Fibroblasts as Sentinel Cells

Kaufman, Julia; Graf, Beth A.; Leung, Edmund; Pollock, Stephen J.; Koumas, Laura; Reddy, Sireesha; Blieden, Timothy M.; Smith, Terry J.; Phipps, Richard P.

doi:10.1378/chest.120.1_suppl.s53

Cited by 62 publications

(13 citation statements)

References 11 publications

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“…Interestingly, the majority of cardiac fibroblast cells expressed high levels of all three antigens. Interestingly, Thy-1 heterogeneity seems to differently affect their proliferative and synthetic characteristics [46]. Thy-1 + lung fibroblast phenotype exhibits profibrogenic properties with enhanced collagen deposition [47], whereas the Thy-1 - cell shows more apparent myofibroblastic features, particularly when the cells were stimulated with TGF-β or connective tissue growth factor (CTGF) [48].…”

Section: Molecular Markersmentioning

confidence: 99%

Mesenchymal Stem Cell-Like Properties in Fibroblasts

Chang

Guo

2014

Cell Physiol Biochem

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Fibroblasts are biologically dynamic and morphologically heterogeneous and are the most abundant connective tissue cells, with diverse structures depending on their location and activity. The main function of fibroblasts is to maintain the structural integrity of connective tissues by continuously secreting precursors of the extracellular matrix. Recent advances in our knowledge on pathophysiologic features of fibroblasts revealed that in some situations epithelial cells can give rise to fibroblasts by epithelial-mesenchymal transition (EMT) and conversely, in some other situations, fibroblasts may give rise to epithelia by undergoing a mesenchymal to epithelial transition (MET). Given an opportunity to differentiate to other cells, fibroblasts may foster a novel clue for in situ tissue repair and contribute to cellular mechanisms of mesenchymal stem cell-like features under normal or pathological conditions. They have also been shown to suppress immune responses in vitro. Because of these properties, fibroblasts have recently received a very high profile in the literature. This review summarizes our understanding of the origins, mesenchymal stem cell-like characteristics and potency of directed differentiation of fibroblasts. In addition, we also present the evidence that mesenchymal stem cells and fibroblasts share much more in common than previously recognized.

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Section: Molecular Markersmentioning

confidence: 99%

Mesenchymal Stem Cell-Like Properties in Fibroblasts

Chang

Guo

2014

Cell Physiol Biochem

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“…The data reported in this study indicate that lung fibroblasts also express CD154. The CD40-CD154 pathway is known to play an important role in the activation of a number of cell types including fibroblasts and has been postulated to play a role in the development of fibrosis (17,31,36,37). We next asked whether or not there was altered expression of CD154 in FLF vs NLF.…”

Section: Cd154 Expression By Nlf and Flfmentioning

confidence: 99%

“…The CD40-CD154 pathway potently activates human lung fibroblasts in vitro (18,27,31). Activation of lung fibroblasts in vivo is likely to be a result of the signaling cascade initiated by CD40 ligation, as well as the context (cytokine microenvironment) in which these signals are received.…”

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confidence: 99%

Expression of CD154 (CD40 Ligand) by Human Lung Fibroblasts: Differential Regulation by IFN-γ and IL-13, and Implications for Fibrosis

Kaufman¹,

Sime

Phipps

2004

The Journal of Immunology

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The CD40-CD40 ligand (CD40L) system (CD154) is a central means of immune cell communication crucial for Ig class switching and enhanced Ag presentation. CD40 is also a key signaling conduit to activate nonhematopoietic cells, such as fibroblasts and endothelial cells, to produce proinflammatory mediators. Disruption of the CD40-CD40L pathway reduces lung inflammation and fibrosis, autoimmune disease and atherosclerosis. Non-bone marrow-derived structural cells are not known to express CD40L. In this study, we reveal the intriguing finding that primary strains of human lung fibroblasts derived from normal and scarred lung express both CD40L mRNA and protein. Interestingly, CD40L expression is down-regulated by IFN-γ, a type 1 cytokine with antiscarring properties, and is up-regulated by the profibrogenic type 2 cytokine IL-13. Flow cytometry and laser confocal microscopy revealed that the majority of CD40L was located intracellularly. Importantly, fibroblast strains from human idiopathic pulmonary fibrosis tissue expressed increased levels of CD40L compared with fibroblasts from nonscarred lung. Fibroblasts in the scarred areas of human lung tissue expressed high levels of CD40L. Finally, the blood and lung lavage levels of CD40L are significantly elevated in fibrosis patients compared with normals. These new findings demonstrate that fibroblasts are a new source of CD40L and that those involved in scarring may have undergone a selected expansion for high CD40L expression. Moreover, the antifibrotic activity of IFN-γ may involve the down-regulation of fibroblast CD40L levels. We speculate that fibroblast-derived CD40L plays a role in promoting fibroblast activation and possibly in interaction with CD40 bearing cells.

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“…Proliferating HF were stimulated with 30 g/ml C1q globular heads or intact molecule, or with 10 g/ml C1q tails, and vehicle (0.25% BSA) at 37°C in 5% CO 2 . Cell extracts (20 -30 g of each protein sample) were fractionated by SDS-PAGE and electrotransferred onto nitrocellulose membrane (5).…”

Section: Immunoblottingmentioning

confidence: 99%

“…Fibroblasts encounter activated complement components selectively at inflammatory sites following enhanced vascular permeability and local complement synthesis. Excessive production or inappropriate activation of complement cascade causes disorderly fibroblast behavior, which leads to the irreversible destruction of functional connective tissue (1,2). The molecular events involved in the susceptibility of fibroblasts to direct damages by specific complement components are poorly defined.…”

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confidence: 99%

Cutting Edge: Proliferating Fibroblasts Respond to Collagenous C1q with Phosphorylation of p38 Mitogen-Activated Protein Kinase and Apoptotic Features

Bordin

Whitfield

2003

The Journal of Immunology

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Interactions of C1q collagen tails with human fibroblasts induce G1 mitotic arrest. The hypothesis tested in this study is that the antiproliferative effect of C1q tails is mediated through activation of stress responsive pathway(s). Upon C1q treatment, proliferating fibroblasts were examined by immunoblotting with a panel of Abs to the mitogen-activated protein kinase (MAPK) superfamily. The cells selectively increased phosphorylation of p38 MAPK, upstream dual activator MAPK kinase 3/6, and downstream transcription factors activating transcription factor 2, ETS domain transcription factor 1, and C/EBP homologous protein in a time-dependent manner. Phosphorylations were mediated, in part, by ligation of surface C1q tail-binding calreticulin. These events correlated with the appearance of apoptotic nuclei and DNA fragmentation in the cultures, which increased with a time response curve. The apoptotic features were linked to p38 activities because the selective inhibitor SB203580 prevented both phosphorylation of the pathway and DNA fragmentation. Hence, p38 activation might provide a molecular basis for linking mitotic arrest and apoptosis of fibroblasts by C1q tails.

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Fibroblasts as Sentinel Cells

Cited by 62 publications

References 11 publications

Mesenchymal Stem Cell-Like Properties in Fibroblasts

Mesenchymal Stem Cell-Like Properties in Fibroblasts

Expression of CD154 (CD40 Ligand) by Human Lung Fibroblasts: Differential Regulation by IFN-γ and IL-13, and Implications for Fibrosis

Cutting Edge: Proliferating Fibroblasts Respond to Collagenous C1q with Phosphorylation of p38 Mitogen-Activated Protein Kinase and Apoptotic Features

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