastases, most investigations are concerned with the activated HSCs that are responsible for the formation of cancer stroma and fibrotic capsules.45,46 In addition, in biliary malignancy and hepatocellular carcinoma, activated stellate cells contribute to the accumulation of tumour stroma.47,48 These results support those of the animal studies that suggested that activated stellate cells play a role in hepatic metastases,43,49 and cell culture studies have demonstrated paracrine activation of stellate cells by tumour cells.41

Conclusion

Hepatic stellate cells, also known as FSCs, reside in the space of Disse between hepatocytes and the hepatic sinusoids. In a normal human liver, the main function of HSCs is to store vitamin A as well as to produce extracellular matrix components. After liver injury, cytokines are stimulated following secretion from inflammatory cells, Kupffer cells and dysplastic hepatocytes. HSCs then undergo activation, which marks the transition from quiescent vitamin A-rich cells into proliferative, migrated, contractile and protein-synthesizing myofibroblasts that are regarded as the major cell type responsible for liver fibrosis.1 Myofibroblasts were recently postulated to be a component of the prometastatic liver microenvironment because they can transdifferentiate into highly proliferative and motile myofibroblasts that are implicated in the desmoplastic reaction and tumour growth.50 The activation of HSCs is a complex process regulated by multiple factors, for example TGF-β1 and PDGF signalling pathways, which may present as therapeutic targets in the prevention and treatment of liver metastases. It would be worth investigating whether targeting the HSCs/myofibroblasts with a growth factor antagonist in coordination with chemotherapy, radiotherapy and surgery would be effective in reducing liver metastases and increasing the survival rate of patients by targeting both tumour cells and the tumour milieu.51

Acknowledgement

I thank Dr NC Bird (Liver Research Group, Floor K, School of Medicine and Biomedical Sciences, Royal Hallamshire Hospital, University of Sheffield) for his guidance and advice in the preparation of this manuscript.

Notes

Disclosure

No author has any potential conflict of interest.

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