Vitamin A-containing lipocytes and formation of type III collagen in liver injury.

Kent, Geoffrey; Inouye, Tohru; Bahu, Raja M.; Minick, O. T.; Pópper, Hans

doi:10.1073/pnas.73.10.3719

Cited by 286 publications

(121 citation statements)

References 11 publications

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“…The role of Type 111 collagen or "reticulin" is not known although it may be hypothesized that it forms a temporary grid for the organization and spatial arrangement of Type I collagen. The possibility also exists that the scleroderma fibroblast initially synthesizes Type 111 collagen and then "switches" to the synthesis of Type I collagen as seen in wound healing (16) and liver cirrhosis (17). In this regard Gay et al (19) of collagen types and ferritin immunoelectron microscopy with anticollagen antibodies are currently in progress.…”

Section: Discussionmentioning

confidence: 99%

Collagen in the cellular and fibrotic stages of scleroderma

Fleischmajer

Meigel

Perlish

1978

Arthritis & Rheumatism

106

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The collagen in localized and systemic scleroderma skin was studied by light microscopy with silver impregnation (50 patients), electron microscopy (14 patients), and immunofluorescence microscopy using specific antibodies against Type I and Type I11 collagens (12 patients). In the cellular stage, the dermis and adipose tissue revealed perivascular or diffuse cellular infiltrates (mostly lymphocytes, plasma cells, and macrophages), accompanied by deposition of Type I11 collagen. The lower dermis also showed an increase in Type I11 collagen. In the fibrotic stage, the papillary layer showed a reduction and/or clumping of Type I11 collagen as compared to normal skin. The lower dermis and the adipose tissue revealed compact collagen consisting exclusively of Type I collagen or a mixture of Type I and Type 111 collagen. The pattern of Type I11 collagen distribution was similar to that of reticulin, thus suggesting that at least some reticulin fibrils may represent Type I11 collagen.

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Section: Discussionmentioning

confidence: 99%

Collagen in the cellular and fibrotic stages of scleroderma

Fleischmajer

Meigel

Perlish

1978

Arthritis & Rheumatism

106

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“…11 Functionally, Ito cells are known to act as fat-storing cells; hence, lipid droplets are observed in their cytoplasm. 16,17 They are also known to take up vitamin A, [18][19][20] which is contained in cytoplasmic lipid droplets. However, in ordinary primary culture, lipid droplets and vitamin A fluorescence disappear within several days when Ito cells are cultured without vitamin A.…”

Section: [ 3 H]vitaminmentioning

confidence: 99%

Cell growth and differentiation of a novel mouse Ito (fat-storing) cell line transformed by a temperature-sensitive mutant of simian virus 40

et al. 1997

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cell line (GRX cell line), obtained from mouse liver infected A novel mouse Ito (fat-storing) cell line (A640-IS) was eswith Schistosoma, 1,2 rat fat-storing cell lines obtained from tablished by transformation with a temperature-sensitive munormal and CCl 4 -treated rat liver, 3 and a human cell line tant of simian virus 40 (SV40) and the relationships between obtained from a hepatic mesenchymal tumor. 4 However, as the expression of SV40 large T antigen and the growth, differfar as we know, no Ito cell line obtained from normal mouse entiation, and functions of A640-IS cells were investigated.liver has been established. Moreover, in general, native cell A640-IS cells expressed large T antigen when cultured at functions are often lost after cell immortalization. To resolve 33ЊC. At this temperature, the cells grew actively, assumed a these problems, establishment of cell lines with both profibroblastic shape, and showed few Ito cell characteristics. In longed growth potential and persistent native cell functions contrast, when large T-antigen expression was inhibited by is required. culture at 39ЊC, the cells did not grow but differentiated intoThe large T antigen of simian virus 40 (SV40), an oncoIto cells as assessed by both morphological and functional genic virus, plays an important role in the immortalization characteristics. Expression of the transcription factor SCL of cells. 5,6 Use of a temperature-sensitive mutant of SV40 (stem cell leukemia), which plays a role in the development (tsA640) allows the expression of the large T antigen to be and differentiation of blood cells, was observed at both 33ЊC controlled by changes in temperature. [7][8][9] In this study, a and 39ЊC, although expression was greater at 33ЊC. Therefore, altering the temperature. This is a very useful feature of the temperature-sensitive mutant of SV40 because it allows the The Ito cell (fat-storing cell, lipocyte, and perisinusoidal growth and differentiation of these cells to be regulated. In stellate cell) is one of the perisinusoidal cells in the liver addition, this novel Ito cell line retains the characteristics of and has many unique characteristics, including the ability the parent cells, in contrast to ordinary primary Ito cell culto synthesize extracellular matrix (ECM) proteins and store tures in which the original Ito cell nature is lost with time. vitamin A. However, little is known about the differentiation and functions of Ito cells at present. In general, a homoge- MATERIALS AND METHODSneous cell group is necessary for the examination of cells. However, in ordinary primary culture, Ito cells form a heteroEstablishment of Cell Lines. Sinusoidal cell fractions were obtained using collagenase and pronase-E digestion according to the method geneous cell group. To the best of our knowledge, only four of Knook et al. and Tsutsumi et al. 10,11 with minor modifications.Ito cell lines originating from pathological liver tissues have Care of the animals followed the appropriate guidelines. Under been established to date. The...

