Collagen-dependent Growth Suppression and Changes in the Shape of Human Dermal Fibroblasts

Yoshizato, Katsutoshi; Taira, Toshio; Shioya, Nobuyuki

doi:10.1097/00000637-198407000-00002

Cited by 54 publications

(25 citation statements)

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“…Because integrins and integrin-associated proteins of focal adhesions synergize with growth factor receptors and contribute to Ras signaling (37)(38)(39)(40), differences between focal adhesions of cells in a monolayer culture versus collagen matrices might be responsible for differences in Ras activation. In any case, lower activation of Ras in collagen matrices compared with a monolayer culture might explain the previous observation that DNA synthesis also is lower under the former conditions (41)(42)(43)(44).…”

Section: Discussionmentioning

confidence: 83%

Fibroblast Quiescence in Floating Collagen Matrices

Fringer

Grinnell

2003

Journal of Biological Chemistry

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Fibroblasts synthesize, organize, and maintain connective tissues during development and in response to injury and fibrotic disease. Studies on cells in threedimensional collagen matrices have shown that fibroblasts switch between proliferative and quiescence phenotypes, depending upon whether matrices are attached or floating during matrix remodeling. Previous work showed that cell signaling through the ERK pathway was decreased in fibroblasts in floating matrices. In the current research, we extend the previous findings to show that serum stimulation of fibroblasts in floating matrices does not result in ERK translocation to the nucleus. In addition, there was decreased serum activation of upstream members of the ERK signaling pathway, MEK and Raf, even though Ras became GTP loaded. The findings suggest that quiescence of fibroblasts in floating collagen matrices may result from a defect in Ras coupling to its downstream effectors.Form and function of multicellular organisms depends on cell proliferation, migration, and differentiation. Fibroblasts synthesize, organize, and maintain connective tissues during development and in response to injury and fibrotic disease. Studies on cells in three-dimensional matrices suggest that reciprocal and adaptive mechanical interactions play a role in the regulation of morphogenesis. That is, fibroblasts cultured in collagen matrices switch between a proliferative, activated phenotype on one hand and a quiescent, resting phenotype on the other, depending upon whether the matrices are attached or floating during matrix remodeling (1, 2). These differences in phenotype have been attributed to changes in mechanical interactions. As a consequence of remodeling, fibroblasts develop isometric tension in attached matrices but remain mechanically unloaded in floating matrices (3, 4). In addition to becoming quiescent, fibroblasts in floating matrices also begin to enter apoptosis (5-8), and apoptosis has been implicated in the disappearance of wound fibroblasts at the end of repair (9).The proliferation of normal (untransformed) cells typically requires a combination of signals generated by growth factor stimulation and cell adhesion. One target for these signals is the canonical ERK 1 signaling pathway, Ras-Raf-MEK-ERK, which has been suggested in many cells to participate in a wide range of cell functions from proliferation to differentiation to senescence (10, 11). Cell adhesion, shape, and cytoskeletal organization influence the strength and duration of signals through the MAP kinase pathway, whose sustained activation is required for cell cycle progression (12-18).In previous studies, we compared ERK activation in fibroblasts in attached and floating collagen matrices. We found that, in floating matrices, there was decreased signaling through the ERK pathway (19) along with down-regulation of the cell cycle regulatory protein cyclin D1 and an increase in the cyclin-dependent kinase inhibitor p27 Kip1 (20). In the current research, we have extended the previous findings to show...

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Section: Discussionmentioning

confidence: 83%

Fibroblast Quiescence in Floating Collagen Matrices

Fringer

Grinnell

2003

Journal of Biological Chemistry

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“…Other authors even described a strong reduction of DNA synthesis by fibroblasts grown on hydrated collagen lattices as compared to those grown on plastic (Elsdale and Bard, 1972;Sarber et al, 1981;Yoshizato et al, 1984). Such inhibitions of DNA synthesis have also been described in fibroblasts cultured on type I collagen-coated dishes (Yoshizato et al, 1985).…”

Section: Discussionmentioning

confidence: 86%

Reconstituted basement‐membrane matrix modulates fibroblast activities in vitro

Emonard

Grimaud

Nusgens

et al. 1987

Journal Cellular Physiology

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Cellular growth and collagen biosynthesis were compared in dermal calf fibroblasts cultured on plastic or on a reconstituted basement membrane gel, termed matrigel. This matrix, extracted from Engelbreth-Holm-Swarm tumors, consists mainly of laminin, entactin, type IV collagen, and heparan sulfate proteoglycan. The multiplication rate of fibroblasts grown on matrigel was stimulated compared to that of monolayered cells cultured on plastic, and these cells formed multilayers after 4 days. Protein and collagen biosynthesis was reduced in fibroblasts cultured on matrigel. A higher proportion of the newly synthesized collagen (40%) was incorporated to the extracellular matrix in cultures grown on matrigel than in those grown on plastic (14%). Type III collagen was the preferential collagen type deposited on matrigel, and the ratio of type III:type I collagens secreted in the medium was also slightly higher in cultures grown on matrigel. Partially processed collagen was more abundant in fibroblasts grown on matrigel than in cells cultured on plastic. Finally, cells grown on matrigel exhibited a higher catabolic activity than cells grown on plastic. In this experimental model, the reconstituted basement-membrane matrix seems to influence the activities of fibroblasts significantly.

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“…The basis for this reduced cellular proliferation rate on collagen matrices was not identified but seemed to depend on fibrillar organization and required the native (triple helical) conformation of the collagen molecule (Schor, 1980;Yoshizato et al, 1984).…”

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confidence: 99%

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

Rhudy

McPherson

1988

Journal Cellular Physiology

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The culture of adult human skin fibroblasts on reconstituted bovine type 1 fibrillar collagen gels, ranging in concentration from 2.5-35.0 mg/ml, results in a reduction in proliferation rate by 40%-60% as measured by (3H) thymidine incorporation. The suppressive effect was noted when cells were cultured in both human and bovine serum. Drying the gels into thin films abolishes the suppressive effect of the fibrillar collagen on cell proliferation. Cell attachment studies showed that differences in the proliferation rate of cells on the various substrata were not simply due to differences in initial attachment. Studies with purified platelet-derived growth factor (PDGF) demonstrated that the reduced responsiveness of cells to this factor, when cultured on collagen gels as compared to plastic, was largely responsible for the reduced proliferative activity of the cells when cultured in the presence of serum. The reduced proliferative activity of fibroblasts in response to PDGF, when cultured on collagen gels, was confirmed by total DNA determination. It was shown that the reduced responsiveness of cells to PDGF was not simply because the factor bound to the fibrillar collagen gel or was inaccessible to the cells. The data indicate that the reduced proliferation rate of fibroblasts cultured on collagen gels is a direct result of the influence of the extracellular matrix on the cells' ability to respond to a soluble mitogenic mediator.

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Collagen-dependent Growth Suppression and Changes in the Shape of Human Dermal Fibroblasts

Cited by 54 publications

References 0 publications

Fibroblast Quiescence in Floating Collagen Matrices

Fibroblast Quiescence in Floating Collagen Matrices

Reconstituted basement‐membrane matrix modulates fibroblast activities in vitro

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

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