The Physiology of the Liver (original) (raw)
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Cooperation of Liver Cells in Health and Disease, 2001
, by the use of a gold chloride staining method, detected in mammalian livers a population of stellate-shaped cells that were located perisinusoidally, always attached to the sinusoidal capillaries and also to the parenchymal cells (Kupffer 1876, cited by Wake 1980). Although originally Kupffer thought that these cells belonged to perivascular cells of connective tissue, after 20 years he changed his mind and suggested that the cells were a special kind of phagocytic endothelial cells (see discussion by Wake 1980). The cells he described, however, appear to be the perisinusoidal cells, which express quite different functions than liver macrophages (Wake 1971; Wake et al.1989). These cells had been rediscovered after almost 80 years and named Ito cells after one of the persons who described them (Ito and Nemoto 1952). Ito cells are known by a variety of synonyms (vitamin A-storing cells, lipocytes, fat-storing cells, liver-specific pericytes, perisinusoidal cells) reflecting their functions; however, the term "hepatic stellate cells" (HSC) has been recently most often used. 5.1 Morphology of Stellate Cells in Liver Sections Hepatic stellate cells (HSC) are located in the perisinusoidal (Disse) space in direct vicinity to the endothelial cell layer with their cell bodies often compressed into the recesses between hepatocytes. Stellate cells are not engulfed by a true basement membrane unlike typical pericytes in blood capillaries (Wake 1980; Wisse et al.1985). They have two types of cytoplasmic extensions: the intersinusoidal or interhepatocellular processes (Fig. 3), which penetrate the hepatic cell plates and may reach the nearby sinusoids, and shorter perisinusoidal or subendothelial processes that encircle the sinusoid, thus reinforcing its wall (Wake 1988). The processes of HSC contain a prominent cytoskeleton oriented along their long axes, and several ultrastructures like mitochondria, vesicles, rough endoplasmic reticulum, and glycogen particles (Geerts et al.1990). A single stellate cell may provide such processes to more than one neighboring sinusoid and make contact with a great number of hepatocytes (Wake 1980). The most characteristic structural feature of stellate cells is the presence in the cytoplasm of numerous, large (up to 8 jlm in diameter) lipid droplets, which exist in membrane bound and nonmembrane bound forms (Wake 1980), and are composed of retinoids (mainly retinyl palmitate), triglycerides, cholesterol, and free fatty acids (Vogel et al. 1999). The formation, size, and number of lipid droplets depend on physiological circumstances, species, and dietary vitamin A intake (Vogel et al.1999).
On the presence of hepatic stellate cells in portal spaces
Memórias do Instituto Oswaldo Cruz, 2005
Previous studies in mice with hypervitaminosis A have demonstrated that fat-storing cells (hepatic stellate cells-HSCs) participate in schistosomal granuloma fibrogenesis. The origin of such cells in portal areas, away from the Disse spaces, was herein investigated. HSCs were identified in frozen sections of the liver by means of Sudan III staining. They appeared as red-stained cells disposed along the sinusoids of normal mice, but were never found within portal spaces. However, in the chronically inflamed portal spaces of Capillaria hepatica-infected mice, Sudan III-positive cells were frequently present among leukocytes and fibroblast-like cells. Thus, there are no resident HSCs in portal spaces, but their presence there in chronic inflammatory processes indicates that they are able to migrate from peri-sinusoidal areas in order to reach the portal areas.
Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers
Journal of Hepatology, 2002
Background/Aims: Hepatic stellate cells (HSC) are commonly considered the precursor population of septal myofibroblasts (MF) in cirrhosis. We studied the distribution and expression profile of mesenchymal (myo)fibroblast-like populations in fibrotic and cirrhotic liver, in an attempt to elucidate their possible interrelationships.
