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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.

Abstract
We set out to examine the pathophysiological mechanisms of fibrosis in diffuse systemic sclerosis (SSc) using a tissue engineering approach. Skin fibroblasts were isolated from lesional skin of SSc patients with a disease duration of less than 1 year (early-stage SSc) or more than 10 years (late-stage SSc). Fibroblasts were also isolated from non-lesional skin and compared with normal fibroblasts isolated from healthy adults. Cells were cultured using a tissue engineering method to reconstruct a human dermis, and histologically observed. Dermal thickness was measured, as it reflects the global and intrinsic capacity of cells to reconstitute matrix. Collagen I, MMP-1, and MMP activity were evaluated. Cells were treated with TGFbeta1 or CTGF during dermis formation to study their fibrogenic role. Clinical severity of skin involvement was measured by a modified Rodnan score. Thickness of the dermis generated with non-lesional early-stage SSc fibroblasts was similar to normal cells. In contrast, reconstructed dermis from lesional early-stage SSc fibroblasts and non-lesional late-stage SSc cells was thinner, while lesional late-stage SSc fibroblasts made a thicker dermis. Dermis was always thicker when produced with TGFbeta1-treated cells, except when lesional late-stage SSc fibroblasts from patients with high Rodnan skin scores were used. CTGF did not affect dermal thickness. Measurements of collagen I and collagenases in the culture medium of the various reconstructed dermis could explain some of the changes observed. We conclude that the fibrotic phenotype of SSc fibroblasts varies with disease duration and with severity of skin involvement, and this is clearly visualized during in vitro dermis reconstruction.
AuthorsMarie-Pier Corriveau, Inès Boufaied, Julie Lessard, Stéphane Chabaud, Jean-Luc Senécal, Tamara Grodzicky, Suzanne Chartier, Yves Raymond, Véronique J Moulin
JournalThe Journal of pathology (J Pathol) Vol. 217 Issue 4 Pg. 534-42 (Mar 2009) ISSN: 1096-9896 [Electronic] England
PMID19086038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CTGF protein, human
  • Collagen Type I
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 1
Topics
  • Adult
  • Aged
  • Case-Control Studies
  • Cell Proliferation
  • Cells, Cultured
  • Collagen Type I (analysis, secretion)
  • Connective Tissue Growth Factor (pharmacology)
  • Disease Progression
  • Female
  • Fibroblasts (drug effects, pathology, secretion)
  • Fibrosis
  • Humans
  • Male
  • Matrix Metalloproteinase 1 (analysis, metabolism)
  • Matrix Metalloproteinases (analysis, metabolism)
  • Middle Aged
  • Phenotype
  • Scleroderma, Systemic (metabolism, pathology)
  • Skin (metabolism, pathology)
  • Tissue Engineering (methods)
  • Transforming Growth Factor beta1 (pharmacology)

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