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Radovan Borojevic - One of the best experts on this subject based on the ideXlab platform.
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TGF β1 and PDGF AA override Collagen type I inhibition of proliferation in human liver Connective Tissue Cells
BMC gastroenterology, 2004Co-Authors: Alvaro T Geremias, Radovan Borojevic, Marcelo A. Carvalho, Alvaron A. MonteiroAbstract:A marked expansion of the Connective Tissue population and an abnormal deposition of extracellular matrix proteins are hallmarks of chronic and acute injuries to liver Tissue. Liver Connective Tissue Cells, also called stellate Cells, derived from fibrotic liver have been thoroughly characterized and correspond phenotypically to myofibroblasts. They are thought to derive from fat-storing Ito Cells in the perisinusoidal space and acquire a contractile phenotype when activated by Tissue injury. In the last few years it has become evident that several peptide growth factors such as PDGF AA and TGF-β are involved in the development of fibrosis by modulating myofibroblast proliferation and collagen secretion. The fact that during the development of chronic fibrosis there is concomitant deposition of collagen, a known inhibitory factor, and sustained cell proliferation, raises the possibility that stellate Cells from chronic liver fibrosis patients fail to respond to normal physiologic controls. In this study we address whether Cells from fibrotic liver patients respond to normal controls of proliferation. We compared cell proliferation of primary human liver Connective Tissue Cells (LCTC) from patients with liver fibrosis and skin fibroblasts (SF) in the presence of collagens type I and IV; TGF-β, PDGF AA and combinations of collagen type I and TGF-β or PDGF AA. Our results indicate that despite displaying normal contact and collagen-induced inhibition of proliferation LCTC respond more vigorously to lower concentrations of PDGF AA. In addition, we show that collagen type I synergizes with growth factors to promote mitogenesis of LCTC but not SF. The synergistic interaction of growth factors and extracellular matrix proteins may underlie the development of chronic liver fibrosis.
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Schistosoma mansoni egg-induced hepatic granulomas in mice deficient for the interferon-gamma receptor have altered populations of macrophages, lymphocytesand Connective Tissue Cells
Microbes and infection, 2000Co-Authors: Valéria R Oliveira, Márcia C. El-cheikh, Alessandra Melo De Aguiar, Alex Balduino, Maria De Fatima B. Pinho, Luiz F. L. Reis, Radovan BorojevicAbstract:Abstract Systemic production and mobilization of inflammatory Cells and formation of hepatic periovular granulomas were studied in Schistosoma mansoni-infected mice with deficient interferon gamma (IFN-γ) receptor (IFN-γRo/o). The impaired IFN-γ signaling did not cause a significant modification of the overall kinetics of inflammatory Cells, but mutant mice developed smaller hepatic periovular granulomas with a two-fold reduction in all the cell lineages. In granulomas of normal mice, the fully differentiated macrophages were progressively predominant, whilst in IFN-γRo/o mice, the granulomas contained a higher percentage of immature and proliferating monocytes. Granulomas of IFN-γRo/o mice had an enhanced and accelerated fibrotic reaction, corresponding to an increased content of proliferative and activated Connective Tissue Cells. Simultaneously, their granulomas had an increased ratio of T over B Cells, with an increase in CD8+ and a reduction in CD4+ T Cells. The functional IFN-γ receptor was not required for initial recruitment of monocytes and lymphocytes into granulomas, but it was necessary for the maturation of macrophages, upregulation of major histocompatibility class 2 (MHC-II) expression and consequent stimulation of lymphocyte subpopulations depending upon the MHC-II-mediated antigen presentation.
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Complement-dependent induction of DNA synthesis and cell proliferation in human liver Connective Tissue Cells in vitro
In vitro cellular & developmental biology. Animal, 1995Co-Authors: Alvaron A. Monteiro, Radovan BorojevicAbstract:Liver Connective Tissue Cells (LCTC) isolated from patients with fibrotic livers have morphological and biochemical characteristics of myofibroblasts. We have examined the proliferation of LCTC derived from normal livers and from livers with fibrosis of different etiologies, as well as proliferation of skin fibroblasts. We have compared proliferation rates in the presence of fresh human serum and heat-inactivated serum. While skin fibroblast and LCTC from normal liver showed no difference, proliferation of LCTC from fibrotic livers was markedly decreased in the presence of heat-inactivated serum. We demonstrate that the native complement component C1 is a factor involved in the induction of DNA synthesis and proliferation of LCTC isolated from fibrotic livers. We propose that native C1, acting probably in cooperation with other growth factors, is involved in the expansion of Connective Tissue Cells during the development of liver fibrosis.
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Myelopoietic competence of stroma composed of hepatic granuloma-derived Connective Tissue Cells or skin fibroblasts.