Liver cirrhosis and hepatic stellate cells
Acta Cirurgica Brasileira, 2006
The cirrhosis represents the final stage of several chronic hepatic diseases and it is characterized by the presence of fibrosis and morphologic conversion from the normal hepatic architecture into structurally abnormal nodules. In the evolution of the disease there is loss of the normal vascular relationship and portal hypertension. There are also regenerative hepatocelular alterations that become more prominent with the progression of the disease. The liver transplantation continues to be the only therapeutic option in cases of disease in terminal phase. The hepatic stellate cells (HSC) are perisinusoidal cells that store vitamin A and produce growth factors, citocins, prostaglandins and other bioactive substances. They can suffer an activation process that convert them to cells with a phenotype similar to myofibroblasts. When activated, they present increased capacity of proliferation, mobility, contractility and synthesis of collagen and other components of extracelular matrix. ...
Cooperation of Liver Cells in the Process of Liver Fibrosis
Advances in Anatomy Embryology and Cell Biology, 2001
Fibrosis is the common response to chronic liver injury from various origins including metabolic diseases, viral infections, alcohol abuse, and various chemicals. Liver fibrosis is characterized by both quantitative and qualitative changes in the composition and distribution of extracellular matrix (ECM) that are reflected by a three-to fivefold net increase of ECM and replacement of low-density basement membranelike material by interstitial type matrix abundant in fibril-forming collagens {Friedman 1993; Gressner 1998). This gross remodeling of ECM in the fibrotic liver represents an imbalance between the deposition and degradation of ECM molecules. Hepatic stellate cells, which are involved in the regulation of ECM production and degradation (Table 10), have been found to play a pivotal role in the initiation and progression of hepatic fibrosis (Friedman 1993, 2000; Gressner 1998). Following acute or chronic liver injury, hepatic stellate cells transdifferentiate: they proliferate, lose lipid droplets, change morphology from the star-shaped cells to that of myofibroblasts with the expression of smooth muscle a-actin (reviewed by Gressner 1998), and migrate to sites of tissue damage (Ikeda et al. 1999; Marra et al. 1998b). Activation of stellate cells that initiates the development of the inflammatory process results from multiple interactions between many cell types (injured hepatocytes, Kupffer cells, endothelial cells, platelets, infiltrating inflammatory cells) mediated by cytokines and reactive oxygen species, and from the changes in the composition of the perisinusoidal matrix (Arthur 2000; Gressner 1998). In the case of chronic liver damage, HSC activation persists during the "perpetuation phase" (Friedman 1993; Gressner 1998), and progressive accumulation of ECM leads to liver fibrosis, and finally to cirrhosis. The key role of hepatic stellate cells in the development of liver fibrosis may be deduced from the correlation between the number of HSC and the extent of liver fibrosis observed both in experimental liver injury (Friedman 1993) or in patients with chronic hepatitis C treated with interferon (Sakaida et al.1999). 14.1 Factors Involved in the Activation of Hepatic Stellate Cells Fibrogenesis is regarded as a dynamic process related to the extent and duration of parenchymal cell injury. The cascade of events that leads in vivo to the development of liver fibrosis is initiated by noxious agents that may be different in various kinds of liver damage.lt is, however, widely believed that injury to hepatocytes and/or Kupffer and endothelial cells results in the release of many substances that cause transformation of quiescent stellate cells into myofibroblast-like cells. The activation ofHSC may 97
Hepatic Stellate Cells and Liver Fibrosis
Comprehensive Physiology, 2011
Hepatic stellate cells are resident perisinusoidal cells distributed throughout the liver, with a remarkable range of functions in normal and injured liver. Derived embryologically from septum transversum mesenchyme, their precursors include submesothelial cells that invade the liver parenchyma from the hepatic capsule. In normal adult liver, their most characteristic feature is the presence of cytoplasmic perinuclear droplets that are laden with retinyl (vitamin A) esters. Normal stellate cells display several patterns of intermediate filaments expression (e.g., desmin, vimentin, and/or glial fibrillary acidic protein) suggesting that there are subpopulations within this parental cell type. In the normal liver, stellate cells participate in retinoid storage, vasoregulation through endothelial cell interactions, extracellular matrix homeostasis, drug detoxification, immunotolerance, and possibly the preservation of hepatocyte mass through secretion of mitogens including hepatocyte growth factor. During liver injury, stellate cells activate into alpha smooth muscle actin-expressing contractile myofibroblasts, which contribute to vascular distortion and increased vascular resistance, thereby promoting portal hypertension. Other features of stellate cell activation include mitogen-mediated proliferation, increased fibrogenesis driven by connective tissue growth factor, and transforming growth factor beta 1, amplified inflammation and immunoregulation, and altered matrix degradation. Evolving areas of interest in stellate cell biology seek to understand mechanisms of their clearance during fibrosis resolution by either apoptosis, senescence, or reversion, and their contribution to hepatic stem cell amplification, regeneration, and hepatocellular cancer.
Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver
Physiological reviews, 2008
The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.
Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension
Gut, 2002
Accumulating evidence suggests that stellate cells are involved in the regulation of the liver microcirculation and portal hypertension. Activated hepatic stellate cells have the necessary machinery to contract or relax in response to a number of vasoactive substances. Because stellate cells play a role in both fibrosis and portal hypertension, they are currently regarded as therapeutic targets to prevent and treat the complications of chronic liver disease.
Intralobular heterogeneity of perisinusoidal stellate cells in porcine liver
Cell & Tissue Research, 1993
The aim of the present investigation was to elucidate the intralobular heterogeneity of the perisinusoidal stellate cells (fat-storing cells, lipocytes) in the porcine liver. Their three-dimensional structure, desmin immunoreactivity and vitamin-A storage were studied by use of the Golgi silver, immunocytochemical and gold chloride methods. In order to locate the stellate cells, the hepatic lobules were divided into 10 zones. The stellate cells were readily identified in Golgi preparations by their striking dendritic appearance with branching processes encompassing the sinusoids. The stellate cells in the centrolobular zones were conspicuously dendritic with longer processes in comparison to those emitted by periportal elements. Such arborizations were studded with numerous thorn-like microprojections. Desmin immunoreaction in the periportal zones was stronger than that in the centrolobular zones. Vitamin-A storage in the stellate cells was well developed in zones 2-4, but reduced gradually toward the central region. The perisinusoidal stellate cells display marked heterogeneity in morphology and function based on their zonal location in the hepatic lobule.
Biochemistry and Cell Biology-biochimie Et Biologie Cellulaire, 2001
Hepatic stellate cells are intralobular connective tissue cells expressing the myofibroblast or the lipocyte phenotypes. They participate in homeostasis of the liver extracellular matrix, repair, regeneration, and fibrosis under the former phenotype, and control the retinol metabolism, storage, and release under the latter one. They are heterogeneous in terms of their tissue distribution, function, and expression of cytoskeletal proteins. We have studied the expressions of intermediate filaments in the cloned GRX cell line representative of murine hepatic stellate cells, by immunolabeling, reverse transcription polymerase chain reaction (RT-PCR), immunoprecipitation and Western blots. GRX cells expressed vimentin, desmin, glial fibrillary acidic protein (GFAP), and smooth muscle α actin (SM-αA). Vimentin, desmin, and SM-αA were expressed in all cultures. GFAP showed a heterogeneous intensity of expression and did not form a filamentous cytoskeletal network, showing a distinct punctuate cytoplasmic distribution. When activated by inflammatory mediators, GRX cells increased expression of desmin and GFAP. Retinol-mediated induction of the lipocyte phenotype elicited a strong decrease of intermediate filament protein expression and the collapse of the filamentous structure of the cytoskeleton. Quiescent hepatic stellate precursors can respond to physiologic or pathologic stimuli, expressing activated myofibroblast or lipocyte phenotypes with distinct patterns of cytoskeleton structure, metabolic function, and interaction with the tissue environment.