The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform
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 .
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Integrin α1β1 is Involved in the Differentiation into Myofibroblasts in Adult Reactive Tissues in vivo
Journal of cellular and molecular medicine, 2008Co-Authors: Alejandro Rodriguez, Jakob Karén, Bengt Gerdin, Kristofer Rubin, Humphrey Gardner, Christian SundbergAbstract:Connective Tissue Cell activation is of importance during reactive conditions such as solid tumour growth, wound healing and pannus formation in rheumatoid arthritis. Here, we have compared Connective Tissue Cells of mesenchymal origin in human Tissues from these conditions and their normal counterparts using a panel of Cell-type-specific markers. In particular, we investigated variations of integrin expression among Connective Tissue Cell phenotypes. Connective Tissue Cell populations were defined based on their association with the microvasculature and their expression of activation markers. The phenotype of these Cells varied according to the type of pathological Connective Tissue examined. Our morphological data from human Tissues suggested that the α1β1 integrin, a collagen/laminin receptor, is involved in the differentiation of precursor Cells into myofibroblasts. To mechanistically investigate this hypothesis, we employed experimental models for carcinoma growth and wound healing utilizing α1 integrin-deficient mice. The data confirmed that the α1β1 integrin is of importance not only for the differentiation of mesenchymal Cells into myofibroblasts but also for the neovascularization and Connective Tissue organization and emphasize the importance of myofibroblasts in the pathophysiology of Tissue repair, inflammation and tumour growth.
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Tumor Cell and Connective Tissue Cell interactions in human colorectal adenocarcinoma. Transfer of platelet-derived growth factor-AB/BB to stromal Cells.
The American journal of pathology, 1997Co-Authors: Christian Sundberg, M Branting, Bengt Gerdin, Kristofer RubinAbstract:Mechanisms underlying stimulation of platelet-derived growth factor (PDGF) beta-receptors expressed on Connective Tissue Cells in human colorectal adenocarcinoma were investigated in this study. PDGF-AB/BB, but not PDGF receptors, was expressed by tumor Cells in situ, as well as in tumor Cell isolates of low passage from human colorectal adenocarcinoma. In an experimental co-culture system, conditioned medium from tumor Cells only marginally activated PDGF beta-receptors expressed on fibroblasts. In contrast, co-culturing of the two Cell types led to a marked PDGF beta-receptor activation. Functional PDGF-AB/BB was found to be associated with heparinase-I-sensitive components on the tumor Cell surface. PDGF-AB/BB, isolated from heparinase-I-sensitive Cell surface components, induced a marked activation of PDGF beta-receptors. Furthermore, co-culturing tumor Cells together with fibroblasts led to a sustained activation of PDGF beta-receptors expressed on fibroblasts. Double immunofluorescence staining of Tissue sections from human colorectal adenocarcinoma, combined with computer-aided image analysis, revealed that nonproliferating tumor Cells were the predominant Cellular source of PDGF-AB/BB in the tumor stroma. In addition, PDGF-AB/BB-expressing tumor Cells were found juxtapositioned to microvascular Cells expressing activated PDGF beta-receptors. Confocal microscopy revealed a cytoplasmic and Cell-membrane-associated expression of PDGF-AB/BB in tumor Cells situated in the stroma. In contrast, epithelial Cells situated in normal or tumorous acinar structures revealed only a Cell-membrane-associated PDGF-AB/BB expression. The is vitro and in situ results demonstrate that tumor Cells not only facilitate but also have the ability to modulate Connective Tissue Cell responsiveness to PDGF-AB/BB in a paracrine fashion, through direct Cell-Cell interactions in human colorectal adenocarcinoma.
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Connective Tissue Cell activation in human wound healing and colorectal adenocarcinoma : roles of pericytes, PDGF and β1 integrins
1996Co-Authors: Christian SundbergAbstract:Connective Tissue Cell activation in human wound healing and colorectal adenocarcinoma : roles of pricytes, PDGF and s1 integrins
David R Brigstock - One of the best experts on this subject based on the ideXlab platform.
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Connective Tissue growth factor ctgf ccn2 in hepatic fibrosis
Hepatology Research, 2003Co-Authors: Amy W Rachfal, David R BrigstockAbstract:Connective Tissue growth factor (CTGF/CCN2) is a highly profibrogenic molecule which is overexpressed in many fibrotic lesions, including those of the liver. CTGF/CCN2 is transcriptionally activated by transforming growth factor-beta (TGF-β) and appears to mediate some of the extraCellular matrix (ECM)-inducing properties that have been previously attributed to TGF-β. CTGF/CCN2 and TGF-β stimulate Connective Tissue Cell proliferation and ECM synthesis in vitro and exhibit shared fibrogenic and angiogenic properties in vivo. In fibrotic liver, CTGF/CCN2 mRNA and protein are produced by fibroblasts, myofibroblasts, hepatic stellate Cells (HSCs), endothelial Cells, and bile duct epithelial Cells. CTGF/CCN2 is also produced at high levels in hepatocytes during cytochrome P-4502E1-mediated ethanol oxidation. CTGF/CCN2 expression in cultured HSCs is enhanced following their activation or stimulation by TGF-β while exogenous CTGF/CCN2 is able to promote HSC adhesion, proliferation, locomotion, and collagen production. Collectively, these data suggest that during initiating or downstream fibrogenic events in the liver, production of CTGF/CCN2 is regulated primarily by TGF-β in one or more Cell types and that CTGF/CCN2 plays important roles in HSC activation and progression of fibrosis. This article reviews the data that support the importance of CTGF/CCN2 in hepatic fibrosis and highlights the concept that CTGF/CCN2 may represent a new therapeutic target in this disease.
