Phenotypic differences between dermal fibroblasts from different body sites determine their responses to tension and TGFβ1

Chipev, Constantin C; Simon, Marcia

doi:10.1186/1471-5945-2-13

Cited by 72 publications

(52 citation statements)

References 54 publications

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“…addition to up-regulating ␣11, both activin A (39, 40) and mechanical tension (41) have been shown to be involved in the up-regulation of ␣-smooth muscle actin (␣-SMA). This isoform of actin is a classical marker for myofibroblasts, a cell type playing a key role in wound healing (1) and pathological conditions, such as fibrosis (1) and cancer (42).…”

Section: ␣11 Is Part Of the Myofibroblast Phenotype Of Mouse Fibroblamentioning

confidence: 99%

The Fibroblast Integrin α11β1 Is Induced in a Mechanosensitive Manner Involving Activin A and Regulates Myofibroblast Differentiation

Carracedo

Lü

Popova

et al. 2010

Journal of Biological Chemistry

129

116

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Fibrotic tissue is characterized by an overabundance of myofibroblasts. Thus, understanding the factors that induce myofibroblast differentiation is paramount to preventing fibrotic healing. Previous studies have shown that mechanical stress derived from the integrin-mediated interaction between extracellular matrix and the cytoskeleton promotes myofibroblast differentiation. Integrin ␣11␤1 is a collagen receptor on fibroblasts. To determine whether ␣11␤1 can act as a mechanosensor to promote the myofibroblast phenotype, mouse embryonic fibroblasts and human corneal fibroblasts were utilized. We found that ␣11 mRNA and protein levels were up-regulated in mouse embryonic fibroblasts grown in attached three-dimensional collagen gels and conversely down-regulated in cells grown in floating gels. ␣11 up-regulation could be prevented by manually detaching the collagen gels or by cytochalasin D treatment. Furthermore, SB-431542, an inhibitor of signaling via ALK4, ALK5, and ALK7, prevented the up-regulation of ␣11 and the concomitant phosphorylation of Smad3 under attached conditions. In attached gels, TGF-␤1 was secreted in its inactive form but surprisingly not further activated, thus not influencing ␣11 regulation. However, inhibition of activin A attenuated the up-regulation of ␣11. To determine the role of ␣11 in myofibroblast differentiation, human corneal fibroblasts were transfected with small interfering RNA to ␣11, which decreased ␣-smooth muscle actin expression and myofibroblast differentiation. Our data suggest that ␣11␤1 is regulated by cell/matrix stress involving activin A and Smad3 and that ␣11␤1 regulates myofibroblast differentiation.

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Section: ␣11 Is Part Of the Myofibroblast Phenotype Of Mouse Fibroblamentioning

confidence: 99%

The Fibroblast Integrin α11β1 Is Induced in a Mechanosensitive Manner Involving Activin A and Regulates Myofibroblast Differentiation

Carracedo

Lü

Popova

et al. 2010

Journal of Biological Chemistry

129

116

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“…28 These studies suggest that a reduction in the mechanical tension in the extracellular matrix serves as a trigger for the initiation of fibroblast apoptosis, thus participating in cell homeostasis during physiological wound healing. 29 Conversely, the loss of such a cell/matrix homeostasis can lead to the formation of an abnormal, fibroproliferative, keloid scar. 30 …”