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“…However, upon activation, these cells undergo transformation, assuming a myofibroblast morphology and expressing smooth muscle actin (Ramadori et al, 1990;Schmitt-Graff et al, 1991). These activated stellate cells secrete collagen types I and III, the principle matrix protein responsible for the development of liver fibrosis and cirrhosis (Friedman, 2000;Kent et al, 1976). Over time, activated stellate cells are thought to be responsible for the exuberant and unbalanced wound-healing response so characteristic of cirrhosis.…”

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confidence: 99%

Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic

Canbay

Taimr

Torok

et al. 2003

Laboratory Investigation

375

274

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SUMMARY:Hepatocyte apoptosis and stellate cell activation are both features of chronic liver diseases, but a relationship between these events has not been explored. In macrophages, engulfment of apoptotic bodies induces expression of transforming growth factor-␤ (TGF-␤), a profibrogenic cytokine. We examined whether a similar response occurs in stellate cells. Fluorescently labeled hepatocyte apoptotic bodies were added to cultures of primary and immortalized human stellate cells. Stellate cells, but not hepatocytes, readily engulfed apoptotic bodies in a time-dependent manner as assessed by confocal microscopy. The activation of primary and immortalized human stellate cells after incubation with apoptotic bodies, as well as their fibrogenic activity, was indicated by an increase in ␣-smooth muscle actin (primary cells), TGF-␤1, and collagen ␣1(I) mRNA (primary and immortalized cells). The profibrogenic response was dependent upon apoptotic body engulfment, because nocodazole, a microtubule-inhibiting agent, blocked both the engulfment and the increase of TGF-␤1 and collagen ␣1(I) mRNA. As described in primary rodent stellate cells, up-regulation of collagen ␣1(I) mRNA was inhibited by a PI-3K inhibitor (LY294002) and a p38 mitogen-activated protein kinase inhibitor (SB203580) in LX-1 cells. In conclusion, these data support a model in which engulfment of hepatocyte apoptotic bodies by stellate cells leads to a fibrogenic response by eliciting a kinase-signaling pathway. (Lab Invest 2003, 83:655-663).L iver fibrosis is a cardinal feature of chronic liver injury. Indeed, despite the wide array of metabolic, genetic, viral, and cholestatic pathologies causing human liver injury, fibrosis is a common, if not generic, response of the liver to these injury processes. Extensive liver fibrosis results from the deposition and accumulation of type I collagen within the liver parenchyma and is recognized clinically as cirrhosis. The clinical complications of cirrhosis include portal hypertension and chronic liver failure. For many patients with advanced liver cirrhosis, the only viable treatment option is liver transplantation, highlighting the clinical severity of this fibrotic process. Insights into the mechanisms initiating and promoting liver fibrosis are, therefore, of broad scientific and clinical importance.Activated hepatic stellate cells have been established as the source of type I collagen in the liver (de Leeuw et al, 1984;Friedman et al, 1985;McGee and Patrick, 1972). Under basal conditions, hepatic stellate cells are in a quiescent state and function to store retinoids within the liver (Blomhoff et al, 1990;Geerts, 2001). However, upon activation, these cells undergo transformation, assuming a myofibroblast morphology and expressing smooth muscle actin (Ramadori et al, 1990;Schmitt-Graff et al, 1991). These activated stellate cells secrete collagen types I and III, the principle matrix protein responsible for the development of liver fibrosis and cirrhosis (Friedman, 2000;Kent et al, 1976). Over time, activ...

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Vitamin A-containing lipocytes and formation of type III collagen in liver injury.

Cited by 286 publications

References 11 publications

Collagen in the cellular and fibrotic stages of scleroderma

Collagen in the cellular and fibrotic stages of scleroderma

Cell growth and differentiation of a novel mouse Ito (fat-storing) cell line transformed by a temperature-sensitive mutant of simian virus 40

Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic

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