Influence of the extracellular matrix on the proliferative response of human skin fibroblasts to serum and purified platelet‐derived growth factor

Rhudy, Roberta W.; McPherson, John M.

doi:10.1002/jcp.1041370123

Cited by 44 publications

(16 citation statements)

References 23 publications

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“…Polymerized type I collagen suppresses normal fibroblast proliferation. [1][2][3][4] The mechanism involves inhibition of the PI3K/Akt signal by high PTEN phosphatase activity. 1 This provides an effective physiological mechanism to limit fibroproliferation after tissue injury.…”

Section: Idiopathic Pulmonary Fibrosis (Ipf) Is a Progressivementioning

confidence: 99%

Pathologic Caveolin-1 Regulation of PTEN in Idiopathic Pulmonary Fibrosis

Xia

Khalil

Kahm

et al. 2010

The American Journal of Pathology

139

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Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder refractory to current pharmacological therapies. Fibroblasts isolated from IPF patients display pathological activation of PI3K/Akt caused by low PTEN phosphatase activity. This enables these cells to escape the negative proliferative properties of polymerized collagen. The mechanism underlying low PTEN activity in IPF fibroblasts is unclear, but our prior studies indicate that membrane-associated PTEN expression is decreased in these cells. Caveolin-1 is an integral membrane protein whose expression is decreased in IPF lung tissue, but how low caveolin-1 contributes to pathological fibrosis is incompletely understood. The objective of this study was to examine the hypothesis that caveolin-1 regulates PTEN function in IPF fibroblasts. Here we demonstrate that caveolin-1 expression is a determinant of membrane PTEN levels and show that PTEN interacts with caveolin-1 via its caveolin-1-binding sequence. We demonstrate that caveolin-1 expression is low in IPF fibroblasts and that this correlates with low membrane PTEN levels , whereas overexpression of caveolin-1 restores membrane PTEN levels, inhibits Akt phosphorylation, and suppresses proliferation. We demonstrate that caveolin-1 and PTEN expression are low in myofibroblasts within IPF fibroblastic foci. These data indicate that IPF fibroblasts display low caveolin-1 expression, which results in low membrane-associated PTEN expression. This creates a membrane microenvironment depleted of inhibitory phosphatase activity, facilitating the aberrant activation PI3K/Akt and pathological proliferation. (Am J Pathol

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Section: Idiopathic Pulmonary Fibrosis (Ipf) Is a Progressivementioning

confidence: 99%

Pathologic Caveolin-1 Regulation of PTEN in Idiopathic Pulmonary Fibrosis

Xia

Khalil

Kahm

et al. 2010

The American Journal of Pathology

139

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“…The stroma consists of cells and their extracellular matrix (ECM) products. Fibroblasts maintain stromal homeostasis by integrating signals from the ECM that control their function and fate (1)(2)(3)(4). Stromal pathology, characterized by pathological fibroblasts and a stiff ECM, is the signature of human diseases ranging from cardiovascular and pulmonary diseases to cancer (5)(6)(7)(8), and yet we have only a limited understanding of the mechanisms governing the transition from healthy to diseased stroma (9,10).…”

Section: Introductionmentioning

confidence: 99%

Fibrotic extracellular matrix activates a profibrotic positive feedback loop

Parker¹,

Rossi²,

Peterson³

et al. 2014

J. Clin. Invest.

482

416

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Pathological remodeling of the extracellular matrix (ECM) by fibroblasts leads to organ failure. Development of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive fibrotic scarring in the lung that ultimately leads to asphyxiation; however, the cascade of events that promote IPF are not well defined. Here, we examined how the interplay between the ECM and fibroblasts affects both the transcriptome and translatome by culturing primary fibroblasts generated from IPF patient lung tissue or nonfibrotic lung tissue on decellularized lung ECM from either IPF or control patients. Surprisingly, the origin of the ECM had a greater impact on gene expression than did cell origin, and differences in translational control were more prominent than alterations in transcriptional regulation. Strikingly, genes that were translationally activated by IPF-derived ECM were enriched for those encoding ECM proteins detected in IPF tissue. We determined that genes encoding IPF-associated ECM proteins are targets for miR-29, which was downregulated in fibroblasts grown on IPF-derived ECM, and baseline expression of ECM targets could be restored by overexpression of miR-29. Our data support a model in which fibroblasts are activated to pathologically remodel the ECM in IPF via a positive feedback loop between fibroblasts and aberrant ECM. Interrupting this loop may be a strategy for IPF treatment.

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“…Heparan sulfate proteoglycans were only a minor component (Fig 6A). None of the 35 S-sulfate-labeled material bound significantly to PDGF-A/B under the chosen conditions (Fig 6B).…”

Section: Stimulation Of Lattice-cultured Smcs By Pdgf-a/bmentioning

confidence: 94%

“…The poor response to growth factor might be due to downregulation of the cell-surface receptor for PDGF-A/B when the cells are cultured within a collagen lattice. 35 Furthermore, the poor response to PDGF-A/B could be due to immobilization and/or inactivation of the growth factor by matrix-associated proteoglycans, eg, heparan sulfate proteoglycans. 36 To prove this possibility, we examined the secreted proteoglycans that accumulated in the type I collagen matrix and tested the binding of the growth factor.…”

mentioning

confidence: 99%

Responsiveness of aortic smooth muscle cells to soluble growth mediators is influenced by cell-matrix contact.

Thie

Harrach

Schönherr

et al. 1993

Arterioscler Thromb

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Excessive proliferation and overexpresslon of collagens by smooth muscle cells (SMCs) are important features of atherogenesis. To understand the role of the extracellular matrix in the regulation of these processes, we examined proliferation and protein/collagen synthesis of SMCs in contact with a collagen matrix. Adult pig SMCs were isolated from the aortic media by collagenase digestion, subcultured as monolayers, and then embedded into a three-dimensional network of type I collagen, ie, a collagen lattice. Cells were subsequently exposed to growth-promoting media, and their behavior was observed in comparison with monolayer cultures on plastic Treatment of monolayers with increasing concentrations of fetal calf serum resulted in activation of the cell cycle, onset of cell proliferation, and increased protein/collagen synthesis. In contrast, similar treatment of collagen lattice-cultured SMCs failed to influence cell proliferation and protein/collagen synthesis. However, stimulation of proliferation of lattice-cultured SMCs by platelet-derived growth factor-A/B was feasible; nevertheless, the rate of proliferation was modest compared with monolayers. In addition, the onset of proliferation was accompanied by a decrease in collagen synthesis of the cells. Thus, a collagenous matrix appears to suppress the responsiveness of SMCs to soluble growth mediators. It is speculated that interactions between SMCs and the extracellular matrix may modify proliferation and protein/collagen synthesis of cells not only in vitro but also in vivo during atherogenesis by making and breaking binding sites between extracellular collagen and matrix receptors.

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Influence of the extracellular matrix on the proliferative response of human skin fibroblasts to serum and purified platelet‐derived growth factor

Cited by 44 publications

References 23 publications

Pathologic Caveolin-1 Regulation of PTEN in Idiopathic Pulmonary Fibrosis

Pathologic Caveolin-1 Regulation of PTEN in Idiopathic Pulmonary Fibrosis

Fibrotic extracellular matrix activates a profibrotic positive feedback loop

Responsiveness of aortic smooth muscle cells to soluble growth mediators is influenced by cell-matrix contact.

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