The fibrotic phenotype of systemic sclerosis fibroblasts varies with disease duration and severity of skin involvement: reconstitution of skin fibrosis development using a tissue engineering approach

Corriveau, Marie-Pier; Boufaied, Inès; Lessard, Julie; Chabaud, Stéphane; Senécal, Jean‐Luc; Grodzicky, Tamara; Chartier, Suzanne; Raymond, Yves; Moulin, Véronique J.

doi:10.1002/path.2482

Cited by 43 publications

(37 citation statements)

References 28 publications

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“…During fibrogenesis, the balance of ECM production and degradation are directed toward production [24,25]. While MMPs degrade the ECM, TIMPs inhibit the activities of MMPs [24,25]. Proteasome inhibition may show its anti-fibrotic property by improving the balance of MMP/TIMP activities in addition to its anti-inflammatory and pro-apoptotic effects [6,7,18,19].…”

Section: Discussionmentioning

confidence: 99%

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Proteasome Inhibition Prevents Development of Experimental Dermal Fibrosis

et al. 2011

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Scleroderma is a chronic fibrotic disorder. Bortezomib, a proteasome inhibitor, is reported to attenuate experimentally induced renal and cardiac fibrosis. This study aimed to evaluate the preventive and therapeutic efficacies of bortezomib on a bleomycin (BLM)-induced scleroderma model. Dermal fibrosis was induced in Balb/c mice by subcutaneous BLM (100 μg/day) injections. Bortezomib (1.6 mg/kg twice/week) was applied intraperitoneally to BLM-injected mice during the first 3 weeks for preventive interventions and in the second 3 weeks for therapeutic interventions. IL-4 and TGF-β1 serum levels, dermal thicknesses, dermal inflammatory cell counts, and α-SMA-positive fibroblastic cell counts were determined, and type-I collagen, NF-κBp65, I-κBα, and JNK1 expressions were assessed. BLM applications increased serum IL-4 level, dermal inflammatory cell counts, α-SMA-positive cell counts, expression of type-I collagen, NF-κB, and JNK1, and dermal thickness in early stage of fibrosis, but serum IL-4 level and dermal inflammatory cell counts showed no increases in later stages. As a preventive intervention, bortezomib decreased dermal thickness, inflammatory cell infiltrations, fibroblastic activity, and expression of type-I collagen, NF-κB, and JNK1, but did not decrease fibroblastic activity and dermal thickness at later stages of fibrosis. Inflammatory status is prominent in the early stage of dermal fibrosis, but declines at later stages. In BLM-induced dermal fibrosis, bortezomib has a preventive anti-fibrotic and anti-inflammatory efficacy, but has no therapeutic anti-fibrotic efficacy in preexisting tissue fibrosis. These findings suggest that the effect of proteasome inhibition in early stages of dermal fibrosis may be related to its anti-inflammatory effects.

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Section: Discussionmentioning

confidence: 99%

“…During fibrogenesis, the balance of ECM production and degradation are directed toward production [24,25]. While MMPs degrade the ECM, TIMPs inhibit the activities of MMPs [24,25].…”

Section: Discussionmentioning

confidence: 99%

Proteasome Inhibition Prevents Development of Experimental Dermal Fibrosis

et al. 2011

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“…39 There is also evidence that the phenotype of fibrotic fibroblasts varies according to disease duration and severity. 40 Developing effective antifibrotic therapies will require understanding of both the cellular sources of the profibrotic fibroblasts, and the mechanisms that activate and recruit these cells to sites of scarring. To elucidate what happens in ocular MMP, knowledge of what happens in a disease such as scleroderma provides framework from which to work, with the understanding that although the processes occurring in the two diseases are clearly not identical, there are some similarities.…”