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 1994Co-Authors: M. Alvarez-silva, Márcia C. El-cheikh, Radovan BorojevicAbstract:1. Connective Tissue Cells isolated from hepatic granulomas (GR Cells), induced in mouse liver Tissue by schistosomal infection, are able to sustain myelopoiesis, while other Connective Tissue Cells such as skin fibroblasts (SF) are not. 2. We compared the ability of SF and GR Cells to sustain in vitro proliferation of the FDC-P1 myeloid cell line, dependent upon IL-3 or GM-CSF. 3. Only the GR stroma sustained the proliferation of co-cultured FDC-P1 Cells. RT-PCR analysis showed that both cell lines expressed the message for GM-CSF, but not for IL-3. We showed that GM-CSF was produced by, and remained bound to the cell layer through heparan sulfate; this growth factor could be released by high-salt treatment in a biologically active form from both cell types. The same activity could be restored to NaCl-treated GR Cells, but not to SF, by incubation with recombinant murine GM-CSF. 4. These results indicate that the ability of Connective Tissue Cells to sustain myelopoiesis depends directly upon the capacity of their heparan sulfate-bearing molecules to bind and present the GM-CSF to the target Cells in a biologically active form. Alternatively, a yet unidentified set of cell layer-associated molecules may be required for the positive or negative control of the membrane-bound GM-CSF.
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In vitro collagen synthesis by liver Connective Tissue Cells isolated from schistosomal granulomas
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 1994Co-Authors: Luciana B. Chiarini, Radovan Borojevic, Alvaron A. MonteiroAbstract:Hepatic injury elicits an excessive deposition of extracellular matrix probably due to a loss of control mechanisms in mesenchymal Cells in fibrotic lesions, or a local activity of growth factors. To study collagen synthesis in an in vitro model of fibrotic lesions, we isolated liver Connective Tissue Cells (LCTC) from murine schistosomal granulomas in C3H/HeN mice. Collagen was quantified in culture supernatants using a sirius red dye assay. LCTC and skin fibroblasts (SF) secreted similar amounts of collagen per cell and secretion was inversely proportional to the cell density. Cells cultured at low density (10,000 Cells/cm2) secreted two- to three-times more collagen per cell when compared to Cells grown in high-density cultures (60,000 Cells/cm2). Collagen secretion was stimulated by transforming growth factor-beta (TGF-beta) in both cell lines, but the response of LCTC was detected from 1 ng/ml on, while SF responded only to higher concentrations (2.5 and 5 ng/ml). These data do not support the hypothesis that Cells from fibrotic livers have lost the normal control mechanisms and suggest that their control is disturbed locally by the presence of peptide growth factors during the development of fibrosis.
Christian Sundberg - One of the best experts on this subject based on the ideXlab platform.
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Phenotypical differences in Connective Tissue Cells emerging from microvascular pericytes in response to overexpression of PDGF-B and TGF-β1 in normal skin in vivo.
The American journal of pathology, 2013Co-Authors: Alejandro Rodriguez, Tomas Friman, Marcin Kowanetz, Tijs Van Wieringen, Renata Gustafsson, Christian SundbergAbstract:Fibrosis is a deleterious consequence of chronic inflammation in a number of human pathologies ultimately leading to organ dysfunction and failure. Two growth factors that are important in blood vessel physiology and Tissue fibrosis, platelet-derived growth factor (PDGF)-B and transforming growth factor (TGF)-β1, were investigated. Adenoviral vectors were used to induce transient overexpression of these growth factors in mouse skin. Changes in Tissue structure and protein and mRNA expressions were investigated. Both PDGF-B and TGF-β1 could initiate but neither could sustain angiogenesis. Instead, vascular regression was observed. Overexpression of both TGF-β1 and PDGF-B led to a marked macrophage influx and an expansion of the Connective Tissue cell population. Over time, this effect was sustained in mice treated with TGF-β1, whereas it was partially reversible in mice treated with PDGF-B. On the basis of structure and expression of phenotypical markers, the emerging Connective Tissue cell population may originate from microvascular pericytes. TGF-β1 induced expansion of Connective Tissue Cells with a myofibroblast phenotype, whereas PDGF-B induced a fibroblast phenotype negative for α-smooth muscle actin. TGF-β1 and PDGF-B overexpressions mediated distinct effects on mRNA transcript levels of fibrillar procollagens, their modifying enzymes, small leucin-rich repeat proteoglycans, and matricellular proteins affecting both the composition and the quantity of the extracellular matrix. This study offers new insight into the effects of PDGF-B and TGF-β1 on the vasculature and Connective Tissue in vivo .
Alvaron A. Monteiro - One of the best experts on this subject based on the ideXlab platform.
