title: Inflammatory microenvironment and tumor necrosis factor alpha as modulators of periostin and CCN2 expression in human non-healing skin wounds and dermal fibroblasts.
abstract: Non-healing skin wounds remain a significant clinical burden, and in recent years, the regulatory role of matricellular proteins in skin healing has received significant attention. Periostin and CCN2 are both upregulated at day 3 post-wounding in murine skin, where they regulate aspects of the proliferative phase of repair including mesenchymal cell infiltration and myofibroblast differentiation. In this study, we examined 1) the wound phenotype and expression patterns of periostin and CCN2 in non-healing skin wounds in humans and 2) the regulation of their expression in wound fibroblasts by tumor necrosis factor α (TNFα) and transforming growth factor-β1 (TGF-β1). Chronic skin wounds had a pro-inflammatory phenotype, characterized by macrophage infiltration, TNFα immunoreactivity, and neutrophil infiltration. Periostin, but not CCN2, was significantly suppressed in non-healing wound edge tissue at the mRNA and protein level compared with non-involved skin. In vitro, human wound edge fibroblasts populations were still able to proliferate and contract collagen gels. Compared to cells from non-involved skin, periostin and α-SMA mRNA levels increased significantly in the presence of TGF-β1 in wound cells and were significantly decreased by TNFα, but not those of Col1A2 or CCN2. In the presence of both TGF-β1 and TNFα, periostin and α-SMA mRNA levels were significantly reduced compared to TGF-β1 treated wound cells. Effects of TGF-β1 and TNFα on gene expression were also more pronounced in wound edge cells compared to non-involved fibroblasts. We conclude that variations in the expression of periostin and CCN2, are related to an inflammatory microenvironment and the presence of TNFα in human chronic wounds.
authors.affiliation: Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, Ontario N6A 5C1, Canada.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Elliott
authors.affiliation: Division of Vascular Surgery, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, Ontario N6A 5C1, Canada.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Forbes
authors.affiliation: Division of Oral Biology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, Ontario N6A 5C1, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
authors.affiliation: Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, Ontario N6A 5C1, Canada; Division of Oral Biology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, Ontario N6A 5C1, Canada. Electronic address: dhamil2@uwo.ca.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Hamilton
mesh_terms: D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D014945:Wound Healing
chemical_list: C526317:CCN2 protein, human; D015815:Cell Adhesion Molecules; C512835:POSTN protein, human; C508960:TGFB1 protein, human; C439524:TNF protein, human; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D055513:Connective Tissue Growth Factor
keywords: CCN2; Dermal fibroblasts; Matricellular; Non-healing wound; Periostin; Tumor necrosis factor α