Section: Discussionmentioning

confidence: 99%

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

Saw

Schmidt

Offiah

et al. 2011

The American Journal of Pathology

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Ocular mucous membrane pemphigoid is an immunobullous disease in which excessive conjunctival fibrosis causes blindness, and the pathogenesis of scarring is incompletely understood. To establish whether profibrotic fibroblasts with an altered phenotype exist in ocular mucous membrane pemphigoid, we compared the functional characteristics of pemphigoid conjunctival fibroblasts to normal conjunctival fibroblasts with respect to cell division; migration; collagen contraction; matrix metalloproteinase, secretion of collagen and chemokines; and myofibroblast differentiation. We found that pemphigoid fibroblasts showed increased cell division (P ‫؍‬ 0.01), increased migration in serum-free medium (72 ؎ 18 migrated cells versus 33 ؎ 11, P ‫؍‬ 0.04), increased collagen contraction in the presence of 10 ng/ml tumor necrosis factor-␣, increased collagen type I secretion (P ‫؍‬ 0.03), increased secretion of matrix metalloproteinase-3 (P ‫؍‬ 0.03), and increased secretion of eotaxin in response to interleukin-13 (P ‫؍‬ 0.04). Differences between pemphigoid and normal conjunctival fibroblasts with respect to collagen contraction and MMP secretion in the presence of interleukin-13 were also observed. Together, these findings indicate that pemphigoid conjunctival fibroblasts have a profibrotic phenotype that is maintained in vitro. No differences between pemphigoid fibroblasts obtained from acutely inflamed versus clinically uninflamed conjunctiva were observed. Developing effective antifibrotic therapies will require understanding of the mechanisms that both induce and maintain the profibrotic phenotype.

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“…The number of cells present in the fibrin gels was determined after 7 days using a fluorescent assay for doublestranded DNA quantification using Picogreen based on the method described by Corriveau [17]. Briefly, fibrin gels were centrifuged for 10 min at 4°C at 7509g and the supernatants were discarded.…”

Section: Cell Counts In Fibrin Gelsmentioning

confidence: 99%

Angiogenic properties of myofibroblasts isolated from normal human skin wounds

et al. 2012

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During wound healing, angiogenesis plays a crucial role in inducing adequate perfusion of the new tissue, thereby allowing its survival. This angiogenic process contributes to the formation of granulation tissue, alongside myofibroblasts. Myofibroblasts are cells specialized in wound contraction and synthesis of new extracellular matrix. Fibroblasts, considered by some to be at the origin of myofibroblasts, have already been shown to promote neovascularization. Thus, we hypothesized that myofibroblasts play a key role during angiogenic development in wound healing. We isolated myofibroblasts from normal human skin wounds and dermal microvascular endothelial cells (HDMVEC) and fibroblasts from skin. Using an in vitro fibrin-based model, we compared the proangiogenic activity of wound myofibroblasts to that of fibroblasts in the presence of HDMVEC. By immunostaining with collagen IV antibodies, we observed the formation of a capillary network significantly more developed when HDMVEC were cultured with myofibroblasts compared to the network formed in the presence of fibroblasts. The differences between these cell types did not result from a differential secretion of Vascular Endothelial Growth Factor or basic Fibroblast Growth Factor. However, in the presence of myofibroblasts, a significant decrease in matrix metalloproteinase activity was observed. This finding was correlated with a significant increase in Tissue Inhibitor of MetalloProteinase (TIMP)-1 and TIMP-3. Furthermore, inhibition of TIMP-1 secretion using shRNA significantly decreased myofibroblasts induced angiogenesis. These results led to the hypothesis that normal wound myofibroblasts contribute to the vascular network development during wound healing. Our data emphasize the critical role of wound myofibroblasts during healing.

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The fibrotic phenotype of systemic sclerosis fibroblasts varies with disease duration and severity of skin involvement: reconstitution of skin fibrosis development using a tissue engineering approach

Cited by 43 publications

References 28 publications

Proteasome Inhibition Prevents Development of Experimental Dermal Fibrosis

Proteasome Inhibition Prevents Development of Experimental Dermal Fibrosis

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

Angiogenic properties of myofibroblasts isolated from normal human skin wounds

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