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Connective Tissue growth factor (CTGF/CCN2) in hepatic fibrosis.
Hepatology Research, 2003Co-Authors: Amy W Rachfal, David R BrigstockAbstract:Connective Tissue growth factor (CTGF/CCN2) is a highly profibrogenic molecule which is overexpressed in many fibrotic lesions, including those of the liver. CTGF/CCN2 is transcriptionally activated by transforming growth factor-beta (TGF-β) and appears to mediate some of the extraCellular matrix (ECM)-inducing properties that have been previously attributed to TGF-β. CTGF/CCN2 and TGF-β stimulate Connective Tissue Cell proliferation and ECM synthesis in vitro and exhibit shared fibrogenic and angiogenic properties in vivo. In fibrotic liver, CTGF/CCN2 mRNA and protein are produced by fibroblasts, myofibroblasts, hepatic stellate Cells (HSCs), endothelial Cells, and bile duct epithelial Cells. CTGF/CCN2 is also produced at high levels in hepatocytes during cytochrome P-4502E1-mediated ethanol oxidation. CTGF/CCN2 expression in cultured HSCs is enhanced following their activation or stimulation by TGF-β while exogenous CTGF/CCN2 is able to promote HSC adhesion, proliferation, locomotion, and collagen production. Collectively, these data suggest that during initiating or downstream fibrogenic events in the liver, production of CTGF/CCN2 is regulated primarily by TGF-β in one or more Cell types and that CTGF/CCN2 plays important roles in HSC activation and progression of fibrosis. This article reviews the data that support the importance of CTGF/CCN2 in hepatic fibrosis and highlights the concept that CTGF/CCN2 may represent a new therapeutic target in this disease.
Gary R Grotendorst - One of the best experts on this subject based on the ideXlab platform.
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individual domains of Connective Tissue growth factor regulate fibroblast proliferation and myofibroblast differentiation
The FASEB Journal, 2005Co-Authors: Gary R Grotendorst, Matthew R DuncanAbstract:All members of the Ctgf, Cyr61, and Nov (CCN) family share a high degree of sequence homology and conservation of structural motifs and domains. Here, we present data about a structure function analysis of Connective Tissue growth factor (CTGF), a prototypic member of the CCN family, which has been shown to be a downstream mediator of transforming growth factor-beta activities on fibroblasts. Our findings demonstrate the two domains of CTGF function to mediate two distinct biological effects. The N-terminal domain of CTGF mediates myofibroblast differentiation and collagen synthesis. The C-terminal domain of CTGF mediates fibroblast proliferation. These data provide a molecular basis for the divergence of CTGF actions on Connective Tissue Cell types and suggest a model for functional analysis of all of the CCN family gene products.
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stimulation of fibroblast Cell growth matrix production and granulation Tissue formation by Connective Tissue growth factor
Journal of Investigative Dermatology, 1996Co-Authors: Ken S Frazier, Shawn Williams, Devashish Kothapalli, Helene Klapper, Gary R GrotendorstAbstract:Connective Tissue growth factor (CTGF) is a 36- to 38-kDa peptide that is selectively induced by transforming growth factor- β (TGF- β ) in fibroblastic Cell types. We compared the biologic activities of CTGF with TGF- β on fibroblasts in culture and in animal models of fibroplasia. CTGF was active as a mitogen in monolayer cultures of normal rat kidney fibroblasts. CTGF did not stimulate anchorage-independent growth of NRK fibroblasts, however, or inhibit the growth of mink lung epithelial Cells, distinguishing CTGF's growth-regulatory activities from those of TGF- β . In NRK fibroblasts, both TGF- β and CTGF significantly increased the transcripts encoding at type I collagen, α 5 integrin, and fibronectin. Stimulation of type I collagen and fibronectin protein synthesis by TGF- β and CTGF was confirmed by pulse labeling of Cells with [ 35 S]methionine. Subcutaneous injection of TGF- β and CTGF into neonatal NIH Swiss mice resulted in a large stimulation of granulation Tissue and fibrosis at the site of injection. In situ hybridization studies revealed that TGF- β injection induced high levels of CTGF mRNA in the dermal fibroblasts at the injection site, demonstrating that TGF- β can induce the expression of CTGF in Connective Tissue Cells in vivo . No CTGF transcripts were detected in the epidermal Cells in either control or TGF- β -injected skin or in fibroblasts in control (saline-injected) skin. These results demonstrate that, like TGF- β , CTGF can induce Connective Tissue Cell proliferation and extraCellular matrix synthesis.