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TGF β1 and PDGF AA override Collagen type I inhibition of proliferation in human liver Connective Tissue Cells
BMC gastroenterology, 2004Co-Authors: Alvaro T Geremias, Radovan Borojevic, Marcelo A. Carvalho, Alvaron A. MonteiroAbstract:A marked expansion of the Connective Tissue population and an abnormal deposition of extracellular matrix proteins are hallmarks of chronic and acute injuries to liver Tissue. Liver Connective Tissue Cells, also called stellate Cells, derived from fibrotic liver have been thoroughly characterized and correspond phenotypically to myofibroblasts. They are thought to derive from fat-storing Ito Cells in the perisinusoidal space and acquire a contractile phenotype when activated by Tissue injury. In the last few years it has become evident that several peptide growth factors such as PDGF AA and TGF-β are involved in the development of fibrosis by modulating myofibroblast proliferation and collagen secretion. The fact that during the development of chronic fibrosis there is concomitant deposition of collagen, a known inhibitory factor, and sustained cell proliferation, raises the possibility that stellate Cells from chronic liver fibrosis patients fail to respond to normal physiologic controls. In this study we address whether Cells from fibrotic liver patients respond to normal controls of proliferation. We compared cell proliferation of primary human liver Connective Tissue Cells (LCTC) from patients with liver fibrosis and skin fibroblasts (SF) in the presence of collagens type I and IV; TGF-β, PDGF AA and combinations of collagen type I and TGF-β or PDGF AA. Our results indicate that despite displaying normal contact and collagen-induced inhibition of proliferation LCTC respond more vigorously to lower concentrations of PDGF AA. In addition, we show that collagen type I synergizes with growth factors to promote mitogenesis of LCTC but not SF. The synergistic interaction of growth factors and extracellular matrix proteins may underlie the development of chronic liver fibrosis.
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Complement-dependent induction of DNA synthesis and cell proliferation in human liver Connective Tissue Cells in vitro
In vitro cellular & developmental biology. Animal, 1995Co-Authors: Alvaron A. Monteiro, Radovan BorojevicAbstract:Liver Connective Tissue Cells (LCTC) isolated from patients with fibrotic livers have morphological and biochemical characteristics of myofibroblasts. We have examined the proliferation of LCTC derived from normal livers and from livers with fibrosis of different etiologies, as well as proliferation of skin fibroblasts. We have compared proliferation rates in the presence of fresh human serum and heat-inactivated serum. While skin fibroblast and LCTC from normal liver showed no difference, proliferation of LCTC from fibrotic livers was markedly decreased in the presence of heat-inactivated serum. We demonstrate that the native complement component C1 is a factor involved in the induction of DNA synthesis and proliferation of LCTC isolated from fibrotic livers. We propose that native C1, acting probably in cooperation with other growth factors, is involved in the expansion of Connective Tissue Cells during the development of liver fibrosis.
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In vitro collagen synthesis by liver Connective Tissue Cells isolated from schistosomal granulomas
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 1994Co-Authors: Luciana B. Chiarini, Radovan Borojevic, Alvaron A. MonteiroAbstract:Hepatic injury elicits an excessive deposition of extracellular matrix probably due to a loss of control mechanisms in mesenchymal Cells in fibrotic lesions, or a local activity of growth factors. To study collagen synthesis in an in vitro model of fibrotic lesions, we isolated liver Connective Tissue Cells (LCTC) from murine schistosomal granulomas in C3H/HeN mice. Collagen was quantified in culture supernatants using a sirius red dye assay. LCTC and skin fibroblasts (SF) secreted similar amounts of collagen per cell and secretion was inversely proportional to the cell density. Cells cultured at low density (10,000 Cells/cm2) secreted two- to three-times more collagen per cell when compared to Cells grown in high-density cultures (60,000 Cells/cm2). Collagen secretion was stimulated by transforming growth factor-beta (TGF-beta) in both cell lines, but the response of LCTC was detected from 1 ng/ml on, while SF responded only to higher concentrations (2.5 and 5 ng/ml). These data do not support the hypothesis that Cells from fibrotic livers have lost the normal control mechanisms and suggest that their control is disturbed locally by the presence of peptide growth factors during the development of fibrosis.
Alejandro Rodriguez - One of the best experts on this subject based on the ideXlab platform.
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Phenotypical differences in Connective Tissue Cells emerging from microvascular pericytes in response to overexpression of PDGF-B and TGF-β1 in normal skin in vivo.
