Lung fibroblast clones from normal and fibrotic subjects differ in hyaluronan and decorin production and rate of proliferation

Westergren‐Thorsson, Gunilla; Sime, Patricia J.; Jordana, Manel; Gauldie, Jack; Särnstrand, Bengt; Malmström, Anders

doi:10.1016/j.biocel.2004.01.009

Cited by 36 publications

(17 citation statements)

References 49 publications

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“…Fadic et al (2006) have also reported increased decorin (and also biglycan synthesis) in muscle-derived fibroblasts from a DMD patient compared with controls. Kuroda and Shinkai (1997) have detected higher levels of decorin transcripts in systemic sclerosis fibroblasts, and Westergren- Thorsson et al (2004) have reported increased levels of decorin secreted by primary fibroblasts derived from a fibrotic lung. In our previous study on the ECM of primary DMD myotube cultures (practically devoid of fibroblasts), we have shown that decorin transcript levels are lower than those in controls (Zanotti et al 2007), in accord with our findings in DMD patient muscle (Zanotti et al 2005).…”

Section: Discussionmentioning

confidence: 97%

Altered production of extra-cellular matrix components by muscle-derived Duchenne muscular dystrophy fibroblasts before and after TGF-β1 treatment

2009

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To probe pro-fibrotic mechanisms in dystrophic muscle, we isolated primary fibroblasts from Duchenne muscular dystrophy (DMD) and control muscle biopsies and induced transdifferentiation in myofibroblasts by transforming growth factor beta1 (TGF-beta1) treatment. We compared proliferating activity, soluble collagen production, and transcript and protein levels of decorin, myostatin, TGF-beta1, matrix metalloproteinase-1 (MMP-1; interstitial collagenase), MMP-2 (gelatinase), MMP-3 (stromelysin), MMP-7 (matrilysin), and the tissue inhibitors of metalloproteinases inhibitors (TIMPs) 1-4, in fibroblasts and myofibroblasts. Principal differences included a significantly greater proliferation rate and soluble collagen production, a significant upregulation of decorin, myostatin and MMP-7 transcripts and proteins, and a significant downregulation of MMP-1 and TIMP-3 transcripts (with MMP-1 protein being reduced as shown by enzyme-linked immunosorbent assay and TIMP-3 protein apparently being reduced on Western blot), in untreated DMD fibroblasts compared with controls. TGF-beta1 transdifferentiation significantly lowered decorin and myostatin and significantly increased TGF-beta1 transcript and protein, significantly increased MMP-1 and TIMP-3, and significantly lowered MMP-7 transcript and protein in DMD cells compared with pretreatment controls. The differences between DMD and control fibroblasts showed that DMD fibroblasts had a profibrotic phenotype, accentuated by TGF-beta1 treatment. Dystrophin absence itself could exert a direct influence on the homeostasis of the extracellular matrix (ECM) by allowing leakage of cellular components to the extracellular space or by abnormal cellular uptake of extracellular growth factors, cytokines, or enzymes influencing muscle fibroblasts either directly by altering adhesion properties or indirectly by interactions with molecules released into the ECM by muscle or inflammatory cells. The transdifferentiation of muscle fibroblasts might serve as a simplified model of fibrosis for further elucidation of the mechanisms of muscle fibrosis and for testing possible anti-fibrotic agents.

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Section: Discussionmentioning

confidence: 97%

Altered production of extra-cellular matrix components by muscle-derived Duchenne muscular dystrophy fibroblasts before and after TGF-β1 treatment

2009

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“…Bars 70 μm distinct subpopulations of fibroblasts. In this situation, selected subpopulations of fibroblasts may be responsible for specific sets of cellular interactions (Smith et al 1997), or a minor subset of fibroblasts may be selectively enhanced for connective tissue pathologies (Botstein et al 1982;Nakaoka et al 1995;Westergren-Thorsson et al 2004). The second level of screening was based upon proliferation kinetics.…”

Section: Discussionmentioning

confidence: 99%

Clonal characterization of fibroblasts in the superficial layer of the adult human dermis

2006

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The dermis of adult human skin contains a physiologically heterogeneous population of fibroblasts that interact to produce its unique architecture and that participate in inflammatory and wound repair functions in vivo. This heterogeneity has been well documented for fibroblasts located in the superficial papillary dermis and the deep reticular dermis. However, the existence of diverse fibroblast subpopulations within a given region of the dermis has not been explored. In this study, fibroblast cultures have been established from the superficial dermis following enzymatic dissociation of the tissue. These fibroblasts have been cloned by limiting dilution and initially selected on the basis of morphology and proliferation kinetics. Fibroblasts in some of the clones selected for study express alpha-smooth muscle actin, a myofibroblast characteristic. Significant differences for fibroblast clones obtained from the same piece of skin have been observed with regard to their rate of collagen lattice contraction, their ability to organize a fibronectin matrix, their release of specific growth factors/cytokines into culture medium, and their response to interleukin-1alpha. These differences in both morphological and physiological characteristics indicate that the superficial papillary dermis contains a heterogeneous population of fibroblasts. This heterogeneity might indicate that diverse subpopulations of fibroblasts are required to interact in both homeostatic and pathological situations in skin.

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“…This hypothesis is appealing, but in vivo evidence supporting an apoptosisresistant phenotype driving severe fibrosis has been elusive. The unrelenting nature of progressive fibrosis in IPF could be considered analogous to tumor cell growth, although fibroblasts isolated from IPF patients are not monoclonal or transformed (81)(82)(83). The pathologic hallmarks of IPF include matrix deposition, basement membrane destruction, and expansion of the mesenchyme.…”

Section: Emergence Of Pathologic Mesenchymal Phenotypesmentioning

confidence: 99%

Pulmonary fibrosis: patterns and perpetrators

Noble¹,

Barkauskas²,

Jiang³

2012

J. Clin. Invest.

469

386

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Lung fibroblast clones from normal and fibrotic subjects differ in hyaluronan and decorin production and rate of proliferation

Cited by 36 publications

References 49 publications

Altered production of extra-cellular matrix components by muscle-derived Duchenne muscular dystrophy fibroblasts before and after TGF-β1 treatment

Altered production of extra-cellular matrix components by muscle-derived Duchenne muscular dystrophy fibroblasts before and after TGF-β1 treatment

Clonal characterization of fibroblasts in the superficial layer of the adult human dermis

Pulmonary fibrosis: patterns and perpetrators

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