Section: Matrix Retractionmentioning

confidence: 99%

Anoïkis in the Cardiovascular System

Michel

2003

ATVB

215

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Abstract-Anoïkis is defined as programmed cell death induced by the loss of cell/matrix interactions. Adhesion to structural glycoproteins of the extracellular matrix is necessary for survival of the differentiated adherent cells in the cardiovascular system, including endothelial cells, smooth muscle cells, fibroblasts, and cardiac myocytes. Adhesion is also a key factor for the differentiation of mesenchymal stem cells. In particular, fibronectin is considered a factor of survival and differentiation for many adherent cells. Adhesion generates cell tensional integrity (tensegrity) and repression of apoptotic signals, whereas detachment has the opposite effect. Anoïkis plays a physiological role by regulating cell homeostasis in tissues. However, anoïkis can also be involved in pathological processes, as illustrated by the resistance to anoïkis in cancer and its enhancement in degenerative tissue remodeling. Extracellular mediators of anoïkis include matrix retraction, leading to loss of tensegrity in fibroblasts, pharmacological disengagement of integrins by RGD-like peptides and fragments of fibronectin, and focal adhesion disassembly by fragments of thrombospondin, plasminogen activator-1, and high-molecular-weight kininogen. In addition to binding of the RGD peptide by integrins, the engagement of the heparin binding sites of adhesive glycoproteins with glycosaminoglycans on the cell surface is also involved in the prevention of cell detachment-induced apoptosis. Proteases able to degrade adhesive glycoproteins, such as fibronectin, induce anoïkis of vascular adherent cells. Active proteases can either be secreted directly by inflammatory cells, as elastase and cathepsin G by polymorphonuclear leukocytes, chymase and tryptase by mast cells, and granzymes by lymphocytes, or generated from circulating zymogens by activation in close contact with the cells. This is the case for the pericellular conversion of plasminogen to plasmin, which degrades fibronectin and induces anoïkis of smooth muscle cells. Involvement of proteases has also been proposed in the apoptotic response of cultured adherent cells to serum starvation. Anoïkis is probably involved in pathological remodeling of cardiovascular tissues, including cardiac myocyte detachment in heart failure, deendothelialization and plaque rupture in atherosclerosis, and smooth muscle cell disappearance in aneurysms and varicose veins. The absence of cell adhesion and growth resulting from cleavage of adhesive proteins also represents a major impediment to cellular healing, including the absence of cell recolonization of proteolytically injured tissue and the low efficacy of cell transplantation. However, the exact role of anoïkis in cardiovascular pathologies remains to be further defined. Key Words: cell adhesion Ⅲ smooth muscle cell Ⅲ endothelium Ⅲ apoptosis Ⅲ aneurysm T he term anoïkis (from the ancient Greek word for homelessness) was first proposed by Frish and Francis in 1994. 1 Anoïkis is defined as a process of programmed cell death induced by the loss ...

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“…It is now understood that matrix stiffness (and the mechanical tension that results from cellular adhesion to stiff substrates) is instrumental in determining the phenotype of many cell types in culture (1,3,9,13,16,19,20,35,38,42,45; for review, see Ref. 11).…”

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confidence: 99%

Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis

Georges¹,

Hui²,

Gombos³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

506

401

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Liver fibrosis, the response to chronic liver injury, results from the activation of mesenchymal cells to fibrogenic myofibroblasts. We have recently shown that two key myofibroblast precursor populations, hepatic stellate cells and portal fibroblasts, undergo activation in culture in response to increasing substrate stiffness. We therefore hypothesized that alterations in liver stiffness precede myofibroblast activation and fibrosis in vivo as well. To test this hypothesis, we induced fibrosis in rats by twice weekly injections of carbon tetrachloride (CCl4) and then killed the animals at various time points ranging from 3 to 70 days after the initiation of injury. The shear storage modulus of the whole liver was measured on fresh tissue; fixed and frozen tissue from the same livers was used to quantify fibrosis. We observed that liver stiffness increased immediately and continued to increase, leveling out by day 28. Fibrosis, measured histologically by trichrome staining as well as by quantitative sirius red staining, increased with time, although these increases were delayed relative to changes in stiffness. There was no direct correlation between stiffness and fibrosis at early or late time points. Treatment of a second cohort of rats with the lysyl oxidase inhibitor, β-aminopropionitrile (BAPN), partially prevented early increases in liver stiffness. We concluded that increases in liver stiffness precede fibrosis and potentially myofibroblast activation. Liver stiffness appears to result from matrix cross-linking and possibly other unknown variables in addition to matrix quantity. We suggest that increased liver stiffness may play an important role in initiating the early stages of fibrosis.

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Phenotypic differences between dermal fibroblasts from different body sites determine their responses to tension and TGFβ1

Cited by 72 publications

References 54 publications

The Fibroblast Integrin α11β1 Is Induced in a Mechanosensitive Manner Involving Activin A and Regulates Myofibroblast Differentiation

The Fibroblast Integrin α11β1 Is Induced in a Mechanosensitive Manner Involving Activin A and Regulates Myofibroblast Differentiation

Anoïkis in the Cardiovascular System

Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis

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