The American journal of pathology, 2013Co-Authors: Alejandro Rodriguez, Tomas Friman, Marcin Kowanetz, Tijs Van Wieringen, Renata Gustafsson, Christian SundbergAbstract:Fibrosis is a deleterious consequence of chronic inflammation in a number of human pathologies ultimately leading to organ dysfunction and failure. Two growth factors that are important in blood vessel physiology and Tissue fibrosis, platelet-derived growth factor (PDGF)-B and transforming growth factor (TGF)-β1, were investigated. Adenoviral vectors were used to induce transient overexpression of these growth factors in mouse skin. Changes in Tissue structure and protein and mRNA expressions were investigated. Both PDGF-B and TGF-β1 could initiate but neither could sustain angiogenesis. Instead, vascular regression was observed. Overexpression of both TGF-β1 and PDGF-B led to a marked macrophage influx and an expansion of the Connective Tissue cell population. Over time, this effect was sustained in mice treated with TGF-β1, whereas it was partially reversible in mice treated with PDGF-B. On the basis of structure and expression of phenotypical markers, the emerging Connective Tissue cell population may originate from microvascular pericytes. TGF-β1 induced expansion of Connective Tissue Cells with a myofibroblast phenotype, whereas PDGF-B induced a fibroblast phenotype negative for α-smooth muscle actin. TGF-β1 and PDGF-B overexpressions mediated distinct effects on mRNA transcript levels of fibrillar procollagens, their modifying enzymes, small leucin-rich repeat proteoglycans, and matricellular proteins affecting both the composition and the quantity of the extracellular matrix. This study offers new insight into the effects of PDGF-B and TGF-β1 on the vasculature and Connective Tissue in vivo .
Myron Spector - One of the best experts on this subject based on the ideXlab platform.
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Novel Cell–Scaffold Interactions Encountered in Tissue Engineering: Contractile Behavior of Musculoskeletal Connective Tissue Cells
Tissue Engineering, 2002Co-Authors: Myron SpectorAbstract:Methods employed in the course of Tissue engineering often offer unique opportunities to observe cell-matrix interactions that cannot otherwise be viewed. These observations may provide insights into cell behavior than can contribute important new knowledge about cell biology. One such set of observations led to the discoveries that musculoskeletal Connective Tissue Cells express a contractile muscle actin isoform, α-smooth muscle actin, and can contract. This knowledge may help to explain how these Cells generate forces required for certain physiological and pathological functions, and this information may inform future approaches to regulate this function to advance Tissue engineering. Tissue engineering science is thus emerging as an importance force that can both contribute to cell and molecular biology and add to the fund of knowledge supporting the production of Tissue in vitro or in vivo to improve the management of a wide variety of disorders.
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Expression of smooth muscle actin in Connective Tissue Cells participating in fracture healing in a murine model
Bone, 2002Co-Authors: B Kinner, Louis C. Gerstenfeld, Thomas A. Einhorn, Myron SpectorAbstract:The role of α-smooth muscle actin (SMA)-expressing fibroblasts in the contraction of skin wounds has been known for three decades. Recent studies have demonstrated that osteoblasts can also express the gene for this contractile muscle actin isoform and can contract a collagen-glycosaminoglycan analog of extracellular matrix in vitro. These findings provided rationale for the hypothesis that SMA-expressing Cells contribute to fracture healing by drawing the bone ends together. To begin to test this hypothesis, immunohistochemistry was employed to evaluate the distribution of Connective Tissue Cells expressing SMA in a mouse model of successful fracture healing. The results demonstrated that the majority of the Cells comprising the mesenchymal Tissue interposed between the fracture ends contained SMA after 7 and 21 days, supporting the working hypothesis. Most of the osteoblasts lining the surfaces of newly forming bone and the chondrocytes comprising the cartilaginous callus also expressed this contractile actin isoform. The maximal SMA expression extended from 7 to 21 days postfracture. The finding of high levels of SMA expression in Connective Tissue Cells participating in fracture healing suggests that SMA-enabled contraction may be playing a role in the healing process. These results warrant further study of the specific SMA-dependent cell behavior.
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Musculoskeletal Connective Tissue Cells with muscle: expression of muscle actin in and contraction of fibroblasts, chondrocytes, and osteoblasts.
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society, 2001Co-Authors: Myron SpectorAbstract:The expression of the gene for a muscle actin in certain nonmuscle Cells and the contraction of these Connective Tissue Cells has been associated with several important physiological and pathological processes; the contraction of healing skin wounds and the contracture in Dupuytren's disease being two notable examples. Studies in recent years have shown that a much wider variety of Connective Tissue Cells than previously considered, including Cells in many of the musculoskeletal Tissues, e.g., chondrocytes and osteoblasts, can express the gene for alpha-smooth muscle actin and can display contractile behavior. These findings suggest that muscle actin-enabled cell contraction may also be playing important roles in the other Connective Tissues comprising the musculoskeletal system, namely, tendon, ligament, meniscus, intervertebral disc, articular cartilage, and bone.