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 .
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Integrin α1β1 is Involved in the Differentiation into Myofibroblasts in Adult Reactive Tissues in vivo
Journal of cellular and molecular medicine, 2008Co-Authors: Alejandro Rodriguez, Jakob Karén, Bengt Gerdin, Kristofer Rubin, Humphrey Gardner, Christian SundbergAbstract:Connective Tissue Cell activation is of importance during reactive conditions such as solid tumour growth, wound healing and pannus formation in rheumatoid arthritis. Here, we have compared Connective Tissue Cells of mesenchymal origin in human Tissues from these conditions and their normal counterparts using a panel of Cell-type-specific markers. In particular, we investigated variations of integrin expression among Connective Tissue Cell phenotypes. Connective Tissue Cell populations were defined based on their association with the microvasculature and their expression of activation markers. The phenotype of these Cells varied according to the type of pathological Connective Tissue examined. Our morphological data from human Tissues suggested that the α1β1 integrin, a collagen/laminin receptor, is involved in the differentiation of precursor Cells into myofibroblasts. To mechanistically investigate this hypothesis, we employed experimental models for carcinoma growth and wound healing utilizing α1 integrin-deficient mice. The data confirmed that the α1β1 integrin is of importance not only for the differentiation of mesenchymal Cells into myofibroblasts but also for the neovascularization and Connective Tissue organization and emphasize the importance of myofibroblasts in the pathophysiology of Tissue repair, inflammation and tumour growth.
Amy W Rachfal - One of the best experts on this subject based on the ideXlab platform.
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Connective Tissue growth factor ctgf ccn2 in hepatic fibrosis
Hepatology Research, 2003Co-Authors: Amy W Rachfal, David R BrigstockAbstract:Connective Tissue growth factor (CTGF/CCN2) is a highly profibrogenic molecule which is overexpressed in many fibrotic lesions, including those of the liver. CTGF/CCN2 is transcriptionally activated by transforming growth factor-beta (TGF-β) and appears to mediate some of the extraCellular matrix (ECM)-inducing properties that have been previously attributed to TGF-β. CTGF/CCN2 and TGF-β stimulate Connective Tissue Cell proliferation and ECM synthesis in vitro and exhibit shared fibrogenic and angiogenic properties in vivo. In fibrotic liver, CTGF/CCN2 mRNA and protein are produced by fibroblasts, myofibroblasts, hepatic stellate Cells (HSCs), endothelial Cells, and bile duct epithelial Cells. CTGF/CCN2 is also produced at high levels in hepatocytes during cytochrome P-4502E1-mediated ethanol oxidation. CTGF/CCN2 expression in cultured HSCs is enhanced following their activation or stimulation by TGF-β while exogenous CTGF/CCN2 is able to promote HSC adhesion, proliferation, locomotion, and collagen production. Collectively, these data suggest that during initiating or downstream fibrogenic events in the liver, production of CTGF/CCN2 is regulated primarily by TGF-β in one or more Cell types and that CTGF/CCN2 plays important roles in HSC activation and progression of fibrosis. This article reviews the data that support the importance of CTGF/CCN2 in hepatic fibrosis and highlights the concept that CTGF/CCN2 may represent a new therapeutic target in this disease.
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Connective Tissue growth factor (CTGF/CCN2) in hepatic fibrosis.
Hepatology Research, 2003Co-Authors: Amy W Rachfal, David R BrigstockAbstract:Connective Tissue growth factor (CTGF/CCN2) is a highly profibrogenic molecule which is overexpressed in many fibrotic lesions, including those of the liver. CTGF/CCN2 is transcriptionally activated by transforming growth factor-beta (TGF-β) and appears to mediate some of the extraCellular matrix (ECM)-inducing properties that have been previously attributed to TGF-β. CTGF/CCN2 and TGF-β stimulate Connective Tissue Cell proliferation and ECM synthesis in vitro and exhibit shared fibrogenic and angiogenic properties in vivo. In fibrotic liver, CTGF/CCN2 mRNA and protein are produced by fibroblasts, myofibroblasts, hepatic stellate Cells (HSCs), endothelial Cells, and bile duct epithelial Cells. CTGF/CCN2 is also produced at high levels in hepatocytes during cytochrome P-4502E1-mediated ethanol oxidation. CTGF/CCN2 expression in cultured HSCs is enhanced following their activation or stimulation by TGF-β while exogenous CTGF/CCN2 is able to promote HSC adhesion, proliferation, locomotion, and collagen production. Collectively, these data suggest that during initiating or downstream fibrogenic events in the liver, production of CTGF/CCN2 is regulated primarily by TGF-β in one or more Cell types and that CTGF/CCN2 plays important roles in HSC activation and progression of fibrosis. This article reviews the data that support the importance of CTGF/CCN2 in hepatic fibrosis and highlights the concept that CTGF/CCN2 may represent a new therapeutic target